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ed6fd5c28538a57761e6f515007f184ec4413a7f	wikidoc	Borescope	Borescope A borescope is an optical device consisting of a rigid or flexible tube with an eyepiece on one end, an objective lens on the other linked together by a relay optical system in between. The optical system is usually surrounded by optical fibers used for illumination of the remote object and a rigid or flexible protective outer sheath. The remote object is illuminated and an internal image formed by the objective lens is relayed to the eyepiece which magnifies the internal image and presents it to the viewer's eye. Borescopes are used for inspection work where the area to be inspected is inaccessible by other means. Rigid borescopes are similar to a fiberscope, but are not flexible and generally much cheaper and provide a superior image. Rigid borescopes are therefore better suited to certain tasks such as inspecting automotive cylinders, fuel injectors, hydraulic manifold bodies and gunsmithing. Rigid or flexible borescopes may be fitted with a magnifying device and a way to illuminate the work being inspected, usually illumination fibers are contained in the insertion tube of the borescope. The eyepiece may be fitted with a coupler lens to allow the borescope to be used with imaging devices such as a video or CCD camera. When in use inside the human body, this device is referred to as an endoscope. Borescopes are commonly used in the visual inspection of aircraft engines, aeroderivative industrial gas turbines, steam turbines, diesel engines and automotive/truck engines. Gas and steam turbines require particular attention because of safety and maintenance requirements. Borescope inspection of engines can be used to prevent unnecessary maintenance, which can become extremely costly for large turbines. They are also used in manufacturing of machined or cast parts to inspect critical interior surfaces for burrs, surface finish or complete through holes. Forensic applications in law enforcement and building inspection are also common uses for borescopes. Rigid borescopes generally provide a superior image at lower cost compared to a flexible borescope, but have the limitation that access to what is to be viewed is a straight line. A flexible borescope can be used to access cavities which are around a bend, such as a combustion chamber or "Burner Cans" in order to view the condition of the compressed air inlets, turbine blades and seals without disassembling the engine. Criteria for selecting a borescope is usually image clarity and access. For similar quality instruments, the largest rigid borescope that will fit the hole, will give the best image. Relay optics in rigid borescopes can be of 3 basic types, Hopkins rod lenses, achromatic doublets and gradient index rod lenses. For large diameter borescopes, the achromatic doublet relays work quite well, but as the diameter of the borescope tube gets smaller (less than about 4 millimeters) the Hopkins rod lens and gradient index rod lens designs provide superior images. For very small rigid borescopes, the gradient index lens relays are better. Flexible borescopes suffer from pixelation and pixel cross talk due to the fiber image guide used in the relay. Image quality varies widely among different models of flexible borescopes depending on the number of fibers and construction used in the fiber image guide. For flexible borescopes, articulation mechanism components, range of articulation, field of view and angles of view of the objective lens are also important. Fiber content in the flexible relay is also critical to provide the highest possible resolution to the viewer. Minimal quantity is 10,000 pixels while the best images are obtained with higher numbers of fibers in the 15,000 to 22,000 range for the larger diameter borescopes.	Borescope A borescope is an optical device consisting of a rigid or flexible tube with an eyepiece on one end, an objective lens on the other linked together by a relay optical system in between. The optical system is usually surrounded by optical fibers used for illumination of the remote object and a rigid or flexible protective outer sheath. The remote object is illuminated and an internal image formed by the objective lens is relayed to the eyepiece which magnifies the internal image and presents it to the viewer's eye. Borescopes are used for inspection work where the area to be inspected is inaccessible by other means. Rigid borescopes are similar to a fiberscope, but are not flexible and generally much cheaper and provide a superior image. Rigid borescopes are therefore better suited to certain tasks such as inspecting automotive cylinders, fuel injectors, hydraulic manifold bodies and gunsmithing. Rigid or flexible borescopes may be fitted with a magnifying device and a way to illuminate the work being inspected, usually illumination fibers are contained in the insertion tube of the borescope. The eyepiece may be fitted with a coupler lens to allow the borescope to be used with imaging devices such as a video or CCD camera. When in use inside the human body, this device is referred to as an endoscope. Borescopes are commonly used in the visual inspection of aircraft engines, aeroderivative industrial gas turbines, steam turbines, diesel engines and automotive/truck engines. Gas and steam turbines require particular attention because of safety and maintenance requirements. Borescope inspection of engines can be used to prevent unnecessary maintenance, which can become extremely costly for large turbines. They are also used in manufacturing of machined or cast parts to inspect critical interior surfaces for burrs, surface finish or complete through holes. Forensic applications in law enforcement and building inspection are also common uses for borescopes. Rigid borescopes generally provide a superior image at lower cost compared to a flexible borescope, but have the limitation that access to what is to be viewed is a straight line. A flexible borescope can be used to access cavities which are around a bend, such as a combustion chamber or "Burner Cans" in order to view the condition of the compressed air inlets, turbine blades and seals without disassembling the engine. Criteria for selecting a borescope is usually image clarity and access. For similar quality instruments, the largest rigid borescope that will fit the hole, will give the best image. Relay optics in rigid borescopes can be of 3 basic types, Hopkins rod lenses, achromatic doublets and gradient index rod lenses. For large diameter borescopes, the achromatic doublet relays work quite well, but as the diameter of the borescope tube gets smaller (less than about 4 millimeters) the Hopkins rod lens and gradient index rod lens designs provide superior images. For very small rigid borescopes, the gradient index lens relays are better. Flexible borescopes suffer from pixelation and pixel cross talk due to the fiber image guide used in the relay. Image quality varies widely among different models of flexible borescopes depending on the number of fibers and construction used in the fiber image guide. For flexible borescopes, articulation mechanism components, range of articulation, field of view and angles of view of the objective lens are also important. Fiber content in the flexible relay is also critical to provide the highest possible resolution to the viewer. Minimal quantity is 10,000 pixels while the best images are obtained with higher numbers of fibers in the 15,000 to 22,000 range for the larger diameter borescopes. # External links Template:WikiDoc Sources Template:Jb1	https://www.wikidoc.org/index.php/Borescope
8efd8b5444bc0533a9b8d5f77bc56a3bd16f119a	wikidoc	Bosutinib	Bosutinib # 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 Bosutinib is an antineoplastic agent that is FDA approved for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. Common adverse reactions include diarrhea , nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue and Serious adverse reactions include anaphylactic shock , myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bosutinib is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. - The recommended dose and schedule of Bosutinib is 500 mg orally once daily with food. Continue treatment with Bosutinib until disease progression or patient intolerance. - If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. - Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily. - Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold Bosutinib until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue Bosutinib. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue Bosutinib. - Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold Bosutinib until recovery to Grade less than or equal to 1. Bosutinib may be resumed at 400 mg once daily. - For other clinically significant, moderate or severe non-hematological toxicity, withhold Bosutinib until the toxicity has resolved, then consider resuming Bosutinib at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of Bosutinib to 500 mg once daily. - Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1). - Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with Bosutinib as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin). - Avoid the concomitant use of strong or moderate CYP3A inducers with Bosutinib as a large reduction in exposure is expected (strong CYP3A inducers include rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine). - In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of Bosutinib is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML. - In patients with pre-existing severe renal impairment (CLcr less than 30 mL/min), the recommended dose of Bosutinib is 300 mg daily. A daily dose of 300 mg in patients with severe renal impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal renal function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 300 mg once daily in patients with severe renal impairment and CML. ## Off-Label Use and Dosage (Adult) ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosutinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. ### Non–Guideline-Supported Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. # Contraindications - Hypersensitivity to Bosutinib. In the Bosutinib clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients. # Warnings - Diarrhea, nausea, vomiting, and abdominal pain occur with Bosutinib treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with Bosutinib was 3 (range 1–221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue Bosutinib as necessary. - Thrombocytopenia, anemia and neutropenia occur with Bosutinib treatment. Patients with CML who are receiving Bosutinib should have a complete blood count performed weekly for the first month and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue Bosutinib as necessary. - One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) occurred in a trial of Bosutinib in combination with letrozole. The patient recovered fully following discontinuation of Bosutinib. This case represented 1 out of 1209 patients in Bosutinib clinical trials. - In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for each was 21 days. - Perform monthly hepatic enzyme tests for the first three months of treatment with Bosutinib and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue Bosutinib as necessary. Fluid retention occurs with Bosutinib and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. - In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema. - Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue Bosutinib as necessary. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling: - Gastrointestinal toxicity. - Myelosuppression. - Hepatic toxicity. - Fluid retention. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Serious adverse reactions reported include anaphylactic shock, myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash. - Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%). - The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of Bosutinib) included 546 CML patients. Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of Bosutinib treatment of 24 months, and a median dose intensity of 484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of Bosutinib treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of Bosutinib treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. - Table 2 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population. - In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. - Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population. ### Additional Data from Multiple Clinical Trials - The following adverse reactions were reported in patients in clinical trials with Bosutinib (less than 10% of Bosutinib-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent Bosutinib. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. - 1% and less than 10% - febrile neutropenia - 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis - 1% and less than 10% - tinnitus - 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage - 1% and less than 10% - chest pain, pain - 1% and less than 10% - hepatotoxicity, abnormal hepatic function; 0.1% and less than 1% - liver injury - 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock - 1% and less than 10% - pneumonia, influenza, bronchitis - 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine - 1% and less than 10% - hyperkalemia, dehydration - 1% and less than 10% - myalgia - 1% and less than 10% - dysgeusia - 1% and less than 10% - acute renal failure, renal failure - 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension. - 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption - Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage - Chest pain includes the following preferred terms: chest pain, chest discomfort *Hepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis - Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder 5 Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bosutinib in the drug label. # Drug Interactions - CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with Bosutinib as an increase in bosutinib plasma concentration is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to Bosutinib alone. - CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers with Bosutinib as a large reduction in exposure is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to Bosutinib alone . - Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to Bosutinib alone . - Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and Bosutinib dosing by more than 2 hours. - Substrates of P-glycoprotein: An in vitro study suggests that Bosutinib may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on its mechanism of action and findings in animals, Bosutinib can cause fetal harm when administered to a pregnant woman. Studies in animals showed reproductive toxicities. If Bosutinib is used during pregnancy, or if the patient becomes pregnant while taking Bosutinib, the patient should be apprised of the potential hazard to the fetus. - Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3 and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. - In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib. - There are no adequate and well controlled studies of Bosutinib in pregnant women. Bosutinib can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid pregnancy while being treated with Bosutinib. 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' Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosutinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bosutinib during labor and delivery. ### Nursing Mothers - It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bosutinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established.. ### Geriatic Use - In the Phase 1/2 clinical trial of Bosutinib in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Bosutinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bosutinib with respect to specific racial populations. ### Renal Impairment - Reduce the Bosutinib dose in patients with CLcr less than 30 mL/min at baseline. For patients with CLcr 30 to 50 mL who cannot tolerate a 500 mg dose, follow dose adjustment recommendations for toxicity. In a dedicated renal impairment trial, compared to volunteers with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively. - Bosutinib has not been studied in patients undergoing hemodialysis. ### Hepatic Impairment - Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial, the exposure to bosutinib increased (Cmax increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold) in patients with hepatic impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9) ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bosutinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bosutinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Perform monthly hepatic enzyme tests for the first three months of treatment with Bosutinib and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue Bosutinib as necessary # IV Compatibility There is limited information regarding IV Compatibility of Bosutinib in the drug label. # Overdosage - Experience with Bosutinib overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of Bosutinib should be observed and given appropriate supportive treatment. # Pharmacology There is limited information regarding Bosutinib Pharmacology in the drug label. ## Mechanism of Action - Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl. ## Structure - Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4--6-methoxy-7--, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: - Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. - Bosutinib® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. - Each 100 mg Bosutinib tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg Bosutinib tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet). ## Pharmacodynamics - The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed. ## Pharmacokinetics - Following administration of a single dose of Bosutinib 500 mg with food in patients with cancer, the median time-to-peak concentration (tmax) was 4–6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. After 15 daily doses of Bosutinib (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng∙h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively. - After administration of a single dose of Bosutinib 500 mg with food in patients with CML, bosutinib had a mean apparent volume of distribution ± standard deviation of 6080 ± 1230 L. - Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters. - Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive. - In patients with CML given single oral doses of Bosutinib 500 mg with food, the mean terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given a single oral dose of radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine. - In a dedicated hepatic impairment trial, a single dose of Bosutinib 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively. - In a dedicated renal impairment trial, a single dose of Bosutinib 200 mg was administered with food to 26 volunteers with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 healthy volunteers with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had a 35% and 60% increase in AUC compared to healthy volunteers with normal renal function, respectively. Bosutinib exposure was not changed in patients with mild renal impairment. The Bosutinib dose should be reduced in patients with CLcr less than 30 mL/min and patients with CLcr between 30 to 50 mL/min should have their dose reduced if they are unable to tolerate a 500 mg dose. - CYP3A Inhibitors - In a cross-over trial of 24 healthy volunteers, a single dose of 100 mg of Bosutinib was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively' - CYP3A Inducers - In a cross-over trial of 24 healthy volunteers, a single dose of 500 mg of Bosutinib was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively . - P-gp Substrates - An in vitro study suggests that Bosutinib has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of Bosutinib. - pH Altering Medications - Bosutinib displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 24 healthy volunteers, a single oral dose of 400 mg of Bosutinib was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively. ## Nonclinical Toxicology - A 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5- to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. - Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. - In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure). # Clinical Studies - Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML - A single-arm, Phase 1/2 open-label, multicenter trial was conducted to evaluate the efficacy and safety of Bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within four weeks; (2) failure to achieve a complete hematologic response (CHR) by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-Abl gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial. - The efficacy endpoints for patients with CP CML previously treated with one prior TKI (imatinib) were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR). - The trial enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 503 were considered evaluable for efficacy. Patients were evaluable for efficacy if they had received at least one dose of Bosutinib and had a valid baseline efficacy assessment. Among evaluable patients, there were 266 patients with CP CML previously treated with one prior TKI (imatinib), 108 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 129 patients with advanced phase CML previously treated with at least one TKI. - Median duration of Bosutinib treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), 8 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. - The 24 week efficacy results are present in Table 6. - The minimum follow-up was 23 months for patients with CP CML treated with one prior TKI (imatinib) and 13 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 53.4% of patients with CP CML treated with one prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 52.8% had a MCyR lasting at least 18 months. For the 32.4% of patients with CP CML treated with imatinib and at least one additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 51.4% had a MCyR lasting at least 9 months. Of the 374 evaluable patients with CP CML, 16 patients had confirmed disease transformation to AP or BP while on treatment with Bosutinib. - The 48 week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 7. - The CHR and OHR rates were based on a minimum follow-up of 12 months for patients with AP CML and 18 months for patients with BP CML. Of the 69 evaluable patients with AP CML, 4 patients had confirmed disease transformation to BP while on Bosutinib treatment. # How Supplied - Bosutinib tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. Bosutinib tablets are available in the following packaging configurations (Table 8) ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . - Procedures for proper disposal of anticancer drugs should be considered. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to take Bosutinib exactly as prescribed, not to change their dose or to stop taking Bosutinib unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take Bosutinib with food. Patients should be advised: "Do not crush or cut tablet. Do not touch or handle crushed or broken tablets." - Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with Bosutinib and to seek medical attention promptly for these symptoms. - Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising. - Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice. - Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise. - Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus with Bosutinib and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock. - Advise patients that Bosutinib can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to the fetus and to avoid becoming pregnant. If Bosutinib is used during pregnancy, or if the patient becomes pregnant while taking Bosutinib, the patient should be apprised of the potential hazard to the fetus. Because a potential risk to the nursing infant cannot be excluded, women that are taking Bosutinib should not breast-feed or provide breast milk to infants. - Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with Bosutinib. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take Bosutinib treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. - Advise patients that Bosutinib and certain other medicines, including over the counter medications or herbal supplements (such as St. John's wort) can interact with each other and may alter the effects of Bosutinib # Precautions with Alcohol - Alcohol-Bosutinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Bosutinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Bosutinib is an antineoplastic agent that is FDA approved for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. Common adverse reactions include diarrhea , nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue and Serious adverse reactions include anaphylactic shock , myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bosutinib is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. - The recommended dose and schedule of Bosutinib is 500 mg orally once daily with food. Continue treatment with Bosutinib until disease progression or patient intolerance. - If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. - Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily. - Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold Bosutinib until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue Bosutinib. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue Bosutinib. - Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold Bosutinib until recovery to Grade less than or equal to 1. Bosutinib may be resumed at 400 mg once daily. - For other clinically significant, moderate or severe non-hematological toxicity, withhold Bosutinib until the toxicity has resolved, then consider resuming Bosutinib at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of Bosutinib to 500 mg once daily. - Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1). - Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with Bosutinib as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin). - Avoid the concomitant use of strong or moderate CYP3A inducers with Bosutinib as a large reduction in exposure is expected (strong CYP3A inducers include rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine). - In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of Bosutinib is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML. - In patients with pre-existing severe renal impairment (CLcr less than 30 mL/min), the recommended dose of Bosutinib is 300 mg daily. A daily dose of 300 mg in patients with severe renal impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal renal function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 300 mg once daily in patients with severe renal impairment and CML. ## Off-Label Use and Dosage (Adult) ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosutinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. ### Non–Guideline-Supported Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established. # Contraindications - Hypersensitivity to Bosutinib. In the Bosutinib clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients. # Warnings - Diarrhea, nausea, vomiting, and abdominal pain occur with Bosutinib treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with Bosutinib was 3 (range 1–221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue Bosutinib as necessary. - Thrombocytopenia, anemia and neutropenia occur with Bosutinib treatment. Patients with CML who are receiving Bosutinib should have a complete blood count performed weekly for the first month and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue Bosutinib as necessary. - One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) occurred in a trial of Bosutinib in combination with letrozole. The patient recovered fully following discontinuation of Bosutinib. This case represented 1 out of 1209 patients in Bosutinib clinical trials. - In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for each was 21 days. - Perform monthly hepatic enzyme tests for the first three months of treatment with Bosutinib and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue Bosutinib as necessary. Fluid retention occurs with Bosutinib and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. - In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema. - Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue Bosutinib as necessary. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling: - Gastrointestinal toxicity. - Myelosuppression. - Hepatic toxicity. - Fluid retention. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Serious adverse reactions reported include anaphylactic shock, myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash. - Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%). - The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of Bosutinib) included 546 CML patients. Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of Bosutinib treatment of 24 months, and a median dose intensity of 484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of Bosutinib treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of Bosutinib treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. - Table 2 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population. - In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. - Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population. ### Additional Data from Multiple Clinical Trials - The following adverse reactions were reported in patients in clinical trials with Bosutinib (less than 10% of Bosutinib-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent Bosutinib. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. - 1% and less than 10% - febrile neutropenia - 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis - 1% and less than 10% - tinnitus - 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage - 1% and less than 10% - chest pain, pain - 1% and less than 10% - hepatotoxicity, abnormal hepatic function; 0.1% and less than 1% - liver injury - 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock - 1% and less than 10% - pneumonia, influenza, bronchitis - 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine - 1% and less than 10% - hyperkalemia, dehydration - 1% and less than 10% - myalgia - 1% and less than 10% - dysgeusia - 1% and less than 10% - acute renal failure, renal failure - 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension. - 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption - Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage - Chest pain includes the following preferred terms: chest pain, chest discomfort *Hepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis - Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder 5 Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bosutinib in the drug label. # Drug Interactions - CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with Bosutinib as an increase in bosutinib plasma concentration is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to Bosutinib alone. - CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers with Bosutinib as a large reduction in exposure is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to Bosutinib alone . - Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to Bosutinib alone . - Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and Bosutinib dosing by more than 2 hours. - Substrates of P-glycoprotein: An in vitro study suggests that Bosutinib may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on its mechanism of action and findings in animals, Bosutinib can cause fetal harm when administered to a pregnant woman. Studies in animals showed reproductive toxicities. If Bosutinib is used during pregnancy, or if the patient becomes pregnant while taking Bosutinib, the patient should be apprised of the potential hazard to the fetus. - Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3 and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. - In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib. - There are no adequate and well controlled studies of Bosutinib in pregnant women. Bosutinib can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid pregnancy while being treated with Bosutinib. 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' Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosutinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bosutinib during labor and delivery. ### Nursing Mothers - It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bosutinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and efficacy of Bosutinib in patients less than 18 years of age have not been established.. ### Geriatic Use - In the Phase 1/2 clinical trial of Bosutinib in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Bosutinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bosutinib with respect to specific racial populations. ### Renal Impairment - Reduce the Bosutinib dose in patients with CLcr less than 30 mL/min at baseline. For patients with CLcr 30 to 50 mL who cannot tolerate a 500 mg dose, follow dose adjustment recommendations for toxicity. In a dedicated renal impairment trial, compared to volunteers with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively. - Bosutinib has not been studied in patients undergoing hemodialysis. ### Hepatic Impairment - Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial, the exposure to bosutinib increased (Cmax increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold) in patients with hepatic impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9) ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bosutinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bosutinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Perform monthly hepatic enzyme tests for the first three months of treatment with Bosutinib and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue Bosutinib as necessary # IV Compatibility There is limited information regarding IV Compatibility of Bosutinib in the drug label. # Overdosage - Experience with Bosutinib overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of Bosutinib should be observed and given appropriate supportive treatment. # Pharmacology There is limited information regarding Bosutinib Pharmacology in the drug label. ## Mechanism of Action - Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl. ## Structure - Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3•H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: - Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. - Bosutinib® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. - Each 100 mg Bosutinib tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg Bosutinib tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet). ## Pharmacodynamics - The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed. ## Pharmacokinetics - Following administration of a single dose of Bosutinib 500 mg with food in patients with cancer, the median time-to-peak concentration (tmax) was 4–6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. After 15 daily doses of Bosutinib (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng∙h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively. - After administration of a single dose of Bosutinib 500 mg with food in patients with CML, bosutinib had a mean apparent volume of distribution ± standard deviation of 6080 ± 1230 L. - Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters. - Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive. - In patients with CML given single oral doses of Bosutinib 500 mg with food, the mean terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given a single oral dose of [14C] radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine. - In a dedicated hepatic impairment trial, a single dose of Bosutinib 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively. - In a dedicated renal impairment trial, a single dose of Bosutinib 200 mg was administered with food to 26 volunteers with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 healthy volunteers with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had a 35% and 60% increase in AUC compared to healthy volunteers with normal renal function, respectively. Bosutinib exposure was not changed in patients with mild renal impairment. The Bosutinib dose should be reduced in patients with CLcr less than 30 mL/min and patients with CLcr between 30 to 50 mL/min should have their dose reduced if they are unable to tolerate a 500 mg dose. - CYP3A Inhibitors - In a cross-over trial of 24 healthy volunteers, a single dose of 100 mg of Bosutinib was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively' - CYP3A Inducers - In a cross-over trial of 24 healthy volunteers, a single dose of 500 mg of Bosutinib was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively . - P-gp Substrates - An in vitro study suggests that Bosutinib has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of Bosutinib. - pH Altering Medications - Bosutinib displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 24 healthy volunteers, a single oral dose of 400 mg of Bosutinib was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively. ## Nonclinical Toxicology - A 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5- to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. - Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. - In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure). # Clinical Studies - Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML - A single-arm, Phase 1/2 open-label, multicenter trial was conducted to evaluate the efficacy and safety of Bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within four weeks; (2) failure to achieve a complete hematologic response (CHR) by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-Abl gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial. - The efficacy endpoints for patients with CP CML previously treated with one prior TKI (imatinib) were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR). - The trial enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 503 were considered evaluable for efficacy. Patients were evaluable for efficacy if they had received at least one dose of Bosutinib and had a valid baseline efficacy assessment. Among evaluable patients, there were 266 patients with CP CML previously treated with one prior TKI (imatinib), 108 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 129 patients with advanced phase CML previously treated with at least one TKI. - Median duration of Bosutinib treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), 8 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. - The 24 week efficacy results are present in Table 6. - The minimum follow-up was 23 months for patients with CP CML treated with one prior TKI (imatinib) and 13 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 53.4% of patients with CP CML treated with one prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 52.8% had a MCyR lasting at least 18 months. For the 32.4% of patients with CP CML treated with imatinib and at least one additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 51.4% had a MCyR lasting at least 9 months. Of the 374 evaluable patients with CP CML, 16 patients had confirmed disease transformation to AP or BP while on treatment with Bosutinib. - The 48 week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 7. - The CHR and OHR rates were based on a minimum follow-up of 12 months for patients with AP CML and 18 months for patients with BP CML. Of the 69 evaluable patients with AP CML, 4 patients had confirmed disease transformation to BP while on Bosutinib treatment. # How Supplied - Bosutinib tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. Bosutinib tablets are available in the following packaging configurations (Table 8) ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . - Procedures for proper disposal of anticancer drugs should be considered. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to take Bosutinib exactly as prescribed, not to change their dose or to stop taking Bosutinib unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take Bosutinib with food. Patients should be advised: "Do not crush or cut tablet. Do not touch or handle crushed or broken tablets." - Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with Bosutinib and to seek medical attention promptly for these symptoms. - Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising. - Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice. - Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise. - Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus with Bosutinib and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock. - Advise patients that Bosutinib can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to the fetus and to avoid becoming pregnant. If Bosutinib is used during pregnancy, or if the patient becomes pregnant while taking Bosutinib, the patient should be apprised of the potential hazard to the fetus. Because a potential risk to the nursing infant cannot be excluded, women that are taking Bosutinib should not breast-feed or provide breast milk to infants. - Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with Bosutinib. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take Bosutinib treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. - Advise patients that Bosutinib and certain other medicines, including over the counter medications or herbal supplements (such as St. John's wort) can interact with each other and may alter the effects of Bosutinib # Precautions with Alcohol - Alcohol-Bosutinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bosutinib
1268f5e6579193871fac85562931f1868f49c2c5	wikidoc	Herbalism	Herbalism Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, and phytotherapy. Sometimes the scope of herbal medicine is extended to include fungi and bee products, as well as minerals, shells and certain animal parts. Many plants synthesize substances that are useful to the maintenance of health in humans and other animals. These include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins. Many are secondary metabolites, of which at least 12,000 have been isolated — a number estimated to be less than 10% of the total. In many cases, these substances (particularly the alkaloids) serve as plant defense mechanisms against predation by microorganisms, insects, and herbivores. Many of the herbs and spices used by humans to season food yield useful medicinal compounds. # Anthropology of herbalism People on all continents have used hundreds to thousands of indigenous plants for treatment of ailments since prehistoric times. Anthropologists theorize that animals evolved a tendency to seek out bitter plant parts in response to illness. This behavior arose because bitterness is an indicator of secondary metabolites. The risk benefit ratio favored animals and protohumans that were inclined to experiment in times of sickness. Over time, and with insight, instinct, and trial-and-error, a base of knowledge would have been acquired within early tribal communities. As this knowledge base expanded over the generations, the specialized role of the herbalist emerged. The process would likely have occurred in varying manners within a wide diversity of cultures. Indigenous healers often claim to have learned by observing that sick animals change their food preferences to nibble at bitter herbs they would normally reject. Field biologists have provided corroborating evidence based on observation of diverse species, such as chimpanzees, chickens, sheep and butterflies. Lowland gorillas take 90% of their diet from the fruits of Aframomum melegueta, a relative of the ginger plant, that is a potent antimicrobial and apparently keeps shigellosis and similar infections at bay. Researchers from Ohio Wesleyan University found that some birds select nesting material rich in antimicrobial agents which protect their young from harmful bacteria. Sick animals tend to forage plants rich in secondary metabolites, such as tannins and alkaloids. Since these phytochemicals often have antiviral, antibacterial, antifungal and antihelminthic properties, a plausible case can be made for self-medication by animals in the wild. Some animals have digestive systems especially adapted to cope with certain plant toxins. For example, the koala can live on the leaves and shoots of the eucalyptus, a plant that is dangerous to most animals.A plant that is harmless to a particular animal may not be safe for humans to ingest. A reasonable conjecture is that these discoveries were traditionally collected by the medicine people of indigenous tribes, who then passed on safety information and cautions. The use of herbs and spices in cuisine developed in part as a response to the threat of food-born pathogens. Studies show that in tropical climes where pathogens are the most abundant recipes are the most highly spiced. Further, the spices with the most potent antimicrobial activity tend to be selected.In all cultures vegetables are spiced less than meat, presumably because they are more resistant to spoilage. # Herbs in history In the written record, the study of herbs dates back over 5,000 years to the Sumerians, who described well-established medicinal uses for such plants as laurel, caraway, and thyme. The Egyptians of 1000 B.C. are known to have used garlic, opium, castor oil, coriander, mint, indigo, and other herbs for medicine and the Old Testament also mentions herb use and cultivation, including mandrake, vetch, caraway, wheat, barley, and rye. The first Chinese herb book (or herbal), dating from about 2700 B.C., lists 365 medicinal plants and their uses - including ma-Huang, the shrub that introduced the drug ephedrine to modern medicine. The ancient Greeks and Romans made medicinal use of plants. Greek and Roman medicinal practices, as preserved in the writings of Hippocrates and - especially - Galen, provided the patterns for later western medicine. Hippocrates advocated the use of a few simple herbal drugs - along with fresh air, rest, and proper diet. Galen, on the other had, recommended large doses of drug mixtures - including plant, animal, and mineral ingredients. The Greek physician compiled the first European treatise on the properties and uses of medicinal plants, De Materia Medica. In the first century AD, Dioscorides wrote a compendium of more that 500 plants that remained an authoritative reference into the 17th century. Similarly important for herbalists and botanists of later centuries was the Greek book that founded the science of botany, Theophrastus’ Historia Plantarum, written in the fourth century B.C. The uses of plants for medicine and other purposes changed little during the Middle Ages. The early Christian church discouraged the formal practice of medicine, preferring faith healing; but many Greek and Roman writings on medicine, as on other subjects, were preserved by diligent hand copying of manuscripts in monasteries. The monasteries thus tended to become local centers of medical knowledge, and their herb gardens provided the raw materials for simple treatment of common disorders. At the same time, folk medicine in the home and village continues uninterrupted, supporting numerous wandering and settled herbalists. Among these were the “wise-women,” who prescribed herbal remedies often along with spells and enchantments. It was not until the later Middle Ages that women who were knowledgeable in herb lore became the targets of the witch hysteria. One of the most famous women in the herbal tradition was Hildegard of Bingen. A twelfth century Benedictine nun, she wrote a medical text called Causes and Cures. Medical schools began to return in the eleventh century, teaching Galen’s system. At the time, the Arabic world was more advanced in science than Europe. As a trading culture, the Arabs had access to plant material from distant places such as China and India. Herbals, medical texts and translations of the classics of antiquity filtered in from east to west. Alongside the university system, folk medicine continued to thrive. Plants were burdened with a mass of both pagan and Christian superstition that often was more important than their actual properties. The continuing importance of herbs for the centuries following the Middle Ages is indicated by the hundreds of herbals published after the invention of printing in the fifteenth century. Theophrastus’ Historia Plantarum was one of the first books to be printed, and Dioscorides’ De Materia Medica was not far behind. The fifteenth, sixteenth, and seventeenth centuries were the great age of herbals, many of them available for the first time in English and other languages rather than Latin or Greek. The first herbal to be published in English was the anonymous Grete Herball of 1526. The two best-known herbals in English were The Herball or General History of Plants (1597) by John Gerard and The English Physician Enlarged (1653) by Nicholas Culpeper. Gerard’s text was basically a pirated translation of a book by the Belgian herbalist Dodoens and his illustrations came from a German botanical work. The original edition contained many errors due to faulty matching of the two parts. Culpeper’s blend of traditional medicine with astrology, magic, and folklore was ridiculed by the physicians of his day yet his book - like Gerard’s and other herbals - enjoyed phenomenal popularity. The Age of Exploration and the Columbian Exchange introduced new medicinal plants to Europe. The Badianus Manuscript was an illustrated Aztec herbal translated into Latin in the 16th century. The second millennium, however, also saw the beginning of a slow erosion of the pre-eminent position held by plants as sources of therapeutic effects. This began with the introduction of the physician, the introduction of active chemical drugs (like arsenic, copper sulfate, iron, mercury, and sulfur), followed by the rapid development of chemistry and the other physical sciences, led increasingly to the dominance of chemotherapy - chemical medicine - as the orthodox system of the twentieth century. # Role of herbal medicine in modern human society The use of herbs to treat disease is almost universal among non-industrialized societies. A number of traditions came to dominate the practice of herbal medicine at the end of the twentieth century: - The herbal medicine system, based on Greek and Roman sources - The Siddha and Ayurvedic medicine systems from India - Chinese herbal medicine (Chinese herbology) - Unani-Tibb medicine - Shamanic Herbalism Many of the pharmaceuticals currently available to physicians have a long history of use as herbal remedies, including opium, aspirin, digitalis, and quinine. The World Health Organization (WHO) estimates that 80 percent of the world's population presently uses herbal medicine for some aspect of primary health care.Herbal medicine is a major component in all traditional medicine systems, and a common element in Ayurvedic, homeopathic, naturopathic, traditional Chinese medicine, and Native American medicine. The use of, and search for, drugs and dietary supplements derived from plants have accelerated in recent years. Pharmacologists, microbiologists, botanists, and natural-products chemists are combing the Earth for phytochemicals and leads that could be developed for treatment of various diseases. In fact, according to the World Health Organisation, approximately 25% of modern drugs used in the United States have been derived from plants. - Three quarters of plants that provide active ingredients for prescription drugs came to the attention of researchers because of their use in traditional medicine. - Among the 120 active compounds currently isolated from the higher plants and widely used in modern medicine today, 80 percent show a positive correlation between their modern therapeutic use and the traditional use of the plants from which they are derived. - More than two thirds of the world's plant species - at least 35,000 of which are estimated to have medicinal value - come from the developing countries. - At least 7,000 medical compounds in the modern pharmacopoeia are derived from plants # Biological background All plants produce chemical compounds as part of their normal metabolic activities. These include primary metabolites, such as sugars and fats, found in all plants, and secondary metabolites found in a smaller range of plants, some useful ones found only in a particular genus or species. Pigments harvest light, protect the organism from radiation and display colors to attract pollinators. Many common weeds have medicinal properties. The functions of secondary metabolites are varied. For example, some secondary metabolites are toxins used to deter predation, and others are pheromones used to attract insects for pollination. Phytoalexins protect against bacterial and fungal attacks. Allelochemicals inhibit rival plants that are competing for soil and light. Plants upregulate and downregulate their biochemical paths in response to the local mix of herbivores, pollinators and microorganisms. The chemical profile of a single plant may vary over time as it reacts to changing conditions. It is the secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs. Plants synthesize a bewildering variety of phytochemicals but most are derivatives of a few biochemical motifs. - Alkaloids contain a ring with nitrogen. Many alkaloids have dramatic effects on the central nervous system. Caffeine is an alkaloid that provides a mild lift but the alkaloids in datura cause severe intoxication and even death. - Phenolics contain phenol rings. The anthocyanins that give grapes their purple color, the isoflavones, the phytoestrogens from soy and the tannins that give tea its astringency are phenolics. - Turpenoids are built up from terpene building blocks. Each terpene consists of two paired isoprenes. The names monoterpenes, sesquiterpenes, diterpenes and triterpenes are based on the number of isoprene units. The fragrance of rose and lavender is due to monoterpenes. The carotenoids produce the reds, yellows and oranges of pumpkin, corn and tomatoes. - Glycosides consist of a glucose moiety attached to an aglycone. The aglycone is a molecule that is bioactive in its free form but inert until the glycoside bond is broken by water or enzymes. This mechanism allows the plant to defer the availability of the molecule to an appropriate time, similar to a safety lock on a gun. An example is the cyanoglycosides in cherry pits that release toxins only when bitten by a herbivore. The word drug itself comes from the Swedish word "druug", which means 'dried plant'. Some examples are inulin from the roots of dahlias, quinine from the cinchona, morphine and codeine from the poppy, and digoxin from the foxglove. The active ingredient in willow bark, once prescribed by Hippocrates, is salicin, or salicylic acid. The discovery of salicylic acid, also known as "acetylsalicylic acid", would eventually lead to the development of "aspirin" when it was isolated from a plant known as meadowsweet. The word aspirin comes from an abbreviation of meadowsweet's Latin genus Spiraea, with an additional "A" at the beginning to acknowledge acetylation, and "in" was added at the end for easier pronunciation. "Aspirin" was originally a brand name, and is still a protected trademark in some countries. This medication was patented by Bayer AG. # Herbal philosophy Since herbalism is such a diverse field few generalizations apply universally. Nevertheless a rough consensus can be inferred. Most herbalists concede that pharmaceuticals are more effective in emergency situations where time is of the essence. An example would be where a patient had elevated blood pressure that posed imminent danger. However they claim that over the long term herbs can help the patient resist disease and in addition provide nutritional and immunological support that pharmaceuticals lack. They view their goal as prevention as well as cure. Herbalists tend to use extracts from parts of plants, such as the roots or leaves but not isolate particular phytochemicals. Pharmaceutical medicine prefers single ingredients on the grounds that dosage can be more easily quantified. Herbalists reject the notion of a single active ingredient. They argue that the different phytochemicals present in many herbs will interact to enhance the therapeutic effects of the herb and dilute toxicity.Furthermore, they argue that a single ingredient may contribute to multiple effects. Herbalists deny that herbal synergism can be duplicated with synthetic chemicals. They argue that phytochemical interactions and trace components may alter the drug response in ways that cannot currently be replicated with a combination of a few putative active ingredients. Pharmaceutical researchers recognize the concept of drug synergism but note that clinical trials may be used to investigate the efficacy of a particular herbal preparation, provided the formulation of that herb is consistent. In specific cases the claims of synergy and multifunctionality have been supported by science. The open question is how widely both can be generalized. Herbalists would argue that cases of synergy can be widely generalized, on the basis of their interpretation of evolutionary history, not necessarily shared by the pharmaceutical community. Plants are subject to similar selection pressures as humans and therefore they must develop resistance to threats such as radiation, reactive oxygen species and microbial attack in order to survive. Optimal chemical defenses have been selected for and have thus developed over millions of years.Human diseases are multifactorial and may be treated by consuming the chemical defences that they believe to be present in herbs. Bacteria, inflammation, nutrition and ROS (reactive oxygen species) may all play a role in arterial disease. Herbalists claim a single herb may simultaneously address several of these factors. Likewise a factor such as ROS may underly more than one condition. In short herbalists view their field as the study of a web of relationships rather than a quest for single cause and a single cure for a single condition. In selecting herbal treatments herbalists may use forms of information that are not applicable to pharmacists. Because herbs can moonlight as vegetables, teas or spices they have a huge consumer base and large-scale epidemiological studies become feasible. Ethnobotanical studies are another source of information. For example, when indigenous peoples from geographically dispersed areas use closely related herbs for the same purpose that is taken as supporting evidence for its efficacy. Herbalists contend that historical medical records and herbals are underutilized resources. They favor the use of convergent information in assessing the medical value of plants. An example would be when in-vitro activity is consistent with traditional use. Certain strains of herbalism rely on sources that would be widely considered unreliable and would not be accepted in a scientifically oriented herbal journal. These include astrology, the Bible, intuition, dreams, “plant spirits”, etc. # Popularity A survey released in May 2004 by the National Center for Complementary and Alternative Medicine focused on who used complementary and alternative medicines (CAM), what was used, and why it was used. The survey was limited to adults, aged 18 years and over during 2002, living in the United States. According to this survey, herbal therapy, or use of natural products other than vitamins and minerals, was the most commonly used CAM therapy (18.9%) when all use of prayer was excluded. Herbal remedies are very common in Europe. In Germany, herbal medications are dispensed by apothecaries (e.g., Apotheke). Prescription drugs are sold alongside essential oils, herbal extracts, or herbal teas. Herbal remedies are seen by some as a treatment to be preferred to chemical medications which have been industrially produced. In the United Kingdom, the training of medical herbalists is done by state funded Universities. For example, Bachelor of Science degrees in herbal medicine are offered at Universities such as University of East London, Middlesex University, University of Central Lancashire, University of Westminster, University of Lincoln and Napier University in Edinburgh at the present. # Types of herbal medicine systems Use of medicinal plants can be as informal as, for example, culinary use or consumption of an herbal tea or supplement, although the sale of some herbs considered dangerous is often restricted to the public. Sometimes such herbs are provided to professional herbalists by specialist companies. Many herbalists, both professional and amateur, often grow or "wildcraft" their own herbs. Some researchers trained in both western and traditional Chinese medicine have attempted to deconstruct ancient medical texts in the light of modern science. One idea is that the yin-yang balance, at least with regard to herbs, corresponds to the pro-oxidant and anti-oxidant balance. This interpretation is supported by several investigations of the ORAC ratings of various yin and yang herbs. Eclectic medicine came out of the vitalist tradition, similar to physiomedicalism and bridged the European and Native American traditions. Cherokee medicine tends to divide herbs into foods, medicines and toxins and to use seven plants in the treatment of disease, which is defined with both spiritual and physiological aspects, according to Cherokee herbalist David Winston. In India, Ayurvedic medicine has quite complex formulas with 30 or more ingredients, including a sizable number of ingredients that have undergone "alchemical processing", chosen to balance "Vata", "Pitta" or "Kapha." In addition there are more modern theories of herbal combination like William LeSassier's triune formula which combined Pythagorean imagery with Chinese medicine ideas and resulted in 9 herb formulas which supplemented, drained or neutrally nourished the main organ systems affected and three associated systems. His system has been taught to thousands of influential American herbalists through his own apprenticeship programs during his lifetime, the William LeSassier Archive and the David Winston Center for Herbal Studies Many traditional African remedies have performed well in initial laboratory tests to ensure they are not toxic and in tests on animals. Gawo, a herb used in traditional treatments, has been tested in rats by researchers from Nigeria's University of Jos and the National Institute for Pharmaceutical Research and Development. According to research in the African Journal of Biotechnology, Gawo passed tests for toxicity and reduced induced fevers, diarrhoea and inflammation # Routes of administration The exact composition of a herbal product is influenced by the method of extraction. A tisane will be rich in polar components because water is a polar solvent. Oil on the other hand is a non-polar solvent and it will absorb non-polar compounds. Alcohol lies somewhere in between. There are many forms in which herbs can be administered, these include: - Tinctures (alcoholic extracts of herbs such as echinacea extract. Usually obtained by combining 100% pure ethanol (or a mixture of 100% ethanol with water) with the herb. A completed tincture has a ethanol percentage of at least 40-60% (sometimes up to 90%). - Herbal wine and elixirs; these are alcoholic extract of herbs; usually with an ethanol percentage of 12-38% Herbal wine is a maceration of herbs in wine, while an elixir is is a maceration of herbs in spirits (eg vodka, grappa, ...) - Tisanes (hot-water extracts of herb, such as chamomile) - Decoctions (long-term boiled extract of usually roots or bark) - Macerates (cold infusion of plants with high mucilage-content as sage, thyme, ...) Plants are chopped and added to cold water. They are then left to stand for 7 to 12 hours (depending on herb used). For most macerates 10 hours is used. - Vinegars (prepared at the same way as tinctures) - Topicals: Essential oils- application of essential oil extracts, usually diluted in a carrier oil (many essential oils can burn the skin or are simply too high dose used straight- diluting in olive oil or another food grade oil can allow these to be used safely as a topical). Salves, oils, balms, creams and lotions- Most topical applications are oil extractions of herbs. Taking a food grade oil and soaking herbs in it for anywhere from weeks to months allows certain phytochemicals to be extracted into the oil. This oil can then be made into salves, creams, lotions, or simply used as an oil for topical application. Many massage oils, antibacterial salves and wound healing compounds are made this way. Poultices and compresses- One can also make a poultice or compress using whole herb (or the appropriate part of the plant) usually crushed or dried and re hydrated with a small amount of water and then applied directly in a bandage, cloth or just as is. - Essential oils- application of essential oil extracts, usually diluted in a carrier oil (many essential oils can burn the skin or are simply too high dose used straight- diluting in olive oil or another food grade oil can allow these to be used safely as a topical). - Salves, oils, balms, creams and lotions- Most topical applications are oil extractions of herbs. Taking a food grade oil and soaking herbs in it for anywhere from weeks to months allows certain phytochemicals to be extracted into the oil. This oil can then be made into salves, creams, lotions, or simply used as an oil for topical application. Many massage oils, antibacterial salves and wound healing compounds are made this way. - Poultices and compresses- One can also make a poultice or compress using whole herb (or the appropriate part of the plant) usually crushed or dried and re hydrated with a small amount of water and then applied directly in a bandage, cloth or just as is. - Whole-herb consumption. This can occur in eather dried form (herbal powder, ... ) or fresh (juice, fresh leaves and other plant parts, ...). - Just as Hippocrates said "Let food be thy medicine", it has become clear that eating vegetables also easily fits within this category of getting health trough consumables (besides medicinal herbs). All of the vitamins, minerals and antioxidants are phytochemicals that we are accessing through our diet. There are clearly some whole herbs that we consume that are more powerful than others. Shiitake mushrooms boost the immune system and taste great so they are fabulous in soups or other food preparations for the cold and flu season. Alfalfa is also considered a health food.. Garlic lowers cholesterol, improves blood flow, fights bacteria, viruses and yeast. - Sirups: extracts of herbs made with sirups or honey. 65 parts of sugar are mixed with 35 parts of water and herb. The whole is then boiled and macerated for 3 weeks. - Extracts: include liquid extracts, dry extracts and nebulisates. Liquid extracts are liquids with a lower ethanol percentage than tinctures. They can (and are usually) made by vacuumly distilling tinctures. Dry extracts are extracts of plant material which are evaporated into a dry mass. They can then be further refined to a capsule or tablet. . A nebulisate is a dry extract which has been created by freeze-drying. - Inhalation as in aromatherapy can be used as a mood changing treatment, to fight a sinus infection or cough, or to cleanse the skin on a deeper level (steam not direct inhalation here). # Examples of plants used as medicine Few herbal remedies have conclusively demonstrated any positive effect on humans. Many of the studies cited refer to animal model investigations or in-vitro assays and therefore cannot provide more than weak supportive evidence. - Artichoke may reduce production cholesterol levels in in vitro studies. Clinical evidence of reduction in serum cholesterol is lacking. - Soy and other plants that contain phytoestrogens (plant molecules with estrogen activity) (black cohosh probably has serotonin activity) have some benefits for treatment of symptoms resulting from menopause. - Butterbur (Petasites ) - Calendula - Cranberry may be effective in treating urinary tract infections in women with recurrent symptoms. - Echinacea extracts may limit the length and severity of rhinovirus colds; however, the appropriate dosage levels, which might be higher than is available over-the-counter, require further research. - Elderberry may speed the recovery from type A and B influenza. However it is possibly risky in the case of avian influenza because the immunostimulatory effects may aggravate the cytokine cascade. - Feverfew is sometimes used to treat migraine headaches.However, many reviews of these studies show no or unclear efficacy. However a more recent RTC showed favorable results,Feverfew is not recommended for pregnant women as it may be dangerous to the fetus. - Gawo, a traditional herbal medicine in West Africa, has shown promise in animal tests - Garlic may lower total cholesterol levels - German Chamomile - Ginger - Purified extracts of the seeds of Hibiscus sabdariffa may have some antihypertensive, antifungal and antibacterial effect. Toxicity tested low except for an isolated case of damage to the testes of a rat after prolonged and excessive consumption. - Magnolia - Milk thistle - Nigella sativa (Black cumin) has demonstrated analgesic properties in mice. The mechanism for this effect, however, is unclear. In vitro studies support antibacterial, antifungal, anticancer, anti-inflammatory and immune modulating effects. However few randomized double blind studies have been published. - Oregano may be effective against multi-drug resistant bacteria. - Pawpaw can be used for insecticidal purposes (killing lice, worms)., - Phytolacca or Pokeweed is used as a homeopathic remedy to treat many ailments. It can be applied topically or taken internally. Topical treatments have been used for acne and other ailments. It is used to treatment tonsilitis, swollen glands and weight loss. - Peppermint oil may have benefits for individuals with irritable bowel syndrome. - Pomegranate - Rauvolfia Serpentina, high risk of toxicity if improperly used, used extensively in India for sleeplessness, anxiety, and high blood pressure. - Salvia lavandulaefolia may improve memory - St. John's wort, has yielded positive results, proving more effective than a placebo for the treatment of mild to moderate depression in some clinical trials A subsequent, large, controlled trial, however, found St. John's wort to be no better than a placebo in treating depression However more recent trials have shown positive results or positive trands that failed significance. A 2004 meta-analysis concluded that the positive results can be explained by publication bias but later analyses have been more favorable.The Cochrane Database cautions that the data on St. John's wort for depression are conflicting and ambiguous. - Saw Palmetto can be used for BPH. Supported in some studies, failed to confirm in otherrs. - Shiitake - Stinging nettle In some clinical studies effective for enign prostatic hyperplasia and the pain associated with osteoarthritis. In-vitro tests show antiinflammatory action. In a rodent model, stinging nettle reduced LDL cholesterol and total cholesterol. In another rodent study it reduced platelet aggregation. - Valerian root can be used to treat insomnia. Clinical studies show mixed results and researchers note that many trials are of poor quality. - Vanilla - Ocimum gratissimum and tea tree oil can be used to treat acne. - Green tea components may inhibit growth of breast cancer cells and may heal scars faster. - Lemon grass can lower cholesterol. - Honey may reduce cholesterol. May be useful in wound healing. # Risks Proper double-blind clinical trials are needed to determine the safety and efficacy of each plant before they can be recommended for medical use. In addition, many consumers believe that herbal medicines are safe because they are natural. Herbal medicines may interact with synthetic drugs causing toxicity to the patient, herbal products may have contamination that is a safety consideration, and herbal medicines, without proven efficacy, may be used to replace medicines that have a proven efficacy. Standardization of purity and dosage is not mandated in the United States, but even products made to the same specification may differ as a result of biochemical variations within a species of plant. Plants have chemical defense mechanisms against predators that can have adverse or lethal effects on humans. Examples of highly toxic herbs include poison hemlock and nightshade. They are not marketed to the public as herbs, because the risks are well known, partly due to a long and colorful history in Europe, associated with "sorcery", "magic" and intrigue. Although not frequent, adverse reactions have been reported for herbs in widespread use. On occasion serious untoward outcomes have been linked to herb consumption. A case of major potassium depletion has been attributed to chronic licorice ingestion. Black cohosh has been implicated in a case of liver failure.Few studies are available on the safety of herbs for pregnant women. Herb drug interactions are a concern. In consultation with a physician, usage of herbal remedies should be clarified, as some herbal remedies have the potential to cause adverse drug interactions when used in combination with various prescription and over-the-counter pharmaceuticals. Dangerously low blood pressure may result from the combination of an herbal remedy that lowers blood pressure together with prescription medicine that has the same effect. Some herbs may amplify the effects of anticoagulants. Certain herbs as well as common fruit interfere with cytochrome P450, an enzyme critical to drug metabolism. # Effectiveness File:Phytotherapy3.png The gold standard for pharmaceutical testing is repeated, large-scale, randomized, double-blind tests. Some plant products or pharmaceutical drugs derived from them are incorporated into mainstream medicine. To recoup the considerable costs of testing to the regulatory standards, the substances are patented by pharmaceutical companies and sold at a substantial profit. Most herbal traditions have developed without modern scientific controls to distinguish between the placebo effect, the body's natural ability to heal itself, and the actual benefits of the herbs themselves. Many herbs have shown positive results in in-vitro, animal model or small-scale clinical tests but many studies on herbal treatments have also found negative results. The quality of the trials on herbal remedies is highly and many trials of herbal treatments have been found to be of poor quality, with many trials lacking a intention to treat analysis or a comment on whether blinding was successful. The few randomized, double-blind tests that receive attention in mainstream medical publications are often questioned on methodological grounds or interpretation. Likewise, studies published in peer-reviewed medical journals such as Journal of the American Medical Association receive more consideration than those published in specialized herbal journals. This preference may be due to the possibility of location bias for such trials. One study found that non-impact factor alternative medicine journals published more studies with positive results than negative results and that trials finding positive results were of lower quality than trials finding negative results. High impact factor mainstream medical journals, on the other hand, published equal numbers of trials with positive and negative results. In high impact journals, trials finding positive results were also found to have lower quality scores than trials finding negative results. Another study found studies of phyomedicine to have superior quality to matched studies of pharmaceuticals. However, this study used a matched pair design and excluded all herbal trials that were not controlled, did not use a placebo or did not use random or quasi random assignment. Herbalists criticize mainstream studies on the grounds that they make insufficient use of historical use. They maintain that tradition can guide the selection of factors such as optimal dose, species, time of harvesting and target population. Dosage is in general an outstanding issue for herbal treatments: while most conventional medicines are heavily tested to determine the most effective and safest dosages (especially in relation to things like body weight, drug interactions, etc.), there are few established dosage standards for various herbal treatments on the market. Furthermore, herbal medicines taken in whole form cannot generally guarantee a consistent dosage or drug quality (since certain samples may contain more or less of a given active ingredient. Several methods of standardization may be applied to herbs. One is the ratio of raw materials to solvent. However different specimens of even the same plant species may vary in chemical content. Another method is standardization on a signal chemical. # Clinical studies In 2004 the U.S. National Center for Complementary and Alternative Medicine of the National Institutes of Health began funding clinical trials into the effectiveness of herbal medicine. ## Name confusion The common names of herbs (folk taxonomy) may not reflect differences in scientific taxonomy, and the same (or a very similar) common name might group together different plant species with different effects. For example, in 1993 in Belgium, a formula created by medical doctors including some Traditional Chinese medicine (TCM) herbs for weight loss, one herb (Stephania tetrandra) was swapped for another (Aristolochia fangchi) whose name in Chinese was extremely similar but which contained higher levels of a renal toxin, aristolochic acid; this quid pro quo resulted in 105 cases of kidney damage. Note that neither herb used in a TCM context would be used for weight loss or given for long periods of time. In Chinese medicine these herbs are used for certain forms of acute arthritis and edema. # Standards and quality control The issue of regulation is an area of continuing controversy in the EU and USA. At one end of the spectrum, some herbalists maintain that traditional remedies have a long history of use, and do not require the level of safety testing as xenobiotics or single ingredients in an artificially concentrated form. On the other hand, others are in favor of legally enforced quality standards, safety testing and prescription by a qualified practitioner. Some professional herbalist organizations have made statements calling for a category of regulation for herbal products. Yet others agree with the need for more quality testing but believe it can be managed through reputation without government intervention.The legal status of herbal ingredients varies by country. In the United States, most herbal remedies are regulated as dietary supplements by the Food and Drug Administration. Manufacturers of products falling into this category are not required to prove the safety or efficacy of their product, though the FDA may withdraw a product from sale should it prove harmful. The National Nutritional Foods Association, the industry's largest trade association, has run a program since 2002, examining the products and factory conditions of member companies, giving them the right to display the GMP (Good Manufacturing Practices) seal of approval on their products. In the UK, herbal remedies that are bought over the counter are regulated as supplements, as in the US. However, herbal remedies prescribed and dispensed by a qualified "Medical Herbalist", after a personal consultation, are regulated as medicines. A Medical Herbalist can prescribe some herbs which are not available over the counter, covered by Schedule III of the Medicines Act. Forthcoming changes to laws regulating herbal products in the UK, are intended to ensure the quality of herbal products used. Some herbs, such as cannabis, however, are outright banned in most countries for various reasons. Since 2004, the sales of ephedra as an dietary supplement is prohibited in the United States by the FDA. # Danger of extinction On January 18, 2008, the Botanic Gardens Conservation International (representing botanic gardens in 120 countries) stated that "400 medicinal plants are at risk of extinction, from over-collection and deforestation, threatening the discovery of future cures for disease." These included Yew trees (the bark is used for cancer drugs, paclitaxel); Hoodia (from Namibia, source of weight loss drugs); half of Magnolias (used as Chinese medicine for 5,000 years to fight cancer, dementia and heart disease); and Autumn crocus (for gout). The group also found that 5 billion people benefit from traditional plant-based medicine for health care	Herbalism Template:Biologically based therapy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, and phytotherapy. Sometimes the scope of herbal medicine is extended to include fungi and bee products, as well as minerals, shells and certain animal parts. Many plants synthesize substances that are useful to the maintenance of health in humans and other animals. These include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins. Many are secondary metabolites, of which at least 12,000 have been isolated — a number estimated to be less than 10% of the total. In many cases, these substances (particularly the alkaloids) serve as plant defense mechanisms against predation by microorganisms, insects, and herbivores. Many of the herbs and spices used by humans to season food yield useful medicinal compounds.[1][2] # Anthropology of herbalism People on all continents have used hundreds to thousands of indigenous plants for treatment of ailments since prehistoric times.[3] Anthropologists theorize that animals evolved a tendency to seek out bitter plant parts in response to illness.[4] This behavior arose because bitterness is an indicator of secondary metabolites. The risk benefit ratio favored animals and protohumans that were inclined to experiment in times of sickness. Over time, and with insight, instinct, and trial-and-error, a base of knowledge would have been acquired within early tribal communities.[5] As this knowledge base expanded over the generations, the specialized role of the herbalist emerged. The process would likely have occurred in varying manners within a wide diversity of cultures. Indigenous healers often claim to have learned by observing that sick animals change their food preferences to nibble at bitter herbs they would normally reject.[6] Field biologists have provided corroborating evidence based on observation of diverse species, such as chimpanzees, chickens, sheep and butterflies. Lowland gorillas take 90% of their diet from the fruits of Aframomum melegueta, a relative of the ginger plant, that is a potent antimicrobial and apparently keeps shigellosis and similar infections at bay.[7] Researchers from Ohio Wesleyan University found that some birds select nesting material rich in antimicrobial agents which protect their young from harmful bacteria.[8] Sick animals tend to forage plants rich in secondary metabolites, such as tannins and alkaloids.[9] Since these phytochemicals often have antiviral, antibacterial, antifungal and antihelminthic properties, a plausible case can be made for self-medication by animals in the wild.[7] Some animals have digestive systems especially adapted to cope with certain plant toxins. For example, the koala can live on the leaves and shoots of the eucalyptus, a plant that is dangerous to most animals.[10]A plant that is harmless to a particular animal may not be safe for humans to ingest.[11] A reasonable conjecture is that these discoveries were traditionally collected by the medicine people of indigenous tribes, who then passed on safety information and cautions. The use of herbs and spices in cuisine developed in part as a response to the threat of food-born pathogens. Studies show that in tropical climes where pathogens are the most abundant recipes are the most highly spiced. Further, the spices with the most potent antimicrobial activity tend to be selected.[12]In all cultures vegetables are spiced less than meat, presumably because they are more resistant to spoilage.[13] # Herbs in history In the written record, the study of herbs dates back over 5,000 years to the Sumerians, who described well-established medicinal uses for such plants as laurel, caraway, and thyme. The Egyptians of 1000 B.C. are known to have used garlic, opium, castor oil, coriander, mint, indigo, and other herbs for medicine and the Old Testament also mentions herb use and cultivation, including mandrake, vetch, caraway, wheat, barley, and rye. The first Chinese herb book (or herbal), dating from about 2700 B.C., lists 365 medicinal plants and their uses - including ma-Huang, the shrub that introduced the drug ephedrine to modern medicine. The ancient Greeks and Romans made medicinal use of plants. Greek and Roman medicinal practices, as preserved in the writings of Hippocrates and - especially - Galen, provided the patterns for later western medicine. Hippocrates advocated the use of a few simple herbal drugs - along with fresh air, rest, and proper diet. Galen, on the other had, recommended large doses of drug mixtures - including plant, animal, and mineral ingredients. The Greek physician compiled the first European treatise on the properties and uses of medicinal plants, De Materia Medica. In the first century AD, Dioscorides wrote a compendium of more that 500 plants that remained an authoritative reference into the 17th century. Similarly important for herbalists and botanists of later centuries was the Greek book that founded the science of botany, Theophrastus’ Historia Plantarum, written in the fourth century B.C. The uses of plants for medicine and other purposes changed little during the Middle Ages. The early Christian church discouraged the formal practice of medicine, preferring faith healing; but many Greek and Roman writings on medicine, as on other subjects, were preserved by diligent hand copying of manuscripts in monasteries. The monasteries thus tended to become local centers of medical knowledge, and their herb gardens provided the raw materials for simple treatment of common disorders. At the same time, folk medicine in the home and village continues uninterrupted, supporting numerous wandering and settled herbalists. Among these were the “wise-women,” who prescribed herbal remedies often along with spells and enchantments. It was not until the later Middle Ages that women who were knowledgeable in herb lore became the targets of the witch hysteria. One of the most famous women in the herbal tradition was Hildegard of Bingen. A twelfth century Benedictine nun, she wrote a medical text called Causes and Cures. Medical schools began to return in the eleventh century, teaching Galen’s system. At the time, the Arabic world was more advanced in science than Europe. As a trading culture, the Arabs had access to plant material from distant places such as China and India. Herbals, medical texts and translations of the classics of antiquity filtered in from east to west.[14] Alongside the university system, folk medicine continued to thrive. Plants were burdened with a mass of both pagan and Christian superstition that often was more important than their actual properties. The continuing importance of herbs for the centuries following the Middle Ages is indicated by the hundreds of herbals published after the invention of printing in the fifteenth century. Theophrastus’ Historia Plantarum was one of the first books to be printed, and Dioscorides’ De Materia Medica was not far behind. The fifteenth, sixteenth, and seventeenth centuries were the great age of herbals, many of them available for the first time in English and other languages rather than Latin or Greek. The first herbal to be published in English was the anonymous Grete Herball of 1526. The two best-known herbals in English were The Herball or General History of Plants (1597) by John Gerard and The English Physician Enlarged (1653) by Nicholas Culpeper. Gerard’s text was basically a pirated translation of a book by the Belgian herbalist Dodoens and his illustrations came from a German botanical work. The original edition contained many errors due to faulty matching of the two parts. Culpeper’s blend of traditional medicine with astrology, magic, and folklore was ridiculed by the physicians of his day yet his book - like Gerard’s and other herbals - enjoyed phenomenal popularity. The Age of Exploration and the Columbian Exchange introduced new medicinal plants to Europe. The Badianus Manuscript was an illustrated Aztec herbal translated into Latin in the 16th century. The second millennium, however, also saw the beginning of a slow erosion of the pre-eminent position held by plants as sources of therapeutic effects. This began with the introduction of the physician, the introduction of active chemical drugs (like arsenic, copper sulfate, iron, mercury, and sulfur), followed by the rapid development of chemistry and the other physical sciences, led increasingly to the dominance of chemotherapy - chemical medicine - as the orthodox system of the twentieth century. # Role of herbal medicine in modern human society The use of herbs to treat disease is almost universal among non-industrialized societies.[15] A number of traditions came to dominate the practice of herbal medicine at the end of the twentieth century: - The herbal medicine system, based on Greek and Roman sources - The Siddha and Ayurvedic medicine systems from India - Chinese herbal medicine (Chinese herbology) - Unani-Tibb medicine - Shamanic Herbalism Many of the pharmaceuticals currently available to physicians have a long history of use as herbal remedies, including opium, aspirin, digitalis, and quinine. The World Health Organization (WHO) estimates that 80 percent of the world's population presently uses herbal medicine for some aspect of primary health care.[16]Herbal medicine is a major component in all traditional medicine systems, and a common element in Ayurvedic, homeopathic, naturopathic, traditional Chinese medicine, and Native American medicine. The use of, and search for, drugs and dietary supplements derived from plants have accelerated in recent years. Pharmacologists, microbiologists, botanists, and natural-products chemists are combing the Earth for phytochemicals and leads that could be developed for treatment of various diseases. In fact, according to the World Health Organisation, approximately 25% of modern drugs used in the United States have been derived from plants.[17] - Three quarters of plants that provide active ingredients for prescription drugs came to the attention of researchers because of their use in traditional medicine.[18] - Among the 120 active compounds currently isolated from the higher plants and widely used in modern medicine today, 80 percent show a positive correlation between their modern therapeutic use and the traditional use of the plants from which they are derived.[19] - More than two thirds of the world's plant species - at least 35,000 of which are estimated to have medicinal value - come from the developing countries. - At least 7,000 medical compounds in the modern pharmacopoeia are derived from plants[20] # Biological background All plants produce chemical compounds as part of their normal metabolic activities. These include primary metabolites, such as sugars and fats, found in all plants, and secondary metabolites found in a smaller range of plants, some useful ones found only in a particular genus or species. Pigments harvest light, protect the organism from radiation and display colors to attract pollinators. Many common weeds have medicinal properties.[21][22] The functions of secondary metabolites are varied. For example, some secondary metabolites are toxins used to deter predation, and others are pheromones used to attract insects for pollination. Phytoalexins protect against bacterial and fungal attacks. Allelochemicals inhibit rival plants that are competing for soil and light. Plants upregulate and downregulate their biochemical paths in response to the local mix of herbivores, pollinators and microorganisms.[23] The chemical profile of a single plant may vary over time as it reacts to changing conditions. It is the secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs. Plants synthesize a bewildering variety of phytochemicals but most are derivatives of a few biochemical motifs. - Alkaloids contain a ring with nitrogen. Many alkaloids have dramatic effects on the central nervous system. Caffeine is an alkaloid that provides a mild lift but the alkaloids in datura cause severe intoxication and even death. - Phenolics contain phenol rings. The anthocyanins that give grapes their purple color, the isoflavones, the phytoestrogens from soy and the tannins that give tea its astringency are phenolics. - Turpenoids are built up from terpene building blocks. Each terpene consists of two paired isoprenes. The names monoterpenes, sesquiterpenes, diterpenes and triterpenes are based on the number of isoprene units. The fragrance of rose and lavender is due to monoterpenes. The carotenoids produce the reds, yellows and oranges of pumpkin, corn and tomatoes. - Glycosides consist of a glucose moiety attached to an aglycone. The aglycone is a molecule that is bioactive in its free form but inert until the glycoside bond is broken by water or enzymes. This mechanism allows the plant to defer the availability of the molecule to an appropriate time, similar to a safety lock on a gun. An example is the cyanoglycosides in cherry pits that release toxins only when bitten by a herbivore. The word drug itself comes from the Swedish word "druug", which means 'dried plant'. Some examples are inulin from the roots of dahlias, quinine from the cinchona, morphine and codeine from the poppy, and digoxin from the foxglove. The active ingredient in willow bark, once prescribed by Hippocrates, is salicin, or salicylic acid. The discovery of salicylic acid, also known as "acetylsalicylic acid", would eventually lead to the development of "aspirin" when it was isolated from a plant known as meadowsweet. The word aspirin comes from an abbreviation of meadowsweet's Latin genus Spiraea, with an additional "A" at the beginning to acknowledge acetylation, and "in" was added at the end for easier pronunciation.[24] "Aspirin" was originally a brand name, and is still a protected trademark in some countries. This medication was patented by Bayer AG. # Herbal philosophy Since herbalism is such a diverse field few generalizations apply universally. Nevertheless a rough consensus can be inferred. Most herbalists concede that pharmaceuticals are more effective in emergency situations where time is of the essence. An example would be where a patient had elevated blood pressure that posed imminent danger. However they claim that over the long term herbs can help the patient resist disease and in addition provide nutritional and immunological support that pharmaceuticals lack. They view their goal as prevention as well as cure. Herbalists tend to use extracts from parts of plants, such as the roots or leaves but not isolate particular phytochemicals.[25] Pharmaceutical medicine prefers single ingredients on the grounds that dosage can be more easily quantified. Herbalists reject the notion of a single active ingredient. They argue that the different phytochemicals present in many herbs will interact to enhance the therapeutic effects of the herb and dilute toxicity.[26]Furthermore, they argue that a single ingredient may contribute to multiple effects. Herbalists deny that herbal synergism can be duplicated with synthetic chemicals. They argue that phytochemical interactions and trace components may alter the drug response in ways that cannot currently be replicated with a combination of a few putative active ingredients.[27][28] Pharmaceutical researchers recognize the concept of drug synergism but note that clinical trials may be used to investigate the efficacy of a particular herbal preparation, provided the formulation of that herb is consistent.[29] In specific cases the claims of synergy[30] and multifunctionality[31] have been supported by science. The open question is how widely both can be generalized. Herbalists would argue that cases of synergy can be widely generalized, on the basis of their interpretation of evolutionary history, not necessarily shared by the pharmaceutical community. Plants are subject to similar selection pressures as humans and therefore they must develop resistance to threats such as radiation, reactive oxygen species and microbial attack in order to survive.[32] Optimal chemical defenses have been selected for and have thus developed over millions of years.[33]Human diseases are multifactorial and may be treated by consuming the chemical defences that they believe to be present in herbs. Bacteria, inflammation, nutrition and ROS (reactive oxygen species) may all play a role in arterial disease.[34] Herbalists claim a single herb may simultaneously address several of these factors. Likewise a factor such as ROS may underly more than one condition.[35] In short herbalists view their field as the study of a web of relationships rather than a quest for single cause and a single cure for a single condition. In selecting herbal treatments herbalists may use forms of information that are not applicable to pharmacists. Because herbs can moonlight as vegetables, teas or spices they have a huge consumer base and large-scale epidemiological studies become feasible. Ethnobotanical studies are another source of information. [36] For example, when indigenous peoples from geographically dispersed areas use closely related herbs for the same purpose that is taken as supporting evidence for its efficacy. Herbalists contend that historical medical records and herbals are underutilized resources.[37] They favor the use of convergent information in assessing the medical value of plants. An example would be when in-vitro activity is consistent with traditional use. Certain strains of herbalism rely on sources that would be widely considered unreliable and would not be accepted in a scientifically oriented herbal journal. These include astrology, the Bible, intuition, dreams, “plant spirits”, etc. # Popularity A survey released in May 2004 by the National Center for Complementary and Alternative Medicine focused on who used complementary and alternative medicines (CAM), what was used, and why it was used. The survey was limited to adults, aged 18 years and over during 2002, living in the United States. According to this survey, herbal therapy, or use of natural products other than vitamins and minerals, was the most commonly used CAM therapy (18.9%) when all use of prayer was excluded.[38][39] Herbal remedies are very common in Europe. In Germany, herbal medications are dispensed by apothecaries (e.g., Apotheke). Prescription drugs are sold alongside essential oils, herbal extracts, or herbal teas. Herbal remedies are seen by some as a treatment to be preferred to chemical medications which have been industrially produced.[40] In the United Kingdom, the training of medical herbalists is done by state funded Universities. For example, Bachelor of Science degrees in herbal medicine are offered at Universities such as University of East London, Middlesex University, University of Central Lancashire, University of Westminster, University of Lincoln and Napier University in Edinburgh at the present. # Types of herbal medicine systems Use of medicinal plants can be as informal as, for example, culinary use or consumption of an herbal tea or supplement, although the sale of some herbs considered dangerous is often restricted to the public. Sometimes such herbs are provided to professional herbalists by specialist companies. Many herbalists, both professional and amateur, often grow or "wildcraft" their own herbs. Some researchers trained in both western and traditional Chinese medicine have attempted to deconstruct ancient medical texts in the light of modern science. One idea is that the yin-yang balance, at least with regard to herbs, corresponds to the pro-oxidant and anti-oxidant balance. This interpretation is supported by several investigations of the ORAC ratings of various yin and yang herbs.[41][42] Eclectic medicine came out of the vitalist tradition, similar to physiomedicalism and bridged the European and Native American traditions. Cherokee medicine tends to divide herbs into foods, medicines and toxins and to use seven plants in the treatment of disease, which is defined with both spiritual and physiological aspects, according to Cherokee herbalist David Winston.[43] In India, Ayurvedic medicine has quite complex formulas with 30 or more ingredients, including a sizable number of ingredients that have undergone "alchemical processing", chosen to balance "Vata", "Pitta" or "Kapha."[44] In addition there are more modern theories of herbal combination like William LeSassier's triune formula which combined Pythagorean imagery with Chinese medicine ideas and resulted in 9 herb formulas which supplemented, drained or neutrally nourished the main organ systems affected and three associated systems. His system has been taught to thousands of influential American herbalists through his own apprenticeship programs during his lifetime, the William LeSassier Archive[45] and the David Winston Center for Herbal Studies[46] Many traditional African remedies have performed well in initial laboratory tests to ensure they are not toxic and in tests on animals. Gawo, a herb used in traditional treatments, has been tested in rats by researchers from Nigeria's University of Jos and the National Institute for Pharmaceutical Research and Development. According to research in the African Journal of Biotechnology, Gawo passed tests for toxicity and reduced induced fevers, diarrhoea and inflammation [47] # Routes of administration The exact composition of a herbal product is influenced by the method of extraction. A tisane will be rich in polar components because water is a polar solvent. Oil on the other hand is a non-polar solvent and it will absorb non-polar compounds. Alcohol lies somewhere in between. There are many forms in which herbs can be administered, these include: - Tinctures (alcoholic extracts of herbs such as echinacea extract. Usually obtained by combining 100% pure ethanol (or a mixture of 100% ethanol with water) with the herb. A completed tincture has a ethanol percentage of at least 40-60% (sometimes up to 90%). [48] - Herbal wine and elixirs; these are alcoholic extract of herbs; usually with an ethanol percentage of 12-38% [49] Herbal wine is a maceration of herbs in wine, while an elixir is is a maceration of herbs in spirits (eg vodka, grappa, ...) - Tisanes (hot-water extracts of herb, such as chamomile) - Decoctions (long-term boiled extract of usually roots or bark) - Macerates (cold infusion of plants with high mucilage-content as sage, thyme, ...) Plants are chopped and added to cold water. They are then left to stand for 7 to 12 hours (depending on herb used). For most macerates 10 hours is used.[50] - Vinegars (prepared at the same way as tinctures) - Topicals: Essential oils- application of essential oil extracts, usually diluted in a carrier oil (many essential oils can burn the skin or are simply too high dose used straight- diluting in olive oil or another food grade oil can allow these to be used safely as a topical).[51] Salves, oils, balms, creams and lotions- Most topical applications are oil extractions of herbs. Taking a food grade oil and soaking herbs in it for anywhere from weeks to months allows certain phytochemicals to be extracted into the oil. This oil can then be made into salves, creams, lotions, or simply used as an oil for topical application. Many massage oils, antibacterial salves and wound healing compounds are made this way. Poultices and compresses- One can also make a poultice or compress using whole herb (or the appropriate part of the plant) usually crushed or dried and re hydrated with a small amount of water and then applied directly in a bandage, cloth or just as is. - Essential oils- application of essential oil extracts, usually diluted in a carrier oil (many essential oils can burn the skin or are simply too high dose used straight- diluting in olive oil or another food grade oil can allow these to be used safely as a topical).[51] - Salves, oils, balms, creams and lotions- Most topical applications are oil extractions of herbs. Taking a food grade oil and soaking herbs in it for anywhere from weeks to months allows certain phytochemicals to be extracted into the oil. This oil can then be made into salves, creams, lotions, or simply used as an oil for topical application. Many massage oils, antibacterial salves and wound healing compounds are made this way. - Poultices and compresses- One can also make a poultice or compress using whole herb (or the appropriate part of the plant) usually crushed or dried and re hydrated with a small amount of water and then applied directly in a bandage, cloth or just as is. - Whole-herb consumption. This can occur in eather dried form (herbal powder, ... ) or fresh (juice, fresh leaves and other plant parts, ...). - Just as Hippocrates said "Let food be thy medicine", it has become clear that eating vegetables also easily fits within this category of getting health trough consumables (besides medicinal herbs). All of the vitamins, minerals and antioxidants are phytochemicals that we are accessing through our diet. There are clearly some whole herbs that we consume that are more powerful than others. Shiitake mushrooms boost the immune system and taste great so they are fabulous in soups or other food preparations for the cold and flu season. Alfalfa is also considered a health food.[52]. Garlic lowers cholesterol, improves blood flow, fights bacteria, viruses and yeast. - Sirups: extracts of herbs made with sirups or honey. 65 parts of sugar are mixed with 35 parts of water and herb. The whole is then boiled and macerated for 3 weeks.[53] - Extracts: include liquid extracts, dry extracts and nebulisates. Liquid extracts are liquids with a lower ethanol percentage than tinctures. They can (and are usually) made by vacuumly distilling tinctures. Dry extracts are extracts of plant material which are evaporated into a dry mass. They can then be further refined to a capsule or tablet. [54]. A nebulisate is a dry extract which has been created by freeze-drying. - Inhalation as in aromatherapy can be used as a mood changing treatment[55], to fight a sinus infection or cough, or to cleanse the skin on a deeper level (steam not direct inhalation here). # Examples of plants used as medicine Few herbal remedies have conclusively demonstrated any positive effect on humans.[56] Many of the studies cited refer to animal model investigations or in-vitro assays and therefore cannot provide more than weak supportive evidence. - Artichoke may reduce production cholesterol levels in in vitro studies. Clinical evidence of reduction in serum cholesterol is lacking.[57][58] - Soy and other plants that contain phytoestrogens (plant molecules with estrogen activity) (black cohosh probably has serotonin activity) have some benefits for treatment of symptoms resulting from menopause.[59] - Butterbur (Petasites ) - Calendula - Cranberry may be effective in treating urinary tract infections in women with recurrent symptoms.[60] - Echinacea extracts may limit the length and severity of rhinovirus colds; however, the appropriate dosage levels, which might be higher than is available over-the-counter, require further research.[61][62] - Elderberry may speed the recovery from type A and B influenza.[63] However it is possibly risky in the case of avian influenza because the immunostimulatory effects may aggravate the cytokine cascade.[64] - Feverfew is sometimes used to treat migraine headaches.[65]However, many reviews of these studies show no or unclear efficacy.[66][67] However a more recent RTC showed favorable results,[68]Feverfew is not recommended for pregnant women as it may be dangerous to the fetus.[69][70] - Gawo, a traditional herbal medicine in West Africa, has shown promise in animal tests [71] - Garlic may lower total cholesterol levels[72] - German Chamomile - Ginger - Purified extracts of the seeds of Hibiscus sabdariffa may have some antihypertensive, antifungal and antibacterial effect. Toxicity tested low except for an isolated case of damage to the testes of a rat after prolonged and excessive consumption.[73] - Magnolia - Milk thistle - Nigella sativa (Black cumin) has demonstrated analgesic properties in mice. The mechanism for this effect, however, is unclear. In vitro studies support antibacterial, antifungal, anticancer, anti-inflammatory and immune modulating effects.[74][75][76][77][78][79][80][81][82][83][84][85] However few randomized double blind studies have been published. - Oregano may be effective against multi-drug resistant bacteria.[86] - Pawpaw can be used for insecticidal purposes (killing lice, worms).[87],[88] - Phytolacca or Pokeweed is used as a homeopathic remedy to treat many ailments. It can be applied topically or taken internally. Topical treatments have been used for acne and other ailments. It is used to treatment tonsilitis, swollen glands and weight loss. - Peppermint oil may have benefits for individuals with irritable bowel syndrome.[89][90] - Pomegranate - Rauvolfia Serpentina, high risk of toxicity if improperly used, used extensively in India for sleeplessness, anxiety, and high blood pressure.[91] - Salvia lavandulaefolia may improve memory[92] - St. John's wort, has yielded positive results, proving more effective than a placebo for the treatment of mild to moderate depression in some clinical trials[93] A subsequent, large, controlled trial, however, found St. John's wort to be no better than a placebo in treating depression[94] However more recent trials have shown positive results[95][96][97] or positive trands that failed significance.[98] A 2004 meta-analysis concluded that the positive results can be explained by publication bias[99] but later analyses have been more favorable.[100][101]The Cochrane Database cautions that the data on St. John's wort for depression are conflicting and ambiguous.[102] - Saw Palmetto can be used for BPH. Supported in some studies,[103] failed to confirm in otherrs.[104] - Shiitake - Stinging nettle In some clinical studies effective for enign prostatic hyperplasia[105] and the pain associated with osteoarthritis.[106] In-vitro tests show antiinflammatory action.[107] In a rodent model, stinging nettle reduced LDL cholesterol and total cholesterol. [108] In another rodent study it reduced platelet aggregation.[109] - Valerian root can be used to treat insomnia. Clinical studies show mixed results and researchers note that many trials are of poor quality.[110][111][112] - Vanilla - Ocimum gratissimum[113][114] and tea tree oil can be used to treat acne. - Green tea components may inhibit growth of breast cancer cells[115] and may heal scars faster.[116] - Lemon grass can lower cholesterol. - Honey may reduce cholesterol.[117] May be useful in wound healing.[118] # Risks Proper double-blind clinical trials are needed to determine the safety and efficacy of each plant before they can be recommended for medical use.[119] In addition, many consumers believe that herbal medicines are safe because they are natural. Herbal medicines may interact with synthetic drugs causing toxicity to the patient, herbal products may have contamination that is a safety consideration, and herbal medicines, without proven efficacy, may be used to replace medicines that have a proven efficacy.[56] Standardization of purity and dosage is not mandated in the United States, but even products made to the same specification may differ as a result of biochemical variations within a species of plant.[120] Plants have chemical defense mechanisms against predators that can have adverse or lethal effects on humans. Examples of highly toxic herbs include poison hemlock and nightshade.[121] They are not marketed to the public as herbs, because the risks are well known, partly due to a long and colorful history in Europe, associated with "sorcery", "magic" and intrigue.[122] Although not frequent, adverse reactions have been reported for herbs in widespread use.[123] On occasion serious untoward outcomes have been linked to herb consumption. A case of major potassium depletion has been attributed to chronic licorice ingestion.[124] Black cohosh has been implicated in a case of liver failure.[125]Few studies are available on the safety of herbs for pregnant women.[126][127] Herb drug interactions are a concern. In consultation with a physician, usage of herbal remedies should be clarified, as some herbal remedies have the potential to cause adverse drug interactions when used in combination with various prescription and over-the-counter pharmaceuticals. Dangerously low blood pressure may result from the combination of an herbal remedy that lowers blood pressure together with prescription medicine that has the same effect. Some herbs may amplify the effects of anticoagulants.[128] Certain herbs as well as common fruit interfere with cytochrome P450, an enzyme critical to drug metabolism.[129] # Effectiveness File:Phytotherapy3.png The gold standard for pharmaceutical testing is repeated, large-scale, randomized, double-blind tests. Some plant products or pharmaceutical drugs derived from them are incorporated into mainstream medicine. To recoup the considerable costs of testing to the regulatory standards, the substances are patented by pharmaceutical companies and sold at a substantial profit.[130] Most herbal traditions have developed without modern scientific controls to distinguish between the placebo effect, the body's natural ability to heal itself, and the actual benefits of the herbs themselves. Many herbs have shown positive results in in-vitro, animal model or small-scale clinical tests[131] but many studies on herbal treatments have also found negative results.[132] The quality of the trials on herbal remedies is highly and many trials of herbal treatments have been found to be of poor quality, with many trials lacking a intention to treat analysis or a comment on whether blinding was successful.[133] The few randomized, double-blind tests that receive attention in mainstream medical publications are often questioned on methodological grounds or interpretation. Likewise, studies published in peer-reviewed medical journals such as Journal of the American Medical Association receive more consideration than those published in specialized herbal journals. This preference may be due to the possibility of location bias for such trials. One study found that non-impact factor alternative medicine journals published more studies with positive results than negative results and that trials finding positive results were of lower quality than trials finding negative results. High impact factor mainstream medical journals, on the other hand, published equal numbers of trials with positive and negative results. In high impact journals, trials finding positive results were also found to have lower quality scores than trials finding negative results.[134] Another study found studies of phyomedicine to have superior quality to matched studies of pharmaceuticals.[135] However, this study used a matched pair design and excluded all herbal trials that were not controlled, did not use a placebo or did not use random or quasi random assignment. Herbalists criticize mainstream studies on the grounds that they make insufficient use of historical use. They maintain that tradition can guide the selection of factors such as optimal dose, species, time of harvesting and target population.[136] Dosage is in general an outstanding issue for herbal treatments: while most conventional medicines are heavily tested to determine the most effective and safest dosages (especially in relation to things like body weight, drug interactions, etc.), there are few established dosage standards for various herbal treatments on the market. Furthermore, herbal medicines taken in whole form cannot generally guarantee a consistent dosage or drug quality (since certain samples may contain more or less of a given active ingredient. Several methods of standardization may be applied to herbs. One is the ratio of raw materials to solvent. However different specimens of even the same plant species may vary in chemical content. Another method is standardization on a signal chemical.[137] # Clinical studies In 2004 the U.S. National Center for Complementary and Alternative Medicine of the National Institutes of Health began funding clinical trials into the effectiveness of herbal medicine.[138] ## Name confusion The common names of herbs (folk taxonomy) may not reflect differences in scientific taxonomy, and the same (or a very similar) common name might group together different plant species with different effects. For example, in 1993 in Belgium, a formula created by medical doctors including some Traditional Chinese medicine (TCM) herbs for weight loss, one herb (Stephania tetrandra) was swapped for another (Aristolochia fangchi) whose name in Chinese was extremely similar but which contained higher levels of a renal toxin, aristolochic acid; this quid pro quo resulted in 105 cases of kidney damage.[139][140] Note that neither herb used in a TCM context would be used for weight loss or given for long periods of time. In Chinese medicine these herbs are used for certain forms of acute arthritis and edema.[141][142][143] # Standards and quality control The issue of regulation is an area of continuing controversy in the EU and USA. At one end of the spectrum, some herbalists maintain that traditional remedies have a long history of use, and do not require the level of safety testing as xenobiotics or single ingredients in an artificially concentrated form. On the other hand, others are in favor of legally enforced quality standards, safety testing and prescription by a qualified practitioner. Some professional herbalist organizations have made statements calling for a category of regulation for herbal products.[144] Yet others agree with the need for more quality testing but believe it can be managed through reputation without government intervention.[145]The legal status of herbal ingredients varies by country. In the United States, most herbal remedies are regulated as dietary supplements by the Food and Drug Administration. Manufacturers of products falling into this category are not required to prove the safety or efficacy of their product, though the FDA may withdraw a product from sale should it prove harmful.[146][147] The National Nutritional Foods Association, the industry's largest trade association, has run a program since 2002, examining the products and factory conditions of member companies, giving them the right to display the GMP (Good Manufacturing Practices) seal of approval on their products.[148] In the UK, herbal remedies that are bought over the counter are regulated as supplements, as in the US. However, herbal remedies prescribed and dispensed by a qualified "Medical Herbalist", after a personal consultation, are regulated as medicines. A Medical Herbalist can prescribe some herbs which are not available over the counter, covered by Schedule III of the Medicines Act. Forthcoming changes to laws regulating herbal products in the UK, are intended to ensure the quality of herbal products used. Some herbs, such as cannabis, however, are outright banned in most countries for various reasons. Since 2004, the sales of ephedra as an dietary supplement is prohibited in the United States by the FDA.[149] # Danger of extinction On January 18, 2008, the Botanic Gardens Conservation International (representing botanic gardens in 120 countries) stated that "400 medicinal plants are at risk of extinction, from over-collection and deforestation, threatening the discovery of future cures for disease." These included Yew trees (the bark is used for cancer drugs, paclitaxel); Hoodia (from Namibia, source of weight loss drugs); half of Magnolias (used as Chinese medicine for 5,000 years to fight cancer, dementia and heart disease); and Autumn crocus (for gout). The group also found that 5 billion people benefit from traditional plant-based medicine for health care[150]	https://www.wikidoc.org/index.php/Botanical_medicine
075289164dffcec941e88efc29c2030e090ec2c8	wikidoc	Intestine	Intestine # Overview In anatomy, the intestine is the segment of the alimentary canal extending from the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine. In humans, the small intestine is further subdivided into the duodenum, jejunum and ileum while the large intestine is subdivided into the cecum and colon. # Structure and Function The intestinal tract can be broadly divided into two different parts, the small and large intestine. Grayish-purple in color and about 35 mm (1.5 inches) in diameter, the small intestine is the first and longest, measuring 6-8 metres (22-25 feet) on average in an adult man. Shorter and relatively stockier, the large intestine is a dark reddish color, measuring roughly 1.5 metres (5 feet) on average. Both intestines share a general structure with the whole gut, and is composed of several layers. The lumen is the cavity where digested material passes through and from where nutrients are absorbed. Along the whole length of the gut in the glandular epithelium are goblet cells. These secrete mucus which lubricates the passage of food along and protects it from digestive enzymes. Villi are vaginations of the mucosa and increase the overall surface area of the intestine while also containing a lacteal, which is connected to the lymph system and aids in the removal of lipids and tissue fluid from the blood supply. Micro villi are present on the epithelium of a villus and further increase the surface area over which absorption can take place. The next layer is the muscularis mucosa which is a layer of smooth muscle that aids in the action of continued peristalsis along the gut. The submucosa contains nerves, blood vessels and elastic fibre with collagen that stretches with increased capacity but maintains the shape of the intestine. Surrounding this is the muscularis externa which comprises longitudinal and smooth muscle that again helps with continued peristalsis and the movement of digested material out of and along the gut. Lastly there is the serosa which is made up of loose connective tissue and coated in mucus so as to prevent friction damage from the intestine rubbing against other tissue. Holding all this in place are the mesenteries which suspend the intestine in the abdominal cavity and stop it being disturbed when a person is physically active. The large intestine hosts several kinds of bacteria that deal with molecules the human body is not able to breakdown itself. This is an example of symbiosis. These bacteria also account for the production of gases inside our intestine (this gas is released as flatulence when removed through the anus). However the large intestine is mainly concerned with the absorption of water from digested material (which is regulated by the hypothalamus), the reabsorption of sodium, as well as any nutrients that may have escaped primary digestion in the ileum. # Absorption of glucose in the ileum Initially, nutrients diffuse passively from the lumen of the ileum via the epithelial cells and into the blood stream. However, certain molecules like glucose passively diffuse in mass quantity some time after a meal, causing a change in concentration gradient. This results in a higher concentration of glucose in the blood (blood sugar level) than in the ileum, such that passive diffusion is no longer possible. Active uptake would be a waste of energy, so another process is used to transport the left-over glucose from the lumen into the blood stream. In this process, called secondary active transport, a glucose molecule associates with a sodium ion and approaches a transporter protein in the membrane of an epithelial cell. The protein allows the sodium ion through, which then "pulls" the glucose molecule into the cell. Once inside the cell, the sodium and glucose dissociate, and the glucose molecule is free to diffuse passively from the cell into the blood stream (this is because the blood flowing past the cell has a lower blood sugar level than the cell cytoplasm). # Diseases - Gastroenteritis is inflammation of the intestines and is the most common disease of the intestines. It can arise as the result of food poisoning. - Ileus is a blockage of the intestines. - Ileitis is an inflammation of the ileum. - Colitis is an inflammation of the large intestine. - Appendicitis is inflammation of the vermiform appendix located at the cecum. This is a potentially fatal disease if left untreated; most cases of appendicitis require surgical intervention. - Coeliac disease is a common form of malabsorption, affecting up to 1% of people of northern European descent. Allergy to gluten proteins, found in wheat, barley and rye, causes villous atrophy in the small intestine. Life-long dietary avoidance of these foodstuffs in a gluten-free diet is the only treatment. - Crohn's disease and ulcerative colitis are examples of inflammatory bowel disease. While Crohn's can affect the entire gastrointestinal tract, ulcerative colitis is limited to the large intestine. Crohn's disease is widely regarded as an autoimmune disease. Although ulcerative colitis is often treated as though it were an autoimmune disease, there is no consensus that it actually is such. (See List of autoimmune diseases). - Enteroviruses are named by their transmission-route through the intestine (enteric = related to intestine), but their symptoms aren't mainly associated with the intestine. # Disorders - Irritable bowel syndrome is the most common functional disorder of the intestine. Functional constipation and chronic functional abdominal pain are other disorders of the intestine that have physiological causes, but do not have identifiable structural, chemical, or infectious pathologies. They are aberrations of normal bowel function but not diseases. - Diverticular disease is a condition that is very common in older people in industrialized countries. It usually affects the large intestine but has been known to affect the small intestine as well. Diverticular disease occurs when pouches form on the intestinal wall. Once the pouches become inflamed it is known as Diverticulitis, or Diverticular disease. - Endometriosis can affect the intestines, with similar symptoms to IBS. - Bowel twist (or similarly, bowel strangulation) is a comparatively rare event (usually developing sometime after major bowel surgery). It is, however, hard to diagnose correctly, and if left uncorrected can lead to bowel infarction and death.	Intestine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In anatomy, the intestine is the segment of the alimentary canal extending from the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine. In humans, the small intestine is further subdivided into the duodenum, jejunum and ileum while the large intestine is subdivided into the cecum and colon. # Structure and Function The intestinal tract can be broadly divided into two different parts, the small and large intestine. Grayish-purple in color and about 35 mm (1.5 inches) in diameter, the small intestine is the first and longest, measuring 6-8 metres (22-25 feet) on average in an adult man. Shorter and relatively stockier, the large intestine is a dark reddish color, measuring roughly 1.5 metres (5 feet) on average. Both intestines share a general structure with the whole gut, and is composed of several layers. The lumen is the cavity where digested material passes through and from where nutrients are absorbed. Along the whole length of the gut in the glandular epithelium are goblet cells. These secrete mucus which lubricates the passage of food along and protects it from digestive enzymes. Villi are vaginations of the mucosa and increase the overall surface area of the intestine while also containing a lacteal, which is connected to the lymph system and aids in the removal of lipids and tissue fluid from the blood supply. Micro villi are present on the epithelium of a villus and further increase the surface area over which absorption can take place. The next layer is the muscularis mucosa which is a layer of smooth muscle that aids in the action of continued peristalsis along the gut. The submucosa contains nerves, blood vessels and elastic fibre with collagen that stretches with increased capacity but maintains the shape of the intestine. Surrounding this is the muscularis externa which comprises longitudinal and smooth muscle that again helps with continued peristalsis and the movement of digested material out of and along the gut. Lastly there is the serosa which is made up of loose connective tissue and coated in mucus so as to prevent friction damage from the intestine rubbing against other tissue. Holding all this in place are the mesenteries which suspend the intestine in the abdominal cavity and stop it being disturbed when a person is physically active. The large intestine hosts several kinds of bacteria that deal with molecules the human body is not able to breakdown itself. This is an example of symbiosis. These bacteria also account for the production of gases inside our intestine (this gas is released as flatulence when removed through the anus). However the large intestine is mainly concerned with the absorption of water from digested material (which is regulated by the hypothalamus), the reabsorption of sodium, as well as any nutrients that may have escaped primary digestion in the ileum. # Absorption of glucose in the ileum Initially, nutrients diffuse passively from the lumen of the ileum via the epithelial cells and into the blood stream. However, certain molecules like glucose passively diffuse in mass quantity some time after a meal, causing a change in concentration gradient. This results in a higher concentration of glucose in the blood (blood sugar level) than in the ileum, such that passive diffusion is no longer possible. Active uptake would be a waste of energy, so another process is used to transport the left-over glucose from the lumen into the blood stream. In this process, called secondary active transport, a glucose molecule associates with a sodium ion and approaches a transporter protein in the membrane of an epithelial cell. The protein allows the sodium ion through, which then "pulls" the glucose molecule into the cell. Once inside the cell, the sodium and glucose dissociate, and the glucose molecule is free to diffuse passively from the cell into the blood stream (this is because the blood flowing past the cell has a lower blood sugar level than the cell cytoplasm). # Diseases - Gastroenteritis is inflammation of the intestines and is the most common disease of the intestines. It can arise as the result of food poisoning. - Ileus is a blockage of the intestines. - Ileitis is an inflammation of the ileum. - Colitis is an inflammation of the large intestine. - Appendicitis is inflammation of the vermiform appendix located at the cecum. This is a potentially fatal disease if left untreated; most cases of appendicitis require surgical intervention. - Coeliac disease is a common form of malabsorption, affecting up to 1% of people of northern European descent. Allergy to gluten proteins, found in wheat, barley and rye, causes villous atrophy in the small intestine. Life-long dietary avoidance of these foodstuffs in a gluten-free diet is the only treatment. - Crohn's disease and ulcerative colitis are examples of inflammatory bowel disease. While Crohn's can affect the entire gastrointestinal tract, ulcerative colitis is limited to the large intestine. Crohn's disease is widely regarded as an autoimmune disease. Although ulcerative colitis is often treated as though it were an autoimmune disease, there is no consensus that it actually is such. (See List of autoimmune diseases). - Enteroviruses are named by their transmission-route through the intestine (enteric = related to intestine), but their symptoms aren't mainly associated with the intestine. # Disorders - Irritable bowel syndrome is the most common functional disorder of the intestine. Functional constipation and chronic functional abdominal pain are other disorders of the intestine that have physiological causes, but do not have identifiable structural, chemical, or infectious pathologies. They are aberrations of normal bowel function but not diseases. - Diverticular disease is a condition that is very common in older people in industrialized countries. It usually affects the large intestine but has been known to affect the small intestine as well. Diverticular disease occurs when pouches form on the intestinal wall. Once the pouches become inflamed it is known as Diverticulitis, or Diverticular disease. - Endometriosis can affect the intestines, with similar symptoms to IBS. - Bowel twist (or similarly, bowel strangulation) is a comparatively rare event (usually developing sometime after major bowel surgery). It is, however, hard to diagnose correctly, and if left uncorrected can lead to bowel infarction and death.	https://www.wikidoc.org/index.php/Bowel
e7b1f4dfc0e5a8173f55b83d076a32f12fff55b0	wikidoc	Zebrafish	Zebrafish The zebrafish or zebra danio, Danio rerio, is a coldwater fish belonging to the minnow family (Cyprinidae). It is a popular aquarium fish, frequently sold under the trade name zebra danio, and is also an important model organism in scientific research. # Taxonomy The zebrafish is a derived member of the genus Danio. It has a sister group relationship with Danio kyathit. # Distribution The zebrafish is native to the streams of the southeastern Himalayan region. It arose in the Ganges region in Eastern India and is also native to Pakistan, Bangladesh, Nepal, and Myanmar. It commonly inhabits streams, canals, ditches, ponds, and slow-moving to stagnant water bodies, including rice fields. Zebrafish have been introduced in aquariums in Japan, the United States and Australia. They have also been sighted in Colombia, presumably having escaped from an aquarium. # Description The fish is named for its five uniform, pigmented, horizontal blue stripes on the side of the body, all of which extend to the end of the caudal fin. Males are torpedo shaped and have gold stripes between the blue stripes; females have a larger, whitish belly and have silver stripes instead of gold. The zebrafish grows to 6.4 cm (2.5 inches), lives for around 5 years, and produces 300-500 eggs per spawning. # Varieties Recently, transgenic zebrafish have become commercially available that express green fluorescent protein, red fluorescent protein, and yellow fluorescent protein. They are tradenamed GloFish. Other varieties include golden, sandy, longfin and leopard. The Leopard danio, previously known as Danio frankeri, is a spotted colour morph of the zebrafish Danio rerio caused by a pigment mutation. Xanthistic forms of both the zebra and leopard pattern, along with long-finned varieties have been obtained via selective breeding programs for the aquarium trade. ## Common strains There are four common strains of zebrafish: AB, TÜ, IN for India and WIK. # Aquarium care Zebrafish are hardy fish and considered good for beginner aquarists. Their ease of keeping and breeding, beauty, price, playful nature and broad availability all contribute to their popularity. They thrive best at temperatures above 22 degrees Celsius (71.6 degrees Fahrenheit) and below 27 degrees Celsius (80.6 degrees Fahrenheit). They feed on worms and small crustaceans and on insect larvae. They also thrive as shoals of 6 or more, although they do interact well with other fish types in the Aquarium. However, they are susceptible to Oodinium, or Velvet disease, Microsporidia (Pseudoloma neurophilia), and mycobacterium species. # Model organism for development and genetics D. rerio are a common and useful model organism for studies of vertebrate development and gene function. They may supplement or replace higher vertebrate models, such as rats and mice. Pioneering work of George Streisinger at the University of Oregon established the zebrafish as a model organism; its importance was consolidated by large scale forward genetic screens (commonly referred to as the Tübingen/Boston screens). The scholarly journal Development devoted an issue to research using the fish in celebration of this landmark. An online database of zebrafish genetic, genomic, and developmental information, the Zebrafish Information Network (ZFIN), has been established. D. rerio is one of the few species of fish to have been flown into space (see Animals in space). Zebrafish embryonic development provides advantages over other vertebrate model organisms. Although the overall generation time of zebrafish is comparable to that of mice, zebrafish embryos develop rapidly, progressing from eggs to larvae in under three days. The embryos are large, robust, and transparent and develop externally to the mother, characteristics which all facilitate experimental manipulation and observation. Their nearly constant size during early development facilitates simple staining techniques, and drugs may be administered by adding directly to the tank. Unfertilised eggs can be made to divide, and the two-celled embryo fused into a single cell, creating a fully homozygous embryo. A common reverse genetics technique is to reduce gene expression or modify splicing in zebrafish using Morpholino antisense technology. Morpholino oligonucleotides are stable, synthetic macromolecules that contain the same bases as DNA or RNA; by binding to complementary RNA sequences, they reduce the expression of specific genes. The journal Genesis devoted an issue to research using Morpholino oligos, mostly in D. rerio. Morpholino oligonucleotides can be injected into one cell of a zebrafish embryo after the 32-cell stage, producing an organism in which gene expression is reduced in only the cells descended from the injected cell. However, cells in the early embryo (<32 cells) are interpermeable to large molecules, , allowing diffusion of Morpholinos between cells. A known problem with gene knockdowns in zebrafish is that, because the genome underwent a duplication after the divergence of ray-finned fishes and lobe-finned fishes, it is not always easy to silence the activity one of the two gene paralogs reliably due to complementation by the other paralog. Despite the complications of the zebrafish genome a number of commercially available global platforms for analysis of both gene expression by microarrays and promoter regulation using ChIP-on-chip exist. Zebrafish have the ability to regenerate fins, skin, the heart and the brain (in larval stages). Zebrafish have also been found to regenerate photoreceptors and retinal neurons following injury. The mechanisms of this regeneration are unknown, but are currently being studied. Researchers frequently cut the dorsal and ventral tail fins and analyze their regrowth to test for mutations. This research is leading the scientific community in the understanding of healing/repair mechanisms in vertebrates. # Recent developments In December 2005, a study of the golden strain identified the gene responsible for the unusual pigmentation of this strain as SLC24A5, a solute carrier that appears to be required for melanin production, and confirmed its function with a Morpholino knockdown. The orthologous gene was then characterized in humans and a one base pair difference was found to segregate strongly between fair-skinned Europeans and dark-skinned Africans. This study featured on the cover of the academic journal Science and demonstrates the power of zebrafish as a model organism in the relatively new field of comparative genomics. In January 2007, Chinese researchers at Fudan University raised genetically modified fish that can detect estrogen pollution in lakes and rivers, showing environmental officials what waterways need to be treated for the substance, which is linked to male infertility. Song Houyan and Zhong Tao, professors at Fudan's molecular medicine lab, spent three years cloning estrogen-sensitive genes and injecting them into the fertile eggs of zebrafish. The modified fish turn green if they are placed into water that is polluted by estrogen. On August 1, 2007, researchers at University College London said they had grown in the laboratory a type of adult stem cell found in the eyes of fish and mammals that develops into neurons in the retina. These cells could be injected in the eye to treat all diseases where the retinal neurons are damaged — nearly every disease of the eye, including macular degeneration, glaucoma, and diabetes-related blindness. Damage to the retina — the part of the eye that sends messages to the brain — is responsible for most cases of sight loss. The researchers studied Mueller glial cells in the eyes of humans aged from 18 months to 91 years and were able to develop them into all types of neurons found in the retina. They were also able to grow them easily in the lab, they reported in the journal Stem Cells. The cells were tested in rats with diseased retinas, where they successfully migrated into the retina and took on the characteristics of the surrounding neurons. Now the team is working on the same approach in humans. In February 2008, researchers at Children's Hospital Boston are breeding zebrafish with see-through bodies in order to make studying disease processes easier, including the spread of cancer.	Zebrafish The zebrafish or zebra danio, Danio rerio, is a coldwater fish belonging to the minnow family (Cyprinidae).[1] It is a popular aquarium fish, frequently sold under the trade name zebra danio, and is also an important model organism in scientific research. # Taxonomy The zebrafish is a derived member of the genus Danio. It has a sister group relationship with Danio kyathit.[2] # Distribution The zebrafish is native to the streams of the southeastern Himalayan region.[2] It arose in the Ganges region in Eastern India and is also native to Pakistan, Bangladesh, Nepal, and Myanmar.[citation needed] It commonly inhabits streams, canals, ditches, ponds, and slow-moving to stagnant water bodies, including rice fields.[citation needed] Zebrafish have been introduced in aquariums in Japan, the United States and Australia.[1] They have also been sighted in Colombia, presumably having escaped from an aquarium. # Description The fish is named for its five uniform, pigmented, horizontal blue stripes on the side of the body, all of which extend to the end of the caudal fin. Males are torpedo shaped and have gold stripes between the blue stripes; females have a larger, whitish belly and have silver stripes instead of gold. The zebrafish grows to 6.4 cm (2.5 inches), lives for around 5 years, and produces 300-500 eggs per spawning. # Varieties Recently, transgenic zebrafish have become commercially available that express green fluorescent protein, red fluorescent protein, and yellow fluorescent protein. They are tradenamed GloFish. Other varieties include golden, sandy, longfin and leopard. The Leopard danio, previously known as Danio frankeri, is a spotted colour morph of the zebrafish Danio rerio caused by a pigment mutation.[3] Xanthistic forms of both the zebra and leopard pattern, along with long-finned varieties have been obtained via selective breeding programs for the aquarium trade.[4] ## Common strains There are four common strains of zebrafish: AB, TÜ, IN for India and WIK. # Aquarium care Zebrafish are hardy fish and considered good for beginner aquarists. Their ease of keeping and breeding, beauty, price, playful nature and broad availability all contribute to their popularity. They thrive best at temperatures above 22 degrees Celsius (71.6 degrees Fahrenheit) and below 27 degrees Celsius (80.6 degrees Fahrenheit). They feed on worms and small crustaceans and on insect larvae. They also thrive as shoals of 6 or more, although they do interact well with other fish types in the Aquarium. However, they are susceptible to Oodinium, or Velvet disease, Microsporidia (Pseudoloma neurophilia), and mycobacterium species. # Model organism for development and genetics D. rerio are a common and useful model organism for studies of vertebrate development and gene function.[2] They may supplement or replace higher vertebrate models, such as rats and mice. Pioneering work of George Streisinger at the University of Oregon established the zebrafish as a model organism; its importance was consolidated by large scale forward genetic screens (commonly referred to as the Tübingen/Boston screens). The scholarly journal Development devoted an issue to research using the fish in celebration of this landmark. [2] An online database of zebrafish genetic, genomic, and developmental information, the Zebrafish Information Network (ZFIN), has been established. D. rerio is one of the few species of fish to have been flown into space (see Animals in space). Zebrafish embryonic development provides advantages over other vertebrate model organisms. Although the overall generation time of zebrafish is comparable to that of mice, zebrafish embryos develop rapidly, progressing from eggs to larvae in under three days. The embryos are large, robust, and transparent and develop externally to the mother, characteristics which all facilitate experimental manipulation and observation. [5] Their nearly constant size during early development facilitates simple staining techniques, and drugs may be administered by adding directly to the tank. Unfertilised eggs can be made to divide, and the two-celled embryo fused into a single cell, creating a fully homozygous embryo. A common reverse genetics technique is to reduce gene expression or modify splicing in zebrafish using Morpholino antisense technology. Morpholino oligonucleotides are stable, synthetic macromolecules that contain the same bases as DNA or RNA; by binding to complementary RNA sequences, they reduce the expression of specific genes. The journal Genesis devoted an issue to research using Morpholino oligos[3], mostly in D. rerio. Morpholino oligonucleotides can be injected into one cell of a zebrafish embryo after the 32-cell stage, producing an organism in which gene expression is reduced in only the cells descended from the injected cell. However, cells in the early embryo (<32 cells) are interpermeable to large molecules[4], [5], allowing diffusion of Morpholinos between cells. A known problem with gene knockdowns in zebrafish is that, because the genome underwent a duplication after the divergence of ray-finned fishes and lobe-finned fishes, it is not always easy to silence the activity one of the two gene paralogs reliably due to complementation by the other paralog. Despite the complications of the zebrafish genome a number of commercially available global platforms for analysis of both gene expression by microarrays and promoter regulation using ChIP-on-chip exist. Zebrafish have the ability to regenerate fins, skin, the heart and the brain (in larval stages). Zebrafish have also been found to regenerate photoreceptors and retinal neurons following injury. The mechanisms of this regeneration are unknown, but are currently being studied. Researchers frequently cut the dorsal and ventral tail fins and analyze their regrowth to test for mutations. This research is leading the scientific community in the understanding of healing/repair mechanisms in vertebrates. # Recent developments In December 2005, a study of the golden strain identified the gene responsible for the unusual pigmentation of this strain as SLC24A5, a solute carrier that appears to be required for melanin production, and confirmed its function with a Morpholino knockdown. The orthologous gene was then characterized in humans and a one base pair difference was found to segregate strongly between fair-skinned Europeans and dark-skinned Africans.[6] This study featured on the cover of the academic journal Science and demonstrates the power of zebrafish as a model organism in the relatively new field of comparative genomics. In January 2007, Chinese researchers at Fudan University raised genetically modified fish that can detect estrogen pollution in lakes and rivers, showing environmental officials what waterways need to be treated for the substance, which is linked to male infertility. Song Houyan and Zhong Tao, professors at Fudan's molecular medicine lab, spent three years cloning estrogen-sensitive genes and injecting them into the fertile eggs of zebrafish. The modified fish turn green if they are placed into water that is polluted by estrogen.[7] On August 1, 2007, researchers at University College London said they had grown in the laboratory a type of adult stem cell found in the eyes of fish and mammals that develops into neurons in the retina. These cells could be injected in the eye to treat all diseases where the retinal neurons are damaged — nearly every disease of the eye, including macular degeneration, glaucoma, and diabetes-related blindness. Damage to the retina — the part of the eye that sends messages to the brain — is responsible for most cases of sight loss. The researchers studied Mueller glial cells in the eyes of humans aged from 18 months to 91 years and were able to develop them into all types of neurons found in the retina. They were also able to grow them easily in the lab, they reported in the journal Stem Cells. The cells were tested in rats with diseased retinas, where they successfully migrated into the retina and took on the characteristics of the surrounding neurons. Now the team is working on the same approach in humans.[8] In February 2008, researchers at Children's Hospital Boston are breeding zebrafish with see-through bodies in order to make studying disease processes easier, including the spread of cancer.[9]	https://www.wikidoc.org/index.php/Brachydanio_rerio
ed7e5cd50c3676226c0b4e86defd39bef764e5d2	wikidoc	Brachyury	Brachyury Brachyury is a protein that, in humans, is encoded by the TBXT gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria. # History The brachyury mutation was first described in mice by Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous animals. In homozygous animals the brachyury mutation is lethal at around embryonic day 10 due to defects in mesoderm formation, notochord differentiation and the absence of structures posterior to the forlimb bud (Dobrovolskaïa-Zavadskaïa, 1927). The name brachyury comes from the Greek brakhus meaning short and oura meaning tail. In 2018 HGNC updated the human gene name from T to TBXT, presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course. The mouse T gene was cloned by Bernhard Herrmann and colleagues and proved to encode a 436 amino acid embryonic nuclear transcription factor. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. T is the founding member of the T-box family which in mammals currently consists of 18 T-box genes. # Function The gene brachyury appears to have a conserved role in defining the midline of a bilaterian organism, and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs. Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore. It also defines the mesoderm during gastrulation. Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak. Transcription of genes required for mesoderm formation and cellular differentiation. Brachyury has also been shown to help establish the cervical vertebral blueprint during fetal development. The number of cervical vertebrae is highly conserved among all mammals; however a spontaneous vertebral and spinal dysplasia (VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven. # Expression In mice T is expressed in the inner cell mass of the blastocyst stage embryo (but not in the majority of mouse embryonic stem cells) followed by the primitive streak (see image). In later development expression is localised to the node and notochord. In Xenopus laevis Xbra (the Xenopus T homologue, also recently renamed t) is expressed in the mesodermal marginal zone of the pre-gastrula embryo followed by localisation to the blastopore and notochord at the mid-gastrula stage. The Danio rerio homologue is known as ntl (no tail) # Cancer Expression of the brachyury gene has been identified as a definitive diagnostic marker of chordoma, a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. Furthermore, germ line duplication of brachyury confers major susceptibility to chordoma. The chromosomal region on 6q27 containing the brachyury gene was gained in 6 of 21 chordomas (29%), and none of the 21 chordomas analyzed showed deletions that could have affected this gene. Brachyury is an important factor in promoting the epithelial-mesenchymal transition (EMT). Cells that over-express brachyury have down-regulated expression of the adhesion molecule E-cadherin, which allows them to undergo EMT. This process is at least partially mediated by the transcription factors AKT and Snail. Overexpression of brachyury has been linked to Hepatocellular carcinoma (HCC, also called malignant hepatoma), a common type of liver cancer. While brachyury is promoting EMT, it can also induce metastasis of HCC cells. Brachyury expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future. Additionally, overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis. Brachyury is overexpressed in a number of tumor types.	Brachyury Brachyury is a protein that, in humans, is encoded by the TBXT gene.[1][2] Brachyury is a transcription factor within the T-box complex of genes.[3] It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.[3] # History The brachyury mutation was first described in mice by Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous animals. In homozygous animals the brachyury mutation is lethal at around embryonic day 10 due to defects in mesoderm formation, notochord differentiation and the absence of structures posterior to the forlimb bud (Dobrovolskaïa-Zavadskaïa, 1927). The name brachyury comes from the Greek brakhus meaning short and oura meaning tail. In 2018 HGNC updated the human gene name from T to TBXT, presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course. The mouse T gene was cloned by Bernhard Herrmann and colleagues[4] and proved to encode a 436 amino acid embryonic nuclear transcription factor. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. T is the founding member of the T-box family which in mammals currently consists of 18 T-box genes. # Function The gene brachyury appears to have a conserved role in defining the midline of a bilaterian organism,[5] and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.[6] Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore.[3] It also defines the mesoderm during gastrulation.[7] Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.[8][9] Transcription of genes required for mesoderm formation and cellular differentiation.[clarification needed] Brachyury has also been shown to help establish the cervical vertebral blueprint during fetal development. The number of cervical vertebrae is highly conserved among all mammals; however a spontaneous vertebral and spinal dysplasia (VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven.[10] # Expression In mice T is expressed in the inner cell mass of the blastocyst stage embryo (but not in the majority of mouse embryonic stem cells) followed by the primitive streak (see image). In later development expression is localised to the node and notochord. In Xenopus laevis Xbra (the Xenopus T homologue, also recently renamed t) is expressed in the mesodermal marginal zone of the pre-gastrula embryo followed by localisation to the blastopore and notochord at the mid-gastrula stage. The Danio rerio homologue is known as ntl (no tail) # Cancer Expression of the brachyury gene has been identified as a definitive diagnostic marker of chordoma, a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae.[11] Furthermore, germ line duplication of brachyury confers major susceptibility to chordoma. The chromosomal region on 6q27 containing the brachyury gene was gained in 6 of 21 chordomas (29%), and none of the 21 chordomas analyzed showed deletions that could have affected this gene. Brachyury is an important factor in promoting the epithelial-mesenchymal transition (EMT). Cells that over-express brachyury have down-regulated expression of the adhesion molecule E-cadherin, which allows them to undergo EMT. This process is at least partially mediated by the transcription factors AKT[12] and Snail.[13] Overexpression of brachyury has been linked to Hepatocellular carcinoma (HCC, also called malignant hepatoma), a common type of liver cancer. While brachyury is promoting EMT, it can also induce metastasis of HCC cells. Brachyury expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.[12] Additionally, overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis.[13] Brachyury is overexpressed in a number of tumor types.	https://www.wikidoc.org/index.php/Brachyury
9aa2e1b310f9dfa175b049725dbb433129db1ec4	wikidoc	Brain fog	Brain fog # Overview Brain fog is a term for the "woolly" sensation of a physical obstruction to clear thinking in the brain, often extended to apply in general to neurocognitive symptoms experienced by many people who suffer from diseases such as ME/CFS, fibromyalgia, amongst others. # Pathophysiology Brain fog can be brought on by upregulated cytokines, neurotransmitter misregulation, or psychological trauma amongst others. Hence it shares common etiology with some mental disorders like depression, bipolar disorder, etc. There have been no studies to explore the causes of brain fog, but since it shares so many of its symptoms with mental disorders it's reasonable to assume that brain fog may be due to frontal lobe hypometabolism, or temporal lobe dysfunction which occur in unipolar depression. # Differentiating Brain Fog from other Disorders Brain fog is not recognized by medical science, and there have been no clinical studies to prove its existence. Some clinicans maintain that brain fog is a form of conversion or somatization disorder. Since brain fog is very similar to symptoms of mental illness, it's possible that persons who report brain fog are actually suffering from mental disorder including depression, schizophrenia, or bipolar disorder. In particular brain fog is very similar to the decrease in concentration in depression and the depressive phase of bipolar disorder and thought blocking which occurs in schizophrenia. # Diagnosis ## Symptoms It can be a symptom of other psychiatric disorders such as schizophrenia, bipolar disorder, or clinical depression. The term brain fog is also often used to describe the relevant symptom or symptoms of inattentive ADHD or resulting from chemotherapy.. Many sufferers of the medical condition Superior canal dehiscence syndrome (SCDS) report experiencing brain fog. Brain fog involves persistent or episodic cognitive dysfunction, and may be associated with forgetfulness, confusion, slowed thinking, distractability, depersonalization, the inability to remember the correct words when speaking or writing (dysphasia or aphasia). Brain fog is so named because the sufferer can feel like a cloud literally surrounds him or her that reduces the speed at which things can be recognized or clearly seen. Sufferers describe it as "feeling like a hangover" or "zoning out" Brain fog may promote feelings of detachment (depersonalization), discouragement and depression. ## Imaging Studies SPECT, PET and brain MRI scans can be used to determine brain functionality. Neuropsychiatric tests may also be performed. # Treatment Treatment with psychotherapy is sometimes recommended. However many M.E sufferers have found psychotherapy unhelpful and exhausting, preferring illness management techniques such as a brief nap at the first signs of brainfog. If a more serious pathology is present psychopharmacology may be beneficial. Neurofeedback is also showing to be effective in the treatment of brain fog.	Brain fog Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Brain fog is a term for the "woolly" sensation of a physical obstruction to clear thinking in the brain, often extended to apply in general to neurocognitive symptoms experienced by many people who suffer from diseases such as ME/CFS, fibromyalgia, amongst others. # Pathophysiology Brain fog can be brought on by upregulated cytokines, neurotransmitter misregulation, or psychological trauma amongst others. Hence it shares common etiology with some mental disorders like depression, bipolar disorder, etc. There have been no studies to explore the causes of brain fog, but since it shares so many of its symptoms with mental disorders it's reasonable to assume that brain fog may be due to frontal lobe hypometabolism, or temporal lobe dysfunction which occur in unipolar depression. # Differentiating Brain Fog from other Disorders Brain fog is not recognized by medical science, and there have been no clinical studies to prove its existence. Some clinicans maintain that brain fog is a form of conversion or somatization disorder. Since brain fog is very similar to symptoms of mental illness, it's possible that persons who report brain fog are actually suffering from mental disorder including depression, schizophrenia, or bipolar disorder. In particular brain fog is very similar to the decrease in concentration in depression and the depressive phase of bipolar disorder and thought blocking which occurs in schizophrenia. # Diagnosis ## Symptoms It can be a symptom of other psychiatric disorders such as schizophrenia, bipolar disorder, or clinical depression. The term brain fog is also often used to describe the relevant symptom or symptoms of inattentive ADHD or resulting from chemotherapy.[1]. Many sufferers of the medical condition Superior canal dehiscence syndrome (SCDS) report experiencing brain fog. Brain fog involves persistent or episodic cognitive dysfunction, and may be associated with forgetfulness, confusion, slowed thinking, distractability, depersonalization, the inability to remember the correct words when speaking or writing (dysphasia or aphasia). Brain fog is so named because the sufferer can feel like a cloud literally surrounds him or her that reduces the speed at which things can be recognized or clearly seen. Sufferers describe it as "feeling like a hangover" or "zoning out" Brain fog may promote feelings of detachment (depersonalization), discouragement and depression. ## Imaging Studies SPECT, PET and brain MRI scans can be used to determine brain functionality. Neuropsychiatric tests may also be performed. # Treatment Treatment with psychotherapy is sometimes recommended. However many M.E sufferers have found psychotherapy unhelpful and exhausting, preferring illness management techniques such as a brief nap at the first signs of brainfog. If a more serious pathology is present psychopharmacology may be beneficial. Neurofeedback is also showing to be effective in the treatment of brain fog.[citation needed]	https://www.wikidoc.org/index.php/Brain_fog
5e3303634ab02583fba42efe7788301bc899adcc	wikidoc	Brain zap	Brain zap # Overview Brain zaps, also known as "brain shocks," "brain shivers," or "head shocks" are a fairly common withdrawal symptom experienced during discontinuation (or reduction of dose) of SSRI and SNRI antidepressant drugs. The symptom is described as brief but repeated electric shock-like sensations in the brain and head. The effect is not only confined to withdrawal periods for all sufferers, but also are experienced while actually taking the prescribed medication (although less commonly), and have been known to continue for years after withdrawal from the associated medication. The phenomenon is most commonly associated with paroxetine (Paxil, Seroxat), fluoxetine (Prozac), venlafaxine (Effexor), sertraline (Zoloft), duloxetine (Cymbalta), fluvoxamine (Luvox), citalopram (Celexa) and escitalopram (Lexapro). In more recent years, drug companies have added to their list of potential side-effects of many of these medications the possibility of "sensory disturbances", believed to be in reference to the strengthening body of anecdotal evidence about this phenomenon's existence. # Description "Brain zaps" are said to defy description for whomever has not experienced them, but the most common themes are of a sudden "jolt," likened to an electric shock, apparently occurring or originating within the brain itself, with associated disorientation for a few seconds. The phenomenon is most often reported as a brief, wave-like electrical pulse that quickly travels across the surface of (or through) the brain. Some people experience these "waves" through the rest of their body, but the sensation dissipates quickly. They are sometimes accompanied by brief tinnitus and vertigo-like feelings. Immediately following this shock is a light-headedness that may last for up to ten seconds. The sensation has also be described by many as a flashbulb going off inside the head or brain. Moving one's eyes from side to side quickly while open has also been known to trigger these zaps and sometimes causing them to come in rapid succession. It is thought to be a form of neuro-epileptiform activity. As withdrawal time increases, the frequency of the shocks decreases. At their peak, brain zaps have been associated with severe headaches. They may last for a period of several weeks after the last dose and usually resolve completely within a month or two. However, anecdotal reports of "zaps" during a protracted withdrawal are known to last a year or longer. # Mechanism of Action Paresthesia and "electric shock sensations" are clinical terms used to describe this symptom, though paresthesia by definition is clinically incorrect. The "brain zap" effect appears to be nearly unique to serotonergic drug formulations which have an extremely short elimination half-life; that is, they are more quickly metabolized by the liver and leave the general circulation faster than longer half-life antidepressants such as fluoxetine (Prozac). This attribute of abruptness leaves the brain a relatively short time to adapt to a major neurochemical change when the medication is stopped, and the symptoms may be caused by the brain's attempt at readjustment. There is no current evidence that these "zaps" present any danger to the patient experiencing them and have rarely been reported as painful however they can be very disconcerting to those patients who have no prior warning or knowledge of them . Many medical professionals are still unaware of the possible occurrence of this phenomenon. Tranylcypromine (Parnate) used at high doses has also been known for causing brain zaps, which may, in some cases, start at the base of the spine and progress to the head, or may occur exclusively in the head. Brain zaps have also been commonly reported following periods of heavy use of the drug MDMA (Ecstasy).	Brain zap Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Brain zaps, also known as "brain shocks," "brain shivers," or "head shocks" are a fairly common withdrawal symptom experienced during discontinuation (or reduction of dose) of SSRI and SNRI antidepressant drugs. The symptom is described as brief but repeated electric shock-like sensations in the brain and head. The effect is not only confined to withdrawal periods for all sufferers, but also are experienced while actually taking the prescribed medication (although less commonly), and have been known to continue for years after withdrawal from the associated medication. The phenomenon is most commonly associated with paroxetine (Paxil, Seroxat), fluoxetine (Prozac), venlafaxine (Effexor), sertraline (Zoloft), duloxetine (Cymbalta), fluvoxamine (Luvox), citalopram (Celexa) and escitalopram (Lexapro). In more recent years, drug companies have added to their list of potential side-effects of many of these medications the possibility of "sensory disturbances", believed to be in reference to the strengthening body of anecdotal evidence about this phenomenon's existence. # Description "Brain zaps" are said to defy description for whomever has not experienced them, but the most common themes are of a sudden "jolt," likened to an electric shock, apparently occurring or originating within the brain itself, with associated disorientation for a few seconds. The phenomenon is most often reported as a brief, wave-like electrical pulse that quickly travels across the surface of (or through) the brain. Some people experience these "waves" through the rest of their body, but the sensation dissipates quickly. They are sometimes accompanied by brief tinnitus and vertigo-like feelings. Immediately following this shock is a light-headedness that may last for up to ten seconds. The sensation has also be described by many as a flashbulb going off inside the head or brain. Moving one's eyes from side to side quickly while open has also been known to trigger these zaps and sometimes causing them to come in rapid succession. It is thought to be a form of neuro-epileptiform activity. [1][2] As withdrawal time increases, the frequency of the shocks decreases. At their peak, brain zaps have been associated with severe headaches. They may last for a period of several weeks after the last dose and usually resolve completely within a month or two. However, anecdotal reports of "zaps" during a protracted withdrawal are known to last a year or longer. # Mechanism of Action Paresthesia and "electric shock sensations" are clinical terms used to describe this symptom, though paresthesia by definition is clinically incorrect. The "brain zap" effect appears to be nearly unique to serotonergic drug formulations which have an extremely short elimination half-life; that is, they are more quickly metabolized by the liver and leave the general circulation faster than longer half-life antidepressants such as fluoxetine (Prozac). This attribute of abruptness leaves the brain a relatively short time to adapt to a major neurochemical change when the medication is stopped, and the symptoms may be caused by the brain's attempt at readjustment. There is no current evidence that these "zaps" present any danger to the patient experiencing them and have rarely been reported as painful however they can be very disconcerting to those patients who have no prior warning or knowledge of them . Many medical professionals are still unaware of the possible occurrence of this phenomenon. Tranylcypromine (Parnate) used at high doses has also been known for causing brain zaps, which may, in some cases, start at the base of the spine and progress to the head, or may occur exclusively in the head. Brain zaps have also been commonly reported following periods of heavy use of the drug MDMA (Ecstasy).	https://www.wikidoc.org/index.php/Brain_shivers
c6c1d73a849b37e229a1ed1f3f751ae3372173e7	wikidoc	Mastopexy	Mastopexy # Overview Mastopexy or breast lift surgery refers to a group of elective surgical operations designed to lessen the degree of breast ptosis (the "droop" of the breasts). Many patients opt for mastopexy alone. When breast implants are placed as part of the procedure, it is known as a breast augmentation. The shape of a breast is determined by its skin, its volume and by its connective tissue. Mastopexy procedures may change any of these by reshaping the skin 'bra', by adding volume with implants, or by altering the structure of the breast tissue. # Procedures ## Full breast lift ### Procedure The full breast lift involves an incision along the crease underneath the breast, incisions around the areola, and a vertical incision between the areola and the base of the breast. This incision is sometimes called an "anchor incision" because of its shape. It is also sometimes called the Wise pattern, after Robert Wise, who described this incision and its use for breast reduction. This approach allows maximal change to the breast, with elevation of the nipple, as well as a redesign of the conical shape of the breast. ### Scarring The scar is in three distinct locations that each have a characteristic pattern of healing. In the peri-areolar area, scarring is partially concealed by the change in color at the transition from breast skin to the pigmented skin of the areola. The vertical incision from the areola to the crease may be hidden in shadow. The inframmary portion of the scar, along the fold created by the breast is often the thickest of the scars, but it may be hidden in the inframammary fold. ## Modified breast lifts ### Procedure Modified breast lifts use fewer incisions than the full procedure. A popular form of the modified breast lift is the Benelli breast lift, otherwise known as the concentric mastopexy. This uses only an incision around the areola. ### Scarring An advantage of this procedure is that there is less scarring, with scarring only around the areola. A drawback is that there can be less change made to the breast's shape, and scars are prone to scar hypertrophy or stretching of the scar. Benelli procedures are frequently performed along with breast augmentation in order to overcome the inability to produce a more conical breast with the anchor or Wise pattern incision. This procedure is criticized because of the tendency to flatten the breast. # Length of effects In most cases, aging breast tissue will not maintain the shape that the mastopexy initially brought. Usually, gravity will eventually cause ptosis to return to some degree. Surgeons may choose to take into account the design of the mastopexy, and choose to make a more pronounced change which will be apparent for the first month or two after surgery. The design may relax into the desired position as the skin redrapes for two months post-operation.	Mastopexy Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2] # Overview Mastopexy or breast lift surgery refers to a group of elective surgical operations designed to lessen the degree of breast ptosis (the "droop" of the breasts). Many patients opt for mastopexy alone. When breast implants are placed as part of the procedure, it is known as a breast augmentation. The shape of a breast is determined by its skin, its volume and by its connective tissue. Mastopexy procedures may change any of these by reshaping the skin 'bra', by adding volume with implants, or by altering the structure of the breast tissue. # Procedures ## Full breast lift ### Procedure The full breast lift involves an incision along the crease underneath the breast, incisions around the areola, and a vertical incision between the areola and the base of the breast. This incision is sometimes called an "anchor incision" because of its shape. It is also sometimes called the Wise pattern, after Robert Wise, who described this incision and its use for breast reduction. This approach allows maximal change to the breast, with elevation of the nipple, as well as a redesign of the conical shape of the breast. ### Scarring The scar is in three distinct locations that each have a characteristic pattern of healing. In the peri-areolar area, scarring is partially concealed by the change in color at the transition from breast skin to the pigmented skin of the areola. The vertical incision from the areola to the crease may be hidden in shadow. The inframmary portion of the scar, along the fold created by the breast is often the thickest of the scars, but it may be hidden in the inframammary fold. ## Modified breast lifts ### Procedure Modified breast lifts use fewer incisions than the full procedure. A popular form of the modified breast lift is the Benelli breast lift, otherwise known as the concentric mastopexy. This uses only an incision around the areola. ### Scarring An advantage of this procedure is that there is less scarring, with scarring only around the areola. A drawback is that there can be less change made to the breast's shape, and scars are prone to scar hypertrophy or stretching of the scar. Benelli procedures are frequently performed along with breast augmentation in order to overcome the inability to produce a more conical breast with the anchor or Wise pattern incision. This procedure is criticized because of the tendency to flatten the breast. # Length of effects In most cases, aging breast tissue will not maintain the shape that the mastopexy initially brought. Usually, gravity will eventually cause ptosis to return to some degree. Surgeons may choose to take into account the design of the mastopexy, and choose to make a more pronounced change which will be apparent for the first month or two after surgery. The design may relax into the desired position as the skin redrapes for two months post-operation.	https://www.wikidoc.org/index.php/Breast_lift
9e9857e1f20e33d5b515d6bb46da331eaf75d57b	wikidoc	Breathing	Breathing # Overview Breathing transports oxygen into the body and carbon dioxide out of the body. Aerobic organisms require oxygen to create energy via respiration, in the form of energy-rich molecules such as glucose. The medical term for normal relaxed breathing is eupnoea. Organisms breathe to avoid death from asphyxiation. # Mechanics Breathing in, or inhaling, is usually an active movement, with the contraction of the diaphragm muscles needed. At rest, breathing out, or exhaling, is normally a passive process powered by the elastic recoil of the chest, similar to a deflating balloon. The following organs are used in respiration: mouth, nose, gullet, windpipe, lungs, diaphragm. # Gas exchange Breathing is only part of the process of delivering oxygen to where it is needed in the body. The process of gas exchange occurs in the alveoli by passive diffusion of gases between the alveolar gas and the blood passing by in the lung capillaries. Once in the blood the heart powers the flow of dissolved gases around the body in the circulation. As well as carbon dioxide, breathing also results in loss of water from the body. Exhaled air has a relative humidity of 100% because of water diffusing across the moist surface of breathing passages and alveoli. # Control of breathing Breathing is one of the few bodily functions which, within limits, can be controlled both consciously and unconsciously. ## Conscious control Conscious attention to breathing is common in many forms of meditation, specifically anapana and other forms of yoga. In swimming, cardio fitness, speech or vocal training, one learns to discipline one's breathing, initially consciously but later sub-consciously, for purposes other than life support. ## Unconscious control Unconsciously, breathing is controlled by specialized centers in the brainstem, which automatically regulate the rate and depth of breathing depending on the body’s needs at any time. When carbon dioxide levels increase in the blood, it reacts with the water in blood, producing carbonic acid. Lactic acid produced by anaerobic exercise also lowers pH. The drop in the blood's pH stimulates chemoreceptors in the carotid and aortic bodies in the blood system to send nerve impulses to the respiration centre in the medulla oblongata and pons in the brain. These, in turn send nerve impulses through the phrenic and thoracic nerves to the diaphragm and the intercostal muscles, increasing the rate of breathing. This automatic control of respiration can be impaired in premature babies, or by drugs or disease. ### Examples For instance, while exercising, the level of carbon dioxide in the blood increases due to increased cellular respiration by the muscles, which activates carotid and aortic bodies and the respiration center, which ultimately cause a higher rate of respiration. During rest, the level of carbon dioxide is lower, so breathing rate is lower. This ensures an appropriate amount of oxygen is delivered to the muscles and other organs. It is important to reiterate that it is the buildup of carbon dioxide making the blood acidic that elicits the desperation for a breath much more than lack of oxygen. ## Interaction It is not possible for a healthy person to voluntarily stop breathing indefinitely. If we do not inhale, the level of carbon dioxide builds up in our blood, and we experience overwhelming air hunger. This irrepressible reflex is not surprising given that without breathing, the body's internal oxygen levels drop dangerously low within minutes, leading to permanent brain damage followed eventually by death. However, there have been instances where people have survived for as long as two hours without air; this is only possible when submerged in cold water, as this triggers the mammalian diving reflex. If a healthy person were to voluntarily stop breathing (i.e. hold his or her breath) for a long enough amount of time, he or she would lose consciousness, and the body would resume breathing on its own. Because of this one cannot suffocate oneself with this method, unless one's breathing was also restricted by something else (e.g. water, see drowning) Hyperventilating causes a drop in CO2 below normal levels, lowering blood acidity to trick the brain into thinking it has more oxygen than is actually present. Hyperventilating can cause your blood oxygen levels to go to dangerous levels. # Relationship to death Breath is sometimes used as a metaphor for life itself, and often "last breath" is the most obvious sign that death has occurred. The association between the end of life and breathing is not absolute, however. As modern treatment can now take over the process of breathing by mechanical ventilation, or cardiopulmonary resuscitation (CPR), breathing can be restarted if it stops. Because of this, modern deaths are now better defined in terms of brain dysfunction. # Composition of air The air we inhale is roughly 78% nitrogen, 21% oxygen, 0.96% argon and 0.04% carbon dioxide, helium, water, and other gases. (% by volume) The permanent gases in air we exhale are roughly 78% nitrogen, 15% to 18% oxygen, 4% to 5% carbon dioxide and 0.96% argon (% by volume). Additionally vapors and trace gases are present: 5% water vapor, several parts per million (ppm) of hydrogen and carbon monoxide, 1 part per million (ppm) of ammonia and less than 1 ppm of acetone, methanol, ethanol and other volatile organic compounds. Not all of the oxygen breathed in is replaced by carbon dioxide; around 15% to 18% of what we breathe out is still oxygen. The exact amount of exhaled oxygen and carbon dioxide varies according to the fitness, energy expenditure and diet of that particular person. Also our reliance on this relatively small amount of oxygen can cause overactivity or euphoria in pure or oxygen rich environments. # Cultural significance In Tai Chi Chuan, aerobic training is combined with breathing to exercise the diaphram muscles, and to train effective posture, which both make better use of the body's energy. In music, breath is used to play wind instruments and many aerophones. Laughter, physically, is simply repeated sharp breaths. Hiccups and yawns are other breath-related phenomena. Ancients commonly linked the breath to a life force. The Hebrew Bible refers to God breathing the breath of life into clay to make Adam a living soul (nephesh, roughly "breather"). It also refers to the breath as returning to God when a mortal dies. The terms "spirit," "qi," and "psyche" are related to the concept of breath.	Breathing Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Breathing transports oxygen into the body and carbon dioxide out of the body. Aerobic organisms require oxygen to create energy via respiration, in the form of energy-rich molecules such as glucose. The medical term for normal relaxed breathing is eupnoea. Organisms breathe to avoid death from asphyxiation. # Mechanics Breathing in, or inhaling, is usually an active movement, with the contraction of the diaphragm muscles needed. At rest, breathing out, or exhaling, is normally a passive process powered by the elastic recoil of the chest, similar to a deflating balloon. The following organs are used in respiration: mouth, nose, gullet, windpipe, lungs, diaphragm. # Gas exchange Breathing is only part of the process of delivering oxygen to where it is needed in the body. The process of gas exchange occurs in the alveoli by passive diffusion of gases between the alveolar gas and the blood passing by in the lung capillaries. Once in the blood the heart powers the flow of dissolved gases around the body in the circulation. As well as carbon dioxide, breathing also results in loss of water from the body. Exhaled air has a relative humidity of 100% because of water diffusing across the moist surface of breathing passages and alveoli. # Control of breathing Breathing is one of the few bodily functions which, within limits, can be controlled both consciously and unconsciously. ## Conscious control Conscious attention to breathing is common in many forms of meditation, specifically anapana and other forms of yoga. In swimming, cardio fitness, speech or vocal training, one learns to discipline one's breathing, initially consciously but later sub-consciously, for purposes other than life support. ## Unconscious control Unconsciously, breathing is controlled by specialized centers in the brainstem, which automatically regulate the rate and depth of breathing depending on the body’s needs at any time. When carbon dioxide levels increase in the blood, it reacts with the water in blood, producing carbonic acid. Lactic acid produced by anaerobic exercise also lowers pH. The drop in the blood's pH stimulates chemoreceptors in the carotid and aortic bodies in the blood system to send nerve impulses to the respiration centre in the medulla oblongata and pons in the brain. These, in turn send nerve impulses through the phrenic and thoracic nerves to the diaphragm and the intercostal muscles, increasing the rate of breathing. This automatic control of respiration can be impaired in premature babies, or by drugs or disease. ### Examples For instance, while exercising, the level of carbon dioxide in the blood increases due to increased cellular respiration by the muscles, which activates carotid and aortic bodies and the respiration center, which ultimately cause a higher rate of respiration. During rest, the level of carbon dioxide is lower, so breathing rate is lower. This ensures an appropriate amount of oxygen is delivered to the muscles and other organs. It is important to reiterate that it is the buildup of carbon dioxide making the blood acidic that elicits the desperation for a breath much more than lack of oxygen. ## Interaction It is not possible for a healthy person to voluntarily stop breathing indefinitely. If we do not inhale, the level of carbon dioxide builds up in our blood, and we experience overwhelming air hunger. This irrepressible reflex is not surprising given that without breathing, the body's internal oxygen levels drop dangerously low within minutes, leading to permanent brain damage followed eventually by death. However, there have been instances where people have survived for as long as two hours without air; this is only possible when submerged in cold water, as this triggers the mammalian diving reflex.[1] If a healthy person were to voluntarily stop breathing (i.e. hold his or her breath) for a long enough amount of time, he or she would lose consciousness, and the body would resume breathing on its own. Because of this one cannot suffocate oneself with this method, unless one's breathing was also restricted by something else (e.g. water, see drowning) Hyperventilating causes a drop in CO2 below normal levels, lowering blood acidity to trick the brain into thinking it has more oxygen than is actually present. Hyperventilating can cause your blood oxygen levels to go to dangerous levels. # Relationship to death Breath is sometimes used as a metaphor for life itself, and often "last breath" is the most obvious sign that death has occurred. The association between the end of life and breathing is not absolute, however. As modern treatment can now take over the process of breathing by mechanical ventilation, or cardiopulmonary resuscitation (CPR), breathing can be restarted if it stops. Because of this, modern deaths are now better defined in terms of brain dysfunction. # Composition of air The air we inhale is roughly 78% nitrogen, 21% oxygen, 0.96% argon and 0.04% carbon dioxide, helium, water, and other gases. (% by volume) The permanent gases in air we exhale are roughly 78% nitrogen, 15% to 18% oxygen, 4% to 5% carbon dioxide and 0.96% argon (% by volume). Additionally vapors and trace gases are present: 5% water vapor, several parts per million (ppm) of hydrogen and carbon monoxide, 1 part per million (ppm) of ammonia and less than 1 ppm of acetone, methanol, ethanol and other volatile organic compounds. Not all of the oxygen breathed in is replaced by carbon dioxide; around 15% to 18% of what we breathe out is still oxygen. The exact amount of exhaled oxygen and carbon dioxide varies according to the fitness, energy expenditure and diet of that particular person. Also our reliance on this relatively small amount of oxygen can cause overactivity or euphoria in pure or oxygen rich environments. # Cultural significance In Tai Chi Chuan, aerobic training is combined with breathing to exercise the diaphram muscles, and to train effective posture, which both make better use of the body's energy. In music, breath is used to play wind instruments and many aerophones. Laughter, physically, is simply repeated sharp breaths. Hiccups and yawns are other breath-related phenomena. Ancients commonly linked the breath to a life force. The Hebrew Bible refers to God breathing the breath of life into clay to make Adam a living soul (nephesh, roughly "breather"). It also refers to the breath as returning to God when a mortal dies. The terms "spirit," "qi," and "psyche"[2] are related to the concept of breath.	https://www.wikidoc.org/index.php/Breath
d52bce2b426107bc3c4f47a2127f4d0688ebfb61	wikidoc	Platypnea	Platypnea # Overview Platypnea refers to shortness of breath (dyspnea) that is relieved when lying down, and worsens when sitting or standing up. It is the opposite of orthopnea. The word is derived from the Greek platus (= flat) and pnoia (=breath). # Causes - Left atrial thrombus - Left atrial tumors - Pulmonary arteriovenous fistula Platypnea is due to either hepatopulmonary syndrome or an anatomical cardiovascular defect increasing positional right-to-left shunting (bloodflow from the right to the left part of the circulatory system). These defects include rare syndromes in which the venous blood from the liver does not pass through the lungs, or if venous blood from the portal circulation reaches the inferior vena cava without passing through the liver (Abernethy malformation, type 1). Insufficiency of abdominal muscles causes lower diaphragm position and dyspnea. In clinostatism, abdominal organs push the diaphragm in its normal, upper position, reducing the respiratory effort.	Platypnea Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Platypnea refers to shortness of breath (dyspnea) that is relieved when lying down,[1] and worsens when sitting or standing up. It is the opposite of orthopnea. The word is derived from the Greek platus (= flat) and pnoia (=breath). # Causes - Left atrial thrombus - Left atrial tumors - Pulmonary arteriovenous fistula Platypnea is due to either hepatopulmonary syndrome or an anatomical cardiovascular defect increasing positional right-to-left shunting (bloodflow from the right to the left part of the circulatory system). These defects include rare syndromes in which the venous blood from the liver does not pass through the lungs, or if venous blood from the portal circulation reaches the inferior vena cava without passing through the liver (Abernethy malformation, type 1). Insufficiency of abdominal muscles causes lower diaphragm position and dyspnea. In clinostatism, abdominal organs push the diaphragm in its normal, upper position, reducing the respiratory effort.	https://www.wikidoc.org/index.php/Breathing_difficulty_that_is_relieved_when_lying_flat
119c89311c9084f84e34eb440a3611e9d8ab93e0	wikidoc	Bretylium	Bretylium # Overview Bretylium (also bretylium tosylate) is an antiarrhythmic agent. It blocks the release of noradrenaline from nerve terminals. In effect, it decreases output from the peripheral sympathetic nervous system. It also acts by blocking K+ channels and is considered a class III antiarrhythmic. The dose is 5–10 mg/kg and side effects are high blood pressure followed by low blood pressure and ventricular ectopy. Originally introduced in 1959 for the treatment of hypertension. Its use as an antiarrhythmic for ventricular fibrilation was discovered and patented by Marvin Bacaner in 1969 at the University of Minnesota. The American Heart Association removed Bretylium from their 2000 ECC/ACC guidelines due to its unproven efficacy and ongoing supply problems. Many have cited these supply problems as an issue of raw materials needed in the production of Bretylium. By the release of the AHA 2005 ECC/ACC guidelines there is no mention of Bretylium and it is virtually unavailable throughout most of the world. As of June 8, 2011 Bretylium Tosylate is permanently no longer available in the US after request of Hospira Inc. to withdraw its NDA from the market. Bretylium will remain on the FDA's discontinued drug list since its withdrawal was not the result of a safety or effectiveness concern. # Uses It was used in emergency medicine, cardiology, and other specialties throughout the 1980s-1990s for the acute management of ventricular tachycardia and ventricular fibrillation refractory to other first line treatments such as defibrillation or lidocaine. It is contraindicated in patients with AV (atrioventricular) heart block or digoxin toxicity. Bretylium should be used only in an ICU or Emergency Department setting and should not be used elsewhere due to its dramatic actions and its predominant side effect of hypotension. # Experimental Uses It is used in physiological and pharmacological research as an inhibitor of sympathetic transmission. Its mechanism of action is the inhibition of neurotransmitter release from sympathetic nerve terminals, both by the inhibition of action potentials in the nerve terminals and by other mechanisms. Its specificity for sympathetic nerves is achieved because it is a substrate for the noradrenaline transporter; hence, it accumulates inside nerve terminals which have this transporter. # Synthesis Quaternization of o-bromo-N,N-dimethylbenzylamine with ethyl-p-toluenesulfonate yields bretylium sulfonate.	Bretylium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bretylium (also bretylium tosylate) is an antiarrhythmic agent.[1] It blocks the release of noradrenaline from nerve terminals. In effect, it decreases output from the peripheral sympathetic nervous system. It also acts by blocking K+ channels and is considered a class III antiarrhythmic. The dose is 5–10 mg/kg and side effects are high blood pressure followed by low blood pressure and ventricular ectopy. Originally introduced in 1959 for the treatment of hypertension.[2] Its use as an antiarrhythmic for ventricular fibrilation was discovered and patented by Marvin Bacaner in 1969 at the University of Minnesota.[3] The American Heart Association removed Bretylium from their 2000 ECC/ACC guidelines due to its unproven efficacy and ongoing supply problems. Many have cited these supply problems as an issue of raw materials needed in the production of Bretylium. By the release of the AHA 2005 ECC/ACC guidelines there is no mention of Bretylium and it is virtually unavailable throughout most of the world.[4][5] As of June 8, 2011 Bretylium Tosylate is permanently no longer available in the US after request of Hospira Inc. to withdraw its NDA from the market. Bretylium will remain on the FDA's discontinued drug list since its withdrawal was not the result of a safety or effectiveness concern.[6] # Uses It was used in emergency medicine, cardiology, and other specialties throughout the 1980s-1990s for the acute management of ventricular tachycardia and ventricular fibrillation refractory to other first line treatments such as defibrillation or lidocaine.[7] It is contraindicated in patients with AV (atrioventricular) heart block or digoxin toxicity. Bretylium should be used only in an ICU or Emergency Department setting and should not be used elsewhere due to its dramatic actions and its predominant side effect of hypotension. # Experimental Uses It is used in physiological and pharmacological research as an inhibitor of sympathetic transmission. Its mechanism of action is the inhibition of neurotransmitter release from sympathetic nerve terminals, both by the inhibition of action potentials in the nerve terminals and by other mechanisms.[8] Its specificity for sympathetic nerves is achieved because it is a substrate for the noradrenaline transporter;[9] hence, it accumulates inside nerve terminals which have this transporter. # Synthesis Quaternization of o-bromo-N,N-dimethylbenzylamine with ethyl-p-toluenesulfonate yields bretylium sulfonate.	https://www.wikidoc.org/index.php/Bretylium
c221b4778ba20e6db3d8a9f975e9a5d79b9a98f6	wikidoc	Brivudine	Brivudine # Overview Brivudine is an antiviral drug used in the treatment of herpes zoster. # History Brivudine is a similar drug to acyclovir. The compound was first synthesized by scientists at the University of Birmingham in the UK in the 1970s. It was shown to be a potent inhibitor of the herpes simplex virus Type 1 (HSV-1) as well as the varicella zoster virus (VZV) by Erik De Clercq at the Rega Institute for Medical Research in Belgium in 1979. In the 1980s the drug became commercially available in East Germany, where it was marketed as Helpin by a pharmaceutical company called Berlin-Chemie. # Approvals Brivudine is approved for use in Germany and other European countries including Italy. # Mechanism of Action Brivudine is an analogue of the nucleoside thymidine. The drug works because it is able to be incorporated into the viral DNA, but then blocks the action of DNA polymerases, thus inhibiting viral replication. The active compound is the 5'-triphosphate of BVDU, which is formed in subsequent phosphorylations by viral thymidine kinase and presumably by nucleoside diphosphate kinase. # Research A Cochrane Systematic Review examined the effectiveness of multiple antiviral drugs in the treatment of herpes simplex virus epithelial keratitis. Brivudine was found to be significantly more effective than idoxuridine in increasing the number of successfully healed eyes of participants. # The drug's name Brivudine derives from the drug's chemical name of bromovinyldeoxyuridine or BVDU for short. The drug's full chemical description is (E)-5-(2-bromovinyl)-2-deoxyuridine. It is also sold as Bridic, Brivox, Brivudin, Helpin, Zerpex, Zonavir and Zostex. # Suppliers Brivudine main supplier is Berlin-Chemie, now part of Italy's Menarini Group. The drug is approved for sale in Austria, Belgium, Germany, Greece, Italy, Luxembourg, Portugal and Spain. In Central America is provided Menarini Centro America and Wyeth.	Brivudine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Brivudine is an antiviral drug used in the treatment of herpes zoster. # History Brivudine is a similar drug to acyclovir[clarification needed]. The compound was first synthesized by scientists at the University of Birmingham in the UK in the 1970s. It was shown to be a potent inhibitor of the herpes simplex virus Type 1 (HSV-1) as well as the varicella zoster virus (VZV) by Erik De Clercq at the Rega Institute for Medical Research in Belgium in 1979. In the 1980s the drug became commercially available in East Germany, where it was marketed as Helpin by a pharmaceutical company called Berlin-Chemie. # Approvals Brivudine is approved for use in Germany and other European countries including Italy. # Mechanism of Action Brivudine is an analogue of the nucleoside thymidine. The drug works because it is able to be incorporated into the viral DNA, but then blocks the action of DNA polymerases, thus inhibiting viral replication. The active compound is the 5'-triphosphate of BVDU, which is formed in subsequent phosphorylations by viral thymidine kinase and presumably by nucleoside diphosphate kinase. # Research A Cochrane Systematic Review examined the effectiveness of multiple antiviral drugs in the treatment of herpes simplex virus epithelial keratitis. Brivudine was found to be significantly more effective than idoxuridine in increasing the number of successfully healed eyes of participants.[1] # The drug's name Brivudine derives from the drug's chemical name of bromovinyldeoxyuridine or BVDU for short. The drug's full chemical description is (E)-5-(2-bromovinyl)-2-deoxyuridine. It is also sold as Bridic, Brivox, Brivudin, Helpin, Zerpex, Zonavir and Zostex. # Suppliers Brivudine main supplier is Berlin-Chemie, now part of Italy's Menarini Group. The drug is approved for sale in Austria, Belgium, Germany, Greece, Italy, Luxembourg, Portugal and Spain. In Central America is provided Menarini Centro America and Wyeth.	https://www.wikidoc.org/index.php/Brivudine
c745e91f3525c58bb4d680c07238442c426e73ca	wikidoc	Bromelain	Bromelain Bromelain can refer to one of two protease enzymes extracted from the plant family Bromeliaceae, or it can refer to a combination of those enzymes along with other compounds produced in an extract. # Components Bromelain is a mixture of sulfur-containing protein-digesting enzymes—called proteolytic enzymes or proteases—and several other substances in smaller quantities. The two main enzymes are: - stem bromelain - EC 3.4.22.32 - fruit bromelain - EC 3.4.22.33 The other substances include peroxidase, acid phosphatase, protease inhibitors, and calcium. # History The first isolation of bromelain was recorded by the Venezuelan chemist Vicente Marcano (BU1 1.Phar. 5,77) in 1891 from the fruit of pineapple. In 1892, Chittenden, assisted by Joslin and Meara, investigated the matter fully (Trans. Conn. Acad. Arts Sci. 8, 281-308), and called it 'bromelin'. Later the term 'bromelain' was introduced and originally applied to any protease from any plant member of the plant family Bromeliaceae. Bromelain was first introduced as a therapeutic supplement in 1957. Research on bromelain apparently was first conducted in Hawaii but more recently has been conducted in countries in Asia, Europe and Latin America. Germany has recently taken a great interest in bromelain research; bromelain is currently the 13th most widely used herbal medicine in Germany. # Source Bromelain is present in all parts of the pineapple plant (Ananas comosus) but the stem is the most common commercial source, presumably because it is readily available after the fruit has been harvested. Pineapples have had a long tradition as a medicinal plant among the natives of South and Central America. However, just eating pineapple will not give you a great deal of extra bromelain, because it is mostly concentrated in the stem, which is not nearly as tasty (albeit still edible). # Uses ## Meat tenderizing Along with papain, Bromelain is one of the most popular substances to use for meat tenderizing. Historically, meat tenderizing enzymes were often injected into the muscle of a food animal while it was still living. This practice was deemed unethical, and has been largely discontinued, replaced with various postmortem application methods which are acceptable for lesser quality cuts. Today, approximately 90% of meat tenderizer use is in consumer households. Bromelain is sold in a powdered form, which is combined with a marinade or directly sprinkled on the uncooked meat. The enzyme will penetrate the meat, and by a process called forking, cause the meat to be tender and palatable when cooked. If the enzyme is allowed to work for too long, the meat may become too "mushy" for many consumers' preferences ## Medical uses Bromelain can be used in a vast array of medical conditions. It was first introduced in this area in 1957, and works by blocking some proinflammatory metabolites that accelerate and worsen the inflammatory process. It is an anti-inflammatory agent, and so can be used for sports injury, trauma, arthritis, and other kinds of swelling. Its main uses are athletic injuries, digestive problems, phlebitis, sinusitis, and aiding healing after surgery. It has also been proposed in the use of arthritis, chronic venous insufficiency, easy bruising, gout, hemorrhoids, menstrual pain, autoimmune disorders, and ulcerative colitis. Studies have shown that bromelain can also be useful in the reduction of platelet clumping and blood clots in the bloodstream, especially in the arteries. It may have treatment potential for HIV. Its side effects include nausea, vomiting, diarrhea, menorrhagia (excessively heavy menstrual flow) and possible allergic reactions. One study has also associated Bromelain with increased heart rate. Bromelain supplementation up to 460 mg has been shown to have no effect on human heart rate or blood pressure; however, increasing doses up to 1840 mg have been shown to increase the heart rate proportionately. # Production It is produced in Thailand, among other tropical parts of the world, where pineapples are grown. Bromelain is prepared from the stem part of the pineapple plant after harvesting the fruit. This stem part is peeled, crushed and pressed to get the juice containing the soluble Bromelain enzyme. Further processing includes concentration of the pressed juice to get a purified enzyme. This process is carried out in factories under strictly controlled conditions to assure microbiological quality and enzyme purity. The Bromelain products are all supplied as powder. # Other plant proteases Other plant proteases include papain (from the papaya), actinidin (from the kiwi fruit), and ficin (from the fig). These proteases may induce a prickly sensation in the mouth when consumed.	Bromelain Bromelain can refer to one of two protease enzymes extracted from the plant family Bromeliaceae, or it can refer to a combination of those enzymes along with other compounds produced in an extract. # Components Bromelain is a mixture of sulfur-containing protein-digesting enzymes—called proteolytic enzymes or proteases—and several other substances in smaller quantities. The two main enzymes are: - stem bromelain - EC 3.4.22.32 - fruit bromelain - EC 3.4.22.33 The other substances include peroxidase, acid phosphatase, protease inhibitors, and calcium. # History The first isolation of bromelain was recorded by the Venezuelan chemist Vicente Marcano[1] (BU1 1.Phar. 5,77) in 1891 from the fruit of pineapple. In 1892, Chittenden, assisted by Joslin and Meara, investigated the matter fully (Trans. Conn. Acad. Arts Sci. 8, 281-308), and called it 'bromelin'. Later the term 'bromelain' was introduced and originally applied to any protease from any plant member of the plant family Bromeliaceae. Bromelain was first introduced as a therapeutic supplement in 1957. Research on bromelain apparently was first conducted in Hawaii but more recently has been conducted in countries in Asia, Europe and Latin America. Germany has recently taken a great interest in bromelain research; bromelain is currently the 13th most widely used herbal medicine in Germany. # Source Bromelain is present in all parts of the pineapple plant (Ananas comosus) but the stem is the most common commercial source, presumably because it is readily available after the fruit has been harvested. Pineapples have had a long tradition as a medicinal plant among the natives of South and Central America. However, just eating pineapple will not give you a great deal of extra bromelain, because it is mostly concentrated in the stem, which is not nearly as tasty (albeit still edible). # Uses ## Meat tenderizing Along with papain, Bromelain is one of the most popular substances to use for meat tenderizing. Historically, meat tenderizing enzymes were often injected into the muscle of a food animal while it was still living. This practice was deemed unethical, and has been largely discontinued, replaced with various postmortem application methods which are acceptable for lesser quality cuts. Today, approximately 90% of meat tenderizer use is in consumer households. Bromelain is sold in a powdered form, which is combined with a marinade or directly sprinkled on the uncooked meat. The enzyme will penetrate the meat, and by a process called forking, cause the meat to be tender and palatable when cooked. If the enzyme is allowed to work for too long, the meat may become too "mushy" for many consumers' preferences ## Medical uses Bromelain can be used in a vast array of medical conditions. It was first introduced in this area in 1957, and works by blocking some proinflammatory metabolites that accelerate and worsen the inflammatory process. It is an anti-inflammatory agent, and so can be used for sports injury, trauma, arthritis, and other kinds of swelling. Its main uses are athletic injuries, digestive problems, phlebitis, sinusitis, and aiding healing after surgery. It has also been proposed in the use of arthritis,[2] chronic venous insufficiency, easy bruising, gout, hemorrhoids, menstrual pain, autoimmune disorders, and ulcerative colitis. Studies have shown that bromelain can also be useful in the reduction of platelet clumping and blood clots in the bloodstream, especially in the arteries. It may have treatment potential for HIV.[3] Its side effects include nausea, vomiting, diarrhea, menorrhagia (excessively heavy menstrual flow) and possible allergic reactions. One study has also associated Bromelain with increased heart rate. Bromelain supplementation up to 460 mg has been shown to have no effect on human heart rate or blood pressure; however, increasing doses up to 1840 mg have been shown to increase the heart rate proportionately. # Production It is produced in Thailand, among other tropical parts of the world, where pineapples are grown. Bromelain is prepared from the stem part of the pineapple plant after harvesting the fruit. This stem part is peeled, crushed and pressed to get the juice containing the soluble Bromelain enzyme. Further processing includes concentration of the pressed juice to get a purified enzyme. This process is carried out in factories under strictly controlled conditions to assure microbiological quality and enzyme purity. The Bromelain products are all supplied as powder. # Other plant proteases Other plant proteases include papain (from the papaya), actinidin (from the kiwi fruit), and ficin (from the fig). These proteases may induce a prickly sensation in the mouth when consumed.	https://www.wikidoc.org/index.php/Bromelain
667a014f37bc4d966962d2e48cfe5ae905c9b602	wikidoc	Bromoform	Bromoform # Overview Bromoform (CHBr3) is a pale yellowish liquid with a sweet odor similar to chloroform, a halomethane or haloform. Its refractive index is 1.595 (20 °C, D). Small amounts are formed naturally by plants in the ocean. It is somewhat soluble in water and readily evaporates into the air. Most of the bromoform that enters the environment is formed as byproducts when chlorine is added to drinking water to kill bacteria. Bromoform is one of the trihalomethanes closely related with fluoroform, chloroform and iodoform. It is soluble in about 800 parts water and is miscible with alcohol, benzene, chloroform, ether, petroleum ether, acetone, and oils. It's LD50 is 7.2 mmol/kg in mice, or 1.8g/kg. It can be prepared by the haloform reaction using acetone and sodium hypobromite or by the electrolysis of alcoholic solution of potassium or sodium bromide. # Uses Only small quantities of bromoform are currently produced industrially in the United States. In the past, it was used as a solvent, sedative and flame retardant, but now it is mainly used as a laboratory reagent. Due to bromoform's relatively high density, it is commonly used for the separation of minerals. In one application of the technique, two samples can be separated by bromoform in a test tube or equivalent glassware. The bottom layer containing the heavier minerals can be frozen with liquid nitrogen, while the remaining top layer can be poured off, free of the other minerals. This ability is explained by the laws of buoyancy. A solid will float in a liquid if its density is less than that of the liquid. Likewise, a solid will sink if its density is more than that of the liquid. If a liquid is to be used to separate minerals according to their densities, it should have a density that is inbetween that of the minerals.	Bromoform Template:Chembox new # Overview Bromoform (CHBr3) is a pale yellowish liquid with a sweet odor similar to chloroform, a halomethane or haloform. Its refractive index is 1.595 (20 °C, D). Small amounts are formed naturally by plants in the ocean. It is somewhat soluble in water and readily evaporates into the air. Most of the bromoform that enters the environment is formed as byproducts when chlorine is added to drinking water to kill bacteria. Bromoform is one of the trihalomethanes closely related with fluoroform, chloroform and iodoform. It is soluble in about 800 parts water and is miscible with alcohol, benzene, chloroform, ether, petroleum ether, acetone, and oils. It's LD50 is 7.2 mmol/kg in mice, or 1.8g/kg. It can be prepared by the haloform reaction using acetone and sodium hypobromite or by the electrolysis of alcoholic solution of potassium or sodium bromide. # Uses Only small quantities of bromoform are currently produced industrially in the United States. In the past, it was used as a solvent, sedative and flame retardant, but now it is mainly used as a laboratory reagent. Due to bromoform's relatively high density, it is commonly used for the separation of minerals. In one application of the technique, two samples can be separated by bromoform in a test tube or equivalent glassware. The bottom layer containing the heavier minerals can be frozen with liquid nitrogen, while the remaining top layer can be poured off, free of the other minerals. This ability is explained by the laws of buoyancy. A solid will float in a liquid if its density is less than that of the liquid. Likewise, a solid will sink if its density is more than that of the liquid. If a liquid is to be used to separate minerals according to their densities, it should have a density that is inbetween that of the minerals.	https://www.wikidoc.org/index.php/Bromoform
4cee8694f47b09bdf49103e31ba0096360bd89c7	wikidoc	Meningism	Meningism # Overview Meningism is the triad of nuchal rigidity, photophobia (intolerance of bright light) and headache. It is a sign of irritation of the meninges, such as seen in meningitis, subarachnoid hemorrhages and various other diseases. "Meningismus" is the term used when the above listed symptoms are present without actual infection or inflammation; usually it is seen in concordance with other acute illnesses in the pediatric population. # Clinical signs The main clinical signs that indicate meningism are nuchal rigidity, Kernig's sign and Brudzinsky's signs. None of the signs are particularly sensitive; in adults with meningitis, nuchal rigidity was present in 30% and Kernig's or Brudzinsky's sign only in 5%. ## Nuchal rigidity Nuchal rigidity is the inability to flex the head forward due to rigidity of the neck muscles; if flexion of the neck is painful but full range of motion is present, nuchal rigidity is absent. ## Kernig's sign Kernig's sign (after Vladimir Mikhailovich Kernig, Russian-Baltic German neurologist 1840-1917) is positive when the leg is fully bent in the hip and knee, and subsequent extension in the knee is painful (leading to resistance).. This may indicate subarachnoid haemorrhage or meningitis. Patients may also show opisthotonus—spasm of the whole body that leads to legs and head being bent back and body bowed forward. ## Brudzinski's signs Josef Brudzinski (1874-1917), a Polish pediatrician, is credited with several signs in meningitis. The most commonly used sign (Brudzinski's neck sign) is the appearance of involuntary lifting of the legs in meningeal irritation when lifting a patient's head. Other signs attributed to Brudzinsky: - The symphyseal sign, in which pressure on the pubic symphysis leads to abduction of the leg and reflexive hip and knee flexion. - The cheek sign, in which pressure on the cheek below the zygoma leads to rising and flexion in the forearm. - Brudzinski's reflex, in which passive flexion of one knee into the abdomen leads to involuntary flexion in the opposite leg, and stretching of a limb that was flexed leads to contralateral extension. # Differential Diagnosis In alphabetical order. - Brain tumors - Cerebellar tumors - Cerebral hemorrhage - Emboli - Intracerebral abscesses - Ischemia - Lead intoxication - Lymphomas - Meningiosis carcinomatosa - Meningitis - Muscular tenseness of the cervical spine - Otitis - Porphyria - Sinusitis - Subarachnoid hemorrhage - Tetanus - Thrombi	Meningism Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Meningism is the triad of nuchal rigidity, photophobia (intolerance of bright light) and headache. It is a sign of irritation of the meninges, such as seen in meningitis, subarachnoid hemorrhages and various other diseases. "Meningismus" is the term used when the above listed symptoms are present without actual infection or inflammation; usually it is seen in concordance with other acute illnesses in the pediatric population. [1] # Clinical signs The main clinical signs that indicate meningism are nuchal rigidity, Kernig's sign and Brudzinsky's signs. None of the signs are particularly sensitive; in adults with meningitis, nuchal rigidity was present in 30% and Kernig's or Brudzinsky's sign only in 5%.[2] ## Nuchal rigidity Nuchal rigidity is the inability to flex the head forward due to rigidity of the neck muscles; if flexion of the neck is painful but full range of motion is present, nuchal rigidity is absent. ## Kernig's sign Kernig's sign (after Vladimir Mikhailovich Kernig, Russian-Baltic German neurologist 1840-1917) is positive when the leg is fully bent in the hip and knee, and subsequent extension in the knee is painful (leading to resistance).[3]. This may indicate subarachnoid haemorrhage or meningitis[4]. Patients may also show opisthotonus—spasm of the whole body that leads to legs and head being bent back and body bowed forward. ## Brudzinski's signs Josef Brudzinski (1874-1917), a Polish pediatrician, is credited with several signs in meningitis. The most commonly used sign (Brudzinski's neck sign) is the appearance of involuntary lifting of the legs in meningeal irritation when lifting a patient's head.[5][2] Other signs attributed to Brudzinsky:[6] - The symphyseal sign, in which pressure on the pubic symphysis leads to abduction of the leg and reflexive hip and knee flexion.[7] - The cheek sign, in which pressure on the cheek below the zygoma leads to rising and flexion in the forearm.[7] - Brudzinski's reflex, in which passive flexion of one knee into the abdomen leads to involuntary flexion in the opposite leg, and stretching of a limb that was flexed leads to contralateral extension.[8] # Differential Diagnosis In alphabetical order. [9] [10] - Brain tumors - Cerebellar tumors - Cerebral hemorrhage - Emboli - Intracerebral abscesses - Ischemia - Lead intoxication - Lymphomas - Meningiosis carcinomatosa - Meningitis - Muscular tenseness of the cervical spine - Otitis - Porphyria - Sinusitis - Subarachnoid hemorrhage - Tetanus - Thrombi	https://www.wikidoc.org/index.php/Brudzinski%27s_Sign
0e361f7ae334a47cc3d8a626bfd613b5738c677b	wikidoc	Bupropion	Bupropion # 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 Bupropion is a tetracyclics and unicyclics that is FDA approved for the {{{indicationType}}} of major depressive disorder (MDD) depression, associated with seasonal affective disorder; prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include suicidal thoughts and behaviors in adolescents and young adults, neuropsychiatric symptoms and suicide risk in smoking cessation treatment, seizure, hypertension, activation of mania or hypomania, psychosis and other neuropsychiatric reactions, hypersensitivity reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Major depressive disorder (MDD) - To minimize the risk of seizure, increase the dose gradually . Increases in dose should not exceed 100 mg per day in a 3‑day period. Bupropion Tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion may be taken with or without food. - The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75- or 100-mg tablets. - A maximum of 450 mg per day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg per day. Administer the 100‑mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose. - It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupropion in Adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non-Guideline-Supported Use of Bupropion in Adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about FDA-labeled indications and dosage information for Bupropion in Pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupropion in Pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non-Guideline-Supported Use of Bupropion in Pediatric patients. # Contraindications - Seizure disorder - Bulimia or anorexia nervosa - Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs # Warnings Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults - Worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior. - Pooled analyses of short‑term placebo‑controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors and others) show that these drugs - Increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short‑term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo‑controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short‑term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1 - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases . - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Bupropion should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment - Bupropion is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur. - In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke. Seizure - Bupropion can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg per day. Increase the dose gradually. Discontinue Bupropion and do not restart treatment if the patient experiences a seizure. - The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with Bupropion. Bupropion is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs . The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates. - Incidence of Seizure With Bupropion Use: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg per day. The estimated seizure incidence for Bupropion increases almost 10-fold between 450 and 600 mg per day. - The risk of seizure can be reduced if the dose of Bupropion does not exceed 450 mg per day, given as 150 mg 3 times daily, and the titration rate is gradual. Hypertension - Treatment with Bupropion can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with Bupropion, and monitor periodically during treatment. The risk of hypertension is increased if Bupropion is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity . - Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment‑emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement. - In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease. Activation of Mania/Hypomania - Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating bupropion, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Bupropion is not approved for use in treating bipolar depression. Psychosis and Other Neuropsychiatric Reactions - Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur. Hypersensitivity Reactions - Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens‑Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment. - There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular Respiratory Gastrointestinal Endocrine metabolic Psychiatric ## Postmarketing Experience Central Nervous System Respiratory Gastrointestinal Body (General) Endocrine Hemic and Lymphatic Musculoskeletal Skin and Appendages Special Senses # Drug Interactions - Potential for Other Drugs to Affect Bupropion - Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6. - Inhibitors of CYP2B6:Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) . - Inducers of CYP2B6:Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose. - Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure . If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. - Potential for Bupropion to Affect Other Drugs - Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. - Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion and such drugs may require increased doses of the drug see Clinical Pharmacology . - Drugs That Lower Seizure Threshold - Use extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually . - Dopaminergic Drugs (Levodopa and Amantadine) - Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering bupropion concomitantly with these drugs. - MAO Inhibitors - Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion. Conversely, at least 14 days should be allowed after stopping bupropion before starting an MAOI antidepressant . - Drug-Laboratory Test Interactions - False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Risk Summary - Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Clinical Considerations - Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. - Human Data - Data from the international bupropion Pregnancy Registry (675 first-trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. - No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. - Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. - Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. - For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. - Animal Data - In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m2basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater. - When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bupropion in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bupropion during labor and delivery. ### Nursing Mothers - Nursing Mothers - Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established . ### Geriatic Use - Geriatric Use - Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. - Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function . ### Gender There is no FDA guidance on the use of Bupropion with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bupropion with respect to specific racial populations. ### Renal Impairment - Renal Impairment - Consider a reduced dose and/or dosing frequency of bupropion in patients with renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures . ### Hepatic Impairment There is no FDA guidance on the use of Bupropion with respect to Hepatic Impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bupropion with respect to Reproductive Potential. ### Immunocompromised Patients There is no FDA guidance on the use of Bupropion with respect to Immunocompromise. # Administration and Monitoring ### Administration There is limited information pertaining to drug administration of Bupropion in patients. ### Monitoring There is limited information pertaining to drug monitoring of Bupropion in patients. # IV Compatibility There is limited information pertaining to the IV compatibility of Bupropion in patients. # Overdosage - Human Overdose Experience - Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. - Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. - Overdosage Management # Pharmacology ## Mechanism of Action The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase. ## Structure Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re‑uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2--1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNOHCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: Bupropion is supplied for oral administration as 75‑mg (yellow‑gold) and 100‑mg (red) film‑coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Bupropion Pharmacodynamics in the drug label. ## Pharmacokinetics - Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. - Absorption - The absolute bioavailability of bupropion in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%. - In humans, following oral administration of bupropion, peak plasma bupropion concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are dose‑proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use. - Distribution - In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. - Metabolism - Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one‑half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. - Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 3 hours after administration of bupropion and are approximately 10 times the peak level of the parent drug at steady state. The elimination half‑life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half‑lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady‑state AUCs are 1.5 and 7 times that of bupropion, respectively. - Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. - Elimination - Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion. - Population Subgroups - Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure , age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion. - Renal Impairment - There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate‑to‑severe renal impairment (GFR 30.9 10.8 mL/min) showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. bupropion should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered . - Hepatic Impairment - The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half‑life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half‑life for bupropion and the other metabolites in the 2 groups were minimal. - The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 3). - Left Ventricular Dysfunction - During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers. - Age - The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady‑state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single‑dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites . - Gender - Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown. - Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers. - Drug Interactions:Potential for Other Drugs to Affect Bupropion: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion. - Inhibitors of CYP2B6 Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (Cmax and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation. - Prasugrel - Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively. - Cimetidine - The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively of the combined moieties of threohydrobupropion and erythrohydrobupropion. - Citalopram - Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites. - Inducers of CYP2B6 - Ritonavir and Lopinavir - In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%. - In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively. - Efavirenz - In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%. - Carbamazepine, Phenobarbital, Phenytoin - While not systematically studied, these drugs may induce the metabolism of bupropion. - Potential for bupropion to Affect Other Drugs - Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of co-administered drugs. - Drugs Metabolized by CYP2D6 - In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied. - Citalopram - Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. - Lamotrigine - Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study. - Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies. - A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility. # Clinical Studies The efficacy of bupropion in the treatment of major depressive disorder was established in two 4‑week, placebo‑controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 4) and in one 6‑week, placebo‑controlled trial in adult outpatients with MDD (Trial 3 in Table 4). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of bupropion for only the 450‑mg-per-day dose. The efficacy results were statistically significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third trial, outpatients were treated with 300 mg per day of bupropion. This trial demonstrated the efficacy of bupropion as measured by the HDRS total score, the HDRS item 1, the Montgomery‑Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score. Effectiveness of bupropion in long‑term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Table 4. Efficacy of bupropion for the Treatment of Major Depressive Disorder # How Supplied - bupropion Tablets, 75 mg of bupropion hydrochloride, are yellow‑gold, round, biconvex tablets printed with “bupropion 75” in bottles of 100 (NDC 0173-0177-55). - Bupropion Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets printed with “bupropion 100” in bottles of 100 (NDC 0173-0178-55). ## Storage - Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) . Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### IMPORTANT WARNING Bupropion (Bupropion hydrochloride) Tablets Read this Medication Guide carefully before you start taking bupropion and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about bupropion, ask your healthcare provider or pharmacist. IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of suicidal thoughts and actions with antidepressant medicines; the second section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; and the third section is entitled “What Other Important Information Should I Know About bupropion?” - Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your healthcare provider or your family member’s healthcare provider about: - All risks and benefits of treatment with antidepressant medicines - All treatment choices for depression or other serious mental illness ### What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? - Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. - Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. - How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? - Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. - Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. - Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. ### Call your healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: ### What else do I need to know about antidepressant medicines? - Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. - Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. - Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. - Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. - It is not known if bupropion is safe and effective in children under the age of 18. ### Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions - This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking. - Although bupropion is not a treatment for quitting smoking, it contains the same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking. - Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or actions while taking bupropion to help them quit smoking. These symptoms can develop during treatment with bupropion or after stopping treatment with bupropion. - If you, your family member, or your caregiver notice agitation, hostility, depression, or changes in thinking or behavior that are not typical for you, or you have any of the following symptoms, stop taking bupropion and call your healthcare provider right away: - When you try to quit smoking, with or without bupropion, you may have symptoms that may be due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and increased appetite or weight gain. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression. - Before taking bupropion, tell your healthcare provider if you have ever had depression or other mental illnesses. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion. ### What Other Important Information Should I Know About bupropion? - Seizures: There is a chance of having a seizure (convulsion, fit) with bupropion, especially in people: with certain medical problems. who take certain medicines. - The chance of having seizures increases with higher doses of bupropion. For more information, see the sections “Who should not take bupropion?” and “What should I tell my healthcare provider before taking bupropion?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking bupropion unless your healthcare provider has said it is okay to take them. - If you have a seizure while taking bupropion, stop taking the tablets and call your healthcare provider right away. Do not take bupropion again if you have a seizure. - High blood pressure (hypertension). Some people get high blood pressure that can be severe, while taking bupropion. The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking. - Manic episodes. Some people may have periods of mania while taking bupropion, including: - Greatly increased energy - Severe trouble sleeping - Racing thoughts - Reckless behavior - Unusually grand ideas - Excessive happiness or irritability - Talking more or faster than usual - If you have any of the above symptoms of mania, call your healthcare provider. - Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while taking bupropion, including delusions (believe you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your healthcare provider. - Severe allergic reactions. Some people can have severe allergic reactions to bupropion. Stop taking bupropion and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction. ### What is bupropion? Bupropion is a prescription medicine used to treat adults with a certain type of depression called major depressive disorder. ### Who should not take bupropion? - Do not take bupropion if you - have or had a seizure disorder or epilepsy. - have or had an eating disorder such as anorexia nervosa or bulimia. - are taking any other medicines that contain bupropion, including ZYBAN (used to help people stop smoking) APLENZIN®, FORFIVO XL™, bupropion SR®, or bupropion XL®. Bupropion is the same active ingredient that is in bupropion. - drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop using them all of a sudden. - take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. - do not take an MAOI within 2 weeks of stopping bupropion unless directed to do so by your healthcare provider. - do not start bupropion if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider. - are allergic to the active ingredient in bupropion, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in bupropion. ### What should I tell my healthcare provider before taking bupropion? Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.” - Tell your healthcare provider about your other medical conditions including if you: - have liver problems, especially cirrhosis of the liver. - have kidney problems. - have, or have had, an eating disorder, such as anorexia nervosa or bulimia. - have had a head injury. - have had a seizure (convulsion, fit). - have a tumor in your nervous system (brain or spine). - have had a heart attack, heart problems, or high blood pressure. - are a diabetic taking insulin or other medicines to control your blood sugar. - drink alcohol. - abuse prescription medicines or street drugs. - are pregnant or plan to become pregnant. - are breastfeeding. bupropion passes into your milk in small amounts - Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking bupropion. ### How should I take bupropion? - Take bupropion exactly as prescribed by your healthcare provider. - Take bupropion at the same time each day. - Take your doses of bupropion at least 6 hours apart. - Do not chew, cut, or crush bupropion tablets. - You may take bupropion with or without food. - If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time. This is very important. Too much bupropion can increase your chance of having a seizure. - If you take too much bupropion, or overdose, call your local emergency room or poison control center right away. - Do not take any other medicines while taking bupropion unless your healthcare provider has told you it is okay. - If you are taking bupropion for the treatment of major depressive disorder, it may take several weeks for you to feel that bupropion is working. Once you feel better, it is important to keep taking bupropion exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel bupropion is working for you. - Do not change your dose or stop taking bupropion without talking with your healthcare provider first. ### What should I avoid while taking bupropion? - Limit or avoid using alcohol during treatment with bupropion. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your risk of having seizures. - Do not drive a car or use heavy machinery until you know how bupropion affects you. bupropion can affect your ability to do these things safely. ### What are possible side effects of bupropion? - See “What Other Important Information Should I Know About bupropion?” - Bupropion can cause serious side effects. - The most common side effects of bupropion include: - Nervousness - Dry mouth - Constipation - Headache - Nausea or vomiting - Dizziness - Heavy sweating - Shakiness (tremor) - Trouble sleeping - Blurred vision - Fast heartbeat - If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your medicine too close to bedtime. - Tell your healthcare provider right away about any side effects that bother you. - These are not all the possible side effects of bupropion. For more information, ask your healthcare provider or pharmacist. - Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088. - You may also report side effects to GlaxoSmithKline at 1-888-825-5249. ### How should I store bupropion? - Store bupropion at room temperature between 59°F and 86°F (15°C to 30°C). - Keep bupropion Tablets dry and out of the light. - Keep bupropion and all medicines out of the reach of children. ### General Information about bupropion - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bupropion for a condition for which it was not prescribed. Do not give bupropion to other people, even if they have the same symptoms you have. It may harm them. - If you take a urine drug screening test, bupropion may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking bupropion, they can do a more specific drug screening test that should not have this problem. - This Medication Guide summarizes important information about bupropion. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bupropion that is written for healthcare professionals. ### What are the ingredients in bupropion? - Active ingredient: bupropion hydrochloride. - Inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. # Precautions with Alcohol - Use With Alcohol - In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with bupropion should be minimized or avoided. # Brand Names There is limited information regarding Bupropion Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bupropion Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Bupropion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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 Bupropion is a tetracyclics and unicyclics that is FDA approved for the {{{indicationType}}} of major depressive disorder (MDD) depression, associated with seasonal affective disorder; prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include suicidal thoughts and behaviors in adolescents and young adults, neuropsychiatric symptoms and suicide risk in smoking cessation treatment, seizure, hypertension, activation of mania or hypomania, psychosis and other neuropsychiatric reactions, hypersensitivity reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Major depressive disorder (MDD) - To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions]. Increases in dose should not exceed 100 mg per day in a 3‑day period. Bupropion Tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion may be taken with or without food. - The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75- or 100-mg tablets. - A maximum of 450 mg per day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg per day. Administer the 100‑mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose. - It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupropion in Adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non-Guideline-Supported Use of Bupropion in Adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about FDA-labeled indications and dosage information for Bupropion in Pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupropion in Pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non-Guideline-Supported Use of Bupropion in Pediatric patients. # Contraindications - Seizure disorder - Bulimia or anorexia nervosa - Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs # Warnings Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults - Worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior. - Pooled analyses of short‑term placebo‑controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs - Increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short‑term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo‑controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short‑term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1 - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see Boxed Warning]. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Bupropion should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment - Bupropion is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur. - In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke. Seizure - Bupropion can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg per day. Increase the dose gradually. Discontinue Bupropion and do not restart treatment if the patient experiences a seizure. - The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with Bupropion. Bupropion is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications and Drug Interactions]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates. - Incidence of Seizure With Bupropion Use: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg per day. The estimated seizure incidence for Bupropion increases almost 10-fold between 450 and 600 mg per day. - The risk of seizure can be reduced if the dose of Bupropion does not exceed 450 mg per day, given as 150 mg 3 times daily, and the titration rate is gradual. Hypertension - Treatment with Bupropion can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with Bupropion, and monitor periodically during treatment. The risk of hypertension is increased if Bupropion is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications]. - Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment‑emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement. - In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease. Activation of Mania/Hypomania - Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating bupropion, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Bupropion is not approved for use in treating bipolar depression. Psychosis and Other Neuropsychiatric Reactions - Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur. Hypersensitivity Reactions - Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens‑Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment. - There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular Respiratory Gastrointestinal Endocrine metabolic Psychiatric ## Postmarketing Experience Central Nervous System Respiratory Gastrointestinal Body (General) Endocrine Hemic and Lymphatic Musculoskeletal Skin and Appendages Special Senses # Drug Interactions - Potential for Other Drugs to Affect Bupropion - Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6. - Inhibitors of CYP2B6:Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology]. - Inducers of CYP2B6:Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology] but should not exceed the maximum recommended dose. - Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. - Potential for Bupropion to Affect Other Drugs - Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. - Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion and such drugs may require increased doses of the drug see Clinical Pharmacology . - Drugs That Lower Seizure Threshold - Use extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Contraindications and Warnings and Precautions]. - Dopaminergic Drugs (Levodopa and Amantadine) - Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering bupropion concomitantly with these drugs. - MAO Inhibitors - Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion. Conversely, at least 14 days should be allowed after stopping bupropion before starting an MAOI antidepressant [see Dosage and Administration and Contraindications]. - Drug-Laboratory Test Interactions - False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Risk Summary - Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Clinical Considerations - Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. - Human Data - Data from the international bupropion Pregnancy Registry (675 first-trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. - No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. - Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. - Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. - For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. - Animal Data - In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m2basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater. - When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bupropion in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bupropion during labor and delivery. ### Nursing Mothers - Nursing Mothers - Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions]. ### Geriatic Use - Geriatric Use - Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. - Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration , Use in Specific Populations , and Clinical Pharmacology ]. ### Gender There is no FDA guidance on the use of Bupropion with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bupropion with respect to specific racial populations. ### Renal Impairment - Renal Impairment - Consider a reduced dose and/or dosing frequency of bupropion in patients with renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see Dosage and Administration and Clinical Pharmacology ]. ### Hepatic Impairment There is no FDA guidance on the use of Bupropion with respect to Hepatic Impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bupropion with respect to Reproductive Potential. ### Immunocompromised Patients There is no FDA guidance on the use of Bupropion with respect to Immunocompromise. # Administration and Monitoring ### Administration There is limited information pertaining to drug administration of Bupropion in patients. ### Monitoring There is limited information pertaining to drug monitoring of Bupropion in patients. # IV Compatibility There is limited information pertaining to the IV compatibility of Bupropion in patients. # Overdosage - Human Overdose Experience - Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. - Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. - Overdosage Management # Pharmacology ## Mechanism of Action The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase. ## Structure Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re‑uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: Bupropion is supplied for oral administration as 75‑mg (yellow‑gold) and 100‑mg (red) film‑coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Bupropion Pharmacodynamics in the drug label. ## Pharmacokinetics - Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. - Absorption - The absolute bioavailability of bupropion in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%. - In humans, following oral administration of bupropion, peak plasma bupropion concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are dose‑proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use. - Distribution - In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. - Metabolism - Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one‑half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. - Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 3 hours after administration of bupropion and are approximately 10 times the peak level of the parent drug at steady state. The elimination half‑life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half‑lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady‑state AUCs are 1.5 and 7 times that of bupropion, respectively. - Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. - Elimination - Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion. - Population Subgroups - Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion. - Renal Impairment - There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate‑to‑severe renal impairment (GFR 30.9 10.8 mL/min) showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. bupropion should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations]. - Hepatic Impairment - The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half‑life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half‑life for bupropion and the other metabolites in the 2 groups were minimal. - The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 3). - Left Ventricular Dysfunction - During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers. - Age - The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady‑state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single‑dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations]. - Gender - Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown. - Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers. - Drug Interactions:Potential for Other Drugs to Affect Bupropion: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion. - Inhibitors of CYP2B6 Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (Cmax and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation. - Prasugrel - Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively. - Cimetidine - The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively of the combined moieties of threohydrobupropion and erythrohydrobupropion. - Citalopram - Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites. - Inducers of CYP2B6 - Ritonavir and Lopinavir - In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%. - In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively. - Efavirenz - In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%. - Carbamazepine, Phenobarbital, Phenytoin - While not systematically studied, these drugs may induce the metabolism of bupropion. - Potential for bupropion to Affect Other Drugs - Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of co-administered drugs. - Drugs Metabolized by CYP2D6 - In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied. - Citalopram - Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. - Lamotrigine - Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study. - Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies. - A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility. # Clinical Studies The efficacy of bupropion in the treatment of major depressive disorder was established in two 4‑week, placebo‑controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 4) and in one 6‑week, placebo‑controlled trial in adult outpatients with MDD (Trial 3 in Table 4). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of bupropion for only the 450‑mg-per-day dose. The efficacy results were statistically significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third trial, outpatients were treated with 300 mg per day of bupropion. This trial demonstrated the efficacy of bupropion as measured by the HDRS total score, the HDRS item 1, the Montgomery‑Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score. Effectiveness of bupropion in long‑term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Table 4. Efficacy of bupropion for the Treatment of Major Depressive Disorder # How Supplied - bupropion Tablets, 75 mg of bupropion hydrochloride, are yellow‑gold, round, biconvex tablets printed with “bupropion 75” in bottles of 100 (NDC 0173-0177-55). - Bupropion Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets printed with “bupropion 100” in bottles of 100 (NDC 0173-0178-55). ## Storage - Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### IMPORTANT WARNING Bupropion (Bupropion hydrochloride) Tablets Read this Medication Guide carefully before you start taking bupropion and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about bupropion, ask your healthcare provider or pharmacist. IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of suicidal thoughts and actions with antidepressant medicines; the second section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; and the third section is entitled “What Other Important Information Should I Know About bupropion?” - Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your healthcare provider or your family member’s healthcare provider about: - All risks and benefits of treatment with antidepressant medicines - All treatment choices for depression or other serious mental illness ### What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? - Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. - Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. - How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? - Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. - Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. - Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. ### Call your healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: ### What else do I need to know about antidepressant medicines? - Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. - Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. - Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. - Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. - It is not known if bupropion is safe and effective in children under the age of 18. ### Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions - This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking. - Although bupropion is not a treatment for quitting smoking, it contains the same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking. - Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or actions while taking bupropion to help them quit smoking. These symptoms can develop during treatment with bupropion or after stopping treatment with bupropion. - If you, your family member, or your caregiver notice agitation, hostility, depression, or changes in thinking or behavior that are not typical for you, or you have any of the following symptoms, stop taking bupropion and call your healthcare provider right away: - When you try to quit smoking, with or without bupropion, you may have symptoms that may be due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and increased appetite or weight gain. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression. - Before taking bupropion, tell your healthcare provider if you have ever had depression or other mental illnesses. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion. ### What Other Important Information Should I Know About bupropion? - Seizures: There is a chance of having a seizure (convulsion, fit) with bupropion, especially in people: with certain medical problems. who take certain medicines. - The chance of having seizures increases with higher doses of bupropion. For more information, see the sections “Who should not take bupropion?” and “What should I tell my healthcare provider before taking bupropion?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking bupropion unless your healthcare provider has said it is okay to take them. - If you have a seizure while taking bupropion, stop taking the tablets and call your healthcare provider right away. Do not take bupropion again if you have a seizure. - High blood pressure (hypertension). Some people get high blood pressure that can be severe, while taking bupropion. The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking. - Manic episodes. Some people may have periods of mania while taking bupropion, including: - Greatly increased energy - Severe trouble sleeping - Racing thoughts - Reckless behavior - Unusually grand ideas - Excessive happiness or irritability - Talking more or faster than usual - If you have any of the above symptoms of mania, call your healthcare provider. - Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while taking bupropion, including delusions (believe you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your healthcare provider. - Severe allergic reactions. Some people can have severe allergic reactions to bupropion. Stop taking bupropion and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction. ### What is bupropion? Bupropion is a prescription medicine used to treat adults with a certain type of depression called major depressive disorder. ### Who should not take bupropion? - Do not take bupropion if you - have or had a seizure disorder or epilepsy. - have or had an eating disorder such as anorexia nervosa or bulimia. - are taking any other medicines that contain bupropion, including ZYBAN (used to help people stop smoking) APLENZIN®, FORFIVO XL™, bupropion SR®, or bupropion XL®. Bupropion is the same active ingredient that is in bupropion. - drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop using them all of a sudden. - take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. - do not take an MAOI within 2 weeks of stopping bupropion unless directed to do so by your healthcare provider. - do not start bupropion if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider. - are allergic to the active ingredient in bupropion, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in bupropion. ### What should I tell my healthcare provider before taking bupropion? Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.” - Tell your healthcare provider about your other medical conditions including if you: - have liver problems, especially cirrhosis of the liver. - have kidney problems. - have, or have had, an eating disorder, such as anorexia nervosa or bulimia. - have had a head injury. - have had a seizure (convulsion, fit). - have a tumor in your nervous system (brain or spine). - have had a heart attack, heart problems, or high blood pressure. - are a diabetic taking insulin or other medicines to control your blood sugar. - drink alcohol. - abuse prescription medicines or street drugs. - are pregnant or plan to become pregnant. - are breastfeeding. bupropion passes into your milk in small amounts - Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking bupropion. ### How should I take bupropion? - Take bupropion exactly as prescribed by your healthcare provider. - Take bupropion at the same time each day. - Take your doses of bupropion at least 6 hours apart. - Do not chew, cut, or crush bupropion tablets. - You may take bupropion with or without food. - If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time. This is very important. Too much bupropion can increase your chance of having a seizure. - If you take too much bupropion, or overdose, call your local emergency room or poison control center right away. - Do not take any other medicines while taking bupropion unless your healthcare provider has told you it is okay. - If you are taking bupropion for the treatment of major depressive disorder, it may take several weeks for you to feel that bupropion is working. Once you feel better, it is important to keep taking bupropion exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel bupropion is working for you. - Do not change your dose or stop taking bupropion without talking with your healthcare provider first. ### What should I avoid while taking bupropion? - Limit or avoid using alcohol during treatment with bupropion. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your risk of having seizures. - Do not drive a car or use heavy machinery until you know how bupropion affects you. bupropion can affect your ability to do these things safely. ### What are possible side effects of bupropion? - See “What Other Important Information Should I Know About bupropion?” - Bupropion can cause serious side effects. - The most common side effects of bupropion include: - Nervousness - Dry mouth - Constipation - Headache - Nausea or vomiting - Dizziness - Heavy sweating - Shakiness (tremor) - Trouble sleeping - Blurred vision - Fast heartbeat - If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your medicine too close to bedtime. - Tell your healthcare provider right away about any side effects that bother you. - These are not all the possible side effects of bupropion. For more information, ask your healthcare provider or pharmacist. - Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088. - You may also report side effects to GlaxoSmithKline at 1-888-825-5249. ### How should I store bupropion? - Store bupropion at room temperature between 59°F and 86°F (15°C to 30°C). - Keep bupropion Tablets dry and out of the light. - Keep bupropion and all medicines out of the reach of children. ### General Information about bupropion - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bupropion for a condition for which it was not prescribed. Do not give bupropion to other people, even if they have the same symptoms you have. It may harm them. - If you take a urine drug screening test, bupropion may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking bupropion, they can do a more specific drug screening test that should not have this problem. - This Medication Guide summarizes important information about bupropion. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bupropion that is written for healthcare professionals. ### What are the ingredients in bupropion? - Active ingredient: bupropion hydrochloride. - Inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. # Precautions with Alcohol - Use With Alcohol - In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with bupropion should be minimized or avoided. # Brand Names There is limited information regarding Bupropion Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bupropion Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/BuPROPion
c85d8340e2d18f798b57b9c1d20b284a4268fc10	wikidoc	Buckthorn	Buckthorn The Buckthorns (Rhamnus) are a genus (or two genera, if Frangula is treated as distinct) of about 100 species of shrubs or small trees from 1-10 m tall (rarely to 15 m), in the buckthorn family Rhamnaceae. They are native throughout the temperate and subtropical Northern Hemisphere, and also more locally in the subtropical Southern Hemisphere in parts of Africa and South America. Both deciduous and evergreen species occur. The leaves are simple, 3-15 cm long, and arranged either alternately or in opposite pairs. One semi-unique characteristic of many buckthorns is the way the veination curves upward towards the tip of the leaf. The plant bears fruits which are dark blue berries. The name comes from the fact that there is a woody spine on the end of each twig in many species. Buckthorns are used as food plants by the larvae of some Lepidoptera species – see list of Lepidoptera which feed on Buckthorns. # Classification The genus is divided into two subgenera, sometimes treated as separate genera: - Subgenus Rhamnus: flowers with four petals, buds with bud scales, leaves opposite or alternate, branches with spines Rhamnus alaternus – Italian Buckthorn Rhamnus alnifolia – Alderleaf Buckthorn Rhamnus arguta – Sharp-tooth Buckthorn Rhamnus cathartica – Common (or Purging) Buckthorn (syn. R. catharticus) Rhamnus crocea – Redberry Buckthorn (ssp. crocea), Hollyleaf Buckthorn (ssp. pilosa) Rhamnus davurica – Dahurian Buckthorn Rhamnus diffusus Rhamnus globosa – Lokao Buckthorn Rhamnus ilicifolia – Hollyleaf Redberry Rhamnus japonica – Japanese Buckthorn Rhamnus lanceolata – Lanceleaf Buckthorn Rhamnus libanotica Rhamnus lycioides Rhamnus petiolaris Rhamnus pirifolia – Island Redberry Buckthorn Rhamnus prinoides – Shiny-leaf Buckthorn Rhamnus saxatilis – Rock Buckthorn, Avignon Buckthorn, Avignon Berry (syn. R. infectoria, R. infectorius) Rhamnus serrata – Sawleaf Buckthorn Rhamnus smithii – Smith's Buckthorn Rhamnus staddo – Staddo (syn. R. rhodesicus) Rhamnus tinctoria - Dyer's Buckthorn (syn. R. saxatilis ssp. tinctorius) Rhamnus utilis – Chinese Buckthorn - Rhamnus alaternus – Italian Buckthorn - Rhamnus alnifolia – Alderleaf Buckthorn - Rhamnus arguta – Sharp-tooth Buckthorn - Rhamnus cathartica – Common (or Purging) Buckthorn (syn. R. catharticus) - Rhamnus crocea – Redberry Buckthorn (ssp. crocea), Hollyleaf Buckthorn (ssp. pilosa) - Rhamnus davurica – Dahurian Buckthorn - Rhamnus diffusus - Rhamnus globosa – Lokao Buckthorn - Rhamnus ilicifolia – Hollyleaf Redberry - Rhamnus japonica – Japanese Buckthorn - Rhamnus lanceolata – Lanceleaf Buckthorn - Rhamnus libanotica - Rhamnus lycioides - Rhamnus petiolaris - Rhamnus pirifolia – Island Redberry Buckthorn - Rhamnus prinoides – Shiny-leaf Buckthorn - Rhamnus saxatilis – Rock Buckthorn, Avignon Buckthorn, Avignon Berry (syn. R. infectoria, R. infectorius) - Rhamnus serrata – Sawleaf Buckthorn - Rhamnus smithii – Smith's Buckthorn - Rhamnus staddo – Staddo (syn. R. rhodesicus) - Rhamnus tinctoria - Dyer's Buckthorn (syn. R. saxatilis ssp. tinctorius) - Rhamnus utilis – Chinese Buckthorn - Subgenus Frangula: flowers with five petals, buds without bud scales, leaves always alternate, branches without spines Rhamnus betulaefolia (Frangula betulifolia) – Birchleaf Buckthorn Rhamnus californica (Frangula californica) – California Buckthorn, Coffeeberry Rhamnus caroliniana (Frangula caroliniana) – Carolina Buckthorn, Indian Cherry (syn. R. carolinianus) Rhamnus frangula (Frangula alnus) – Alder Buckthorn, Glossy or Breaking Buckthorn, Black Dogwood Rhamnus glandulosa - Sanguinho Rhamnus latifolia (Frangula azorica) Rhamnus purshiana (Frangula purshiana) – Cascara Buckthorn (syn. R. purshianus) Rhamnus rubra (Frangula rubra) – Red Buckthorn Rhamnus sphaerosperma (Frangula sphaerosperma) – West Indian Buckthorn - Rhamnus betulaefolia (Frangula betulifolia) – Birchleaf Buckthorn - Rhamnus californica (Frangula californica) – California Buckthorn, Coffeeberry - Rhamnus caroliniana (Frangula caroliniana) – Carolina Buckthorn, Indian Cherry (syn. R. carolinianus) - Rhamnus frangula (Frangula alnus) – Alder Buckthorn, Glossy or Breaking Buckthorn, Black Dogwood - Rhamnus glandulosa - Sanguinho - Rhamnus latifolia (Frangula azorica) - Rhamnus purshiana (Frangula purshiana) – Cascara Buckthorn (syn. R. purshianus) - Rhamnus rubra (Frangula rubra) – Red Buckthorn - Rhamnus sphaerosperma (Frangula sphaerosperma) – West Indian Buckthorn The Purging Buckthorn or Common Buckthorn (R. cathartica) is a widespread European native species, in the past used as a purgative, though its toxicity makes this a very risky herbal medicine and it is no longer used. Introduced into the United States as a garden shrub, this has become an invasive species in many areas there. It has recently been discovered to be a primary host of the soybean aphid Aphis glycines, a problem pest for soybean farmers across the US. The aphids use the buckthorn as a host for the winter and then spread to nearby soybean fields in the spring. Another European species, Alder Buckthorn (R. frangula, syn. Frangula alnus) was of major military importance in the 15th to 19th centuries, as its wood provided the best quality charcoal for gunpowder manufacture. Italian Buckthorn (R. alaternus), an evergreen species from the Mediterranean region, has become a serious weed in some parts of New Zealand—especially on Hauraki Gulf islands. Dyer's Buckthorn (R. tinctoria) is used, together with the Asian Chinese Buckthorn (R. utilis), to produce the dye "china green". Another species, Avignon Buckthorn (R. saxatilis) provides the yellow dye Persian berry, made from the berries. Sanguinho (R. glandulosa) is endemic to the Macaronesian islands, where it is found in the laurisilva forests of the Madeira and Canary Islands. North American species include Alder-leaf Buckthorn (R. alnifolia) right across the continent, Carolina Buckthorn (R. (F.) caroliniana) in the east, Cascara Buckthorn (R. (F.) purshiana) in the west, and the evergreen California Buckthorn or Coffeeberry (R. (F.) californica) and Hollyleaf Buckthorn (R. crocea) in the west. In South America, Rhamnus diffusus is a small shrub native from the Valdivian temperate rain forests in Chile. Buckthorns may be confused with Dogwoods, which share the curved leaf venation; indeed, "dogwood" is a local name for R. prinoides in southern Africa, a plant used to make Ethiopian mead and known as "gesho" in Ethiopia. The two plants are easy to distinguish by slowly pulling a leaf apart; in dogwood thin white latex strings can be seen, strings not present in buckthorn.	Buckthorn The Buckthorns (Rhamnus) are a genus (or two genera, if Frangula is treated as distinct) of about 100 species of shrubs or small trees from 1-10 m tall (rarely to 15 m), in the buckthorn family Rhamnaceae. They are native throughout the temperate and subtropical Northern Hemisphere, and also more locally in the subtropical Southern Hemisphere in parts of Africa and South America. Both deciduous and evergreen species occur. The leaves are simple, 3-15 cm long, and arranged either alternately or in opposite pairs. One semi-unique characteristic of many buckthorns is the way the veination curves upward towards the tip of the leaf. The plant bears fruits which are dark blue berries. The name comes from the fact that there is a woody spine on the end of each twig in many species. Buckthorns are used as food plants by the larvae of some Lepidoptera species – see list of Lepidoptera which feed on Buckthorns. # Classification The genus is divided into two subgenera, sometimes treated as separate genera: - Subgenus Rhamnus: flowers with four petals, buds with bud scales, leaves opposite or alternate, branches with spines Rhamnus alaternus – Italian Buckthorn Rhamnus alnifolia – Alderleaf Buckthorn Rhamnus arguta – Sharp-tooth Buckthorn Rhamnus cathartica – Common (or Purging) Buckthorn (syn. R. catharticus) Rhamnus crocea – Redberry Buckthorn (ssp. crocea), Hollyleaf Buckthorn (ssp. pilosa) Rhamnus davurica – Dahurian Buckthorn Rhamnus diffusus Rhamnus globosa – Lokao Buckthorn Rhamnus ilicifolia – Hollyleaf Redberry Rhamnus japonica – Japanese Buckthorn Rhamnus lanceolata – Lanceleaf Buckthorn Rhamnus libanotica Rhamnus lycioides Rhamnus petiolaris Rhamnus pirifolia – Island Redberry Buckthorn Rhamnus prinoides – Shiny-leaf Buckthorn Rhamnus saxatilis – Rock Buckthorn, Avignon Buckthorn, Avignon Berry (syn. R. infectoria, R. infectorius) Rhamnus serrata – Sawleaf Buckthorn Rhamnus smithii – Smith's Buckthorn Rhamnus staddo – Staddo (syn. R. rhodesicus) Rhamnus tinctoria - Dyer's Buckthorn (syn. R. saxatilis ssp. tinctorius) Rhamnus utilis – Chinese Buckthorn - Rhamnus alaternus – Italian Buckthorn - Rhamnus alnifolia – Alderleaf Buckthorn - Rhamnus arguta – Sharp-tooth Buckthorn - Rhamnus cathartica – Common (or Purging) Buckthorn (syn. R. catharticus) - Rhamnus crocea – Redberry Buckthorn (ssp. crocea), Hollyleaf Buckthorn (ssp. pilosa) - Rhamnus davurica – Dahurian Buckthorn - Rhamnus diffusus - Rhamnus globosa – Lokao Buckthorn - Rhamnus ilicifolia – Hollyleaf Redberry - Rhamnus japonica – Japanese Buckthorn - Rhamnus lanceolata – Lanceleaf Buckthorn - Rhamnus libanotica - Rhamnus lycioides - Rhamnus petiolaris - Rhamnus pirifolia – Island Redberry Buckthorn - Rhamnus prinoides – Shiny-leaf Buckthorn - Rhamnus saxatilis – Rock Buckthorn, Avignon Buckthorn, Avignon Berry (syn. R. infectoria, R. infectorius) - Rhamnus serrata – Sawleaf Buckthorn - Rhamnus smithii – Smith's Buckthorn - Rhamnus staddo – Staddo (syn. R. rhodesicus) - Rhamnus tinctoria - Dyer's Buckthorn (syn. R. saxatilis ssp. tinctorius) - Rhamnus utilis – Chinese Buckthorn - Subgenus Frangula: flowers with five petals, buds without bud scales, leaves always alternate, branches without spines Rhamnus betulaefolia (Frangula betulifolia) – Birchleaf Buckthorn Rhamnus californica (Frangula californica) – California Buckthorn, Coffeeberry Rhamnus caroliniana (Frangula caroliniana) – Carolina Buckthorn, Indian Cherry (syn. R. carolinianus) Rhamnus frangula (Frangula alnus) – Alder Buckthorn, Glossy or Breaking Buckthorn, Black Dogwood Rhamnus glandulosa - Sanguinho Rhamnus latifolia (Frangula azorica) Rhamnus purshiana (Frangula purshiana) – Cascara Buckthorn (syn. R. purshianus) Rhamnus rubra (Frangula rubra) – Red Buckthorn Rhamnus sphaerosperma (Frangula sphaerosperma) – West Indian Buckthorn - Rhamnus betulaefolia (Frangula betulifolia) – Birchleaf Buckthorn - Rhamnus californica (Frangula californica) – California Buckthorn, Coffeeberry - Rhamnus caroliniana (Frangula caroliniana) – Carolina Buckthorn, Indian Cherry (syn. R. carolinianus) - Rhamnus frangula (Frangula alnus) – Alder Buckthorn, Glossy or Breaking Buckthorn, Black Dogwood - Rhamnus glandulosa - Sanguinho - Rhamnus latifolia (Frangula azorica) - Rhamnus purshiana (Frangula purshiana) – Cascara Buckthorn (syn. R. purshianus) - Rhamnus rubra (Frangula rubra) – Red Buckthorn - Rhamnus sphaerosperma (Frangula sphaerosperma) – West Indian Buckthorn The Purging Buckthorn or Common Buckthorn (R. cathartica) is a widespread European native species, in the past used as a purgative, though its toxicity makes this a very risky herbal medicine and it is no longer used. Introduced into the United States as a garden shrub, this has become an invasive species in many areas there. It has recently been discovered to be a primary host of the soybean aphid Aphis glycines, a problem pest for soybean farmers across the US. The aphids use the buckthorn as a host for the winter and then spread to nearby soybean fields in the spring. Another European species, Alder Buckthorn (R. frangula, syn. Frangula alnus) was of major military importance in the 15th to 19th centuries, as its wood provided the best quality charcoal for gunpowder manufacture. Italian Buckthorn (R. alaternus), an evergreen species from the Mediterranean region, has become a serious weed in some parts of New Zealand—especially on Hauraki Gulf islands. Dyer's Buckthorn (R. tinctoria) is used, together with the Asian Chinese Buckthorn (R. utilis), to produce the dye "china green". Another species, Avignon Buckthorn (R. saxatilis) provides the yellow dye Persian berry, made from the berries. Sanguinho (R. glandulosa) is endemic to the Macaronesian islands, where it is found in the laurisilva forests of the Madeira and Canary Islands. North American species include Alder-leaf Buckthorn (R. alnifolia) right across the continent, Carolina Buckthorn (R. (F.) caroliniana) in the east, Cascara Buckthorn (R. (F.) purshiana) in the west, and the evergreen California Buckthorn or Coffeeberry (R. (F.) californica) and Hollyleaf Buckthorn (R. crocea) in the west. In South America, Rhamnus diffusus is a small shrub native from the Valdivian temperate rain forests in Chile. Buckthorns may be confused with Dogwoods, which share the curved leaf venation; indeed, "dogwood" is a local name for R. prinoides in southern Africa, a plant used to make Ethiopian mead and known as "gesho" in Ethiopia. The two plants are easy to distinguish by slowly pulling a leaf apart; in dogwood thin white latex strings can be seen, strings not present in buckthorn. # External links Template:Wikisource1911Enc - Scientific chemical research on African Rhamnus - Rhamnus diffusus pictures from Chilebosque - Frangula caroliniana images at bioimages.vanderbilt.edu ar:نبق ang:Heorotbrér cs:Krušina olšová da:Almindelig Tørst de:Kreuzdorn et:Türnpuu eo:Frangolo lt:Šaltekšnis nl:Sporkehout fi:Korpipaatsama sv:Brakved uk:Крушина ламка	https://www.wikidoc.org/index.php/Buckthorn
a54df050d903bbd4c67e1886ad284e201f765c0d	wikidoc	Bufexamac	Bufexamac # Overview Bufexamac is a drug used as an anti-inflammatory agent on the skin, as well as rectally. Common brand names include Paraderm and Parfenac. It was withdrawn in Europe because of allergic reactions. # Indications Ointments and lotions containing bufexamac are used for the treatment of subacute and chronic eczema of the skin, including atopic eczema, as well as sunburn and other minor burns, and itching. Suppositories containing bufexamac in combination with local anaesthetics are used against haemorrhoids. # Pharmacology Bufexamac is thought to act by inhibiting the enzyme cyclooxygenase, which would make it a non-steroidal anti-inflammatory drug. Evidence on the mechanism of action is scarce. Furthermore, bufexamac was identified as a specific inhibitor of class IIB histone deacetylases (HDAC6 and HDAC10), which may contribute to its clinical efficacy. # Side effects Bufexamac can cause severe contact dermatitis which is often hard to distinguish from the initial condition. As a consequence, the European Medicines Agency recommended to withdraw the marketing approval in April 2010.	Bufexamac Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bufexamac is a drug used as an anti-inflammatory agent on the skin, as well as rectally. Common brand names include Paraderm and Parfenac. It was withdrawn in Europe because of allergic reactions. # Indications Ointments and lotions containing bufexamac are used for the treatment of subacute and chronic eczema of the skin, including atopic eczema, as well as sunburn and other minor burns,[citation needed] and itching. Suppositories containing bufexamac in combination with local anaesthetics are used against haemorrhoids.[1] # Pharmacology Bufexamac is thought to act by inhibiting the enzyme cyclooxygenase, which would make it a non-steroidal anti-inflammatory drug. Evidence on the mechanism of action is scarce.[2] Furthermore, bufexamac was identified as a specific inhibitor of class IIB histone deacetylases (HDAC6 and HDAC10),[3] which may contribute to its clinical efficacy.[citation needed] # Side effects Bufexamac can cause severe contact dermatitis which is often hard to distinguish from the initial condition.[4] As a consequence, the European Medicines Agency recommended to withdraw the marketing approval in April 2010.[5]	https://www.wikidoc.org/index.php/Bufexamac
ad67d2c8eb53c530f45944f6c3dc7de5d29bac2d	wikidoc	Bufotenin	Bufotenin Bufotenin (also known as bufotenine), is a tryptamine related to the neurotransmitter serotonin. It is an alkaloid found in the skin of some species of toads; in mushrooms, higher plants, and mammals; and possibly in the brain, plasma, and urine of schizophrenics. The name bufotenin originates from the Bufo genus of toads, which includes several species of psychoactive toads (such as Bufo alvarius and Bufo marinus) that secrete bufotoxins from their parotoid glands. Bufotenin is very similar in chemical structure to the hallucinogen psilocin; the only structural difference is that the hydroxyl (-OH) group is located one carbon over on the indole ring. However, pharmacologically, it is more closely related to 5-MeO-DMT and DMT, chemicals that often occur in plant and animal species in which bufotenin is found. Whether bufotenine is also hallucingenic has been the subject of debate among researchers. # Nomenclature Bufotenin (bufotenine) is also known by the chemical names 5-hydroxy-dimethyltryptamine (5-OH-DMT), N,N-dimethyl-5-hydroxytryptamine, dimethyl serotonin, and mappine. # History Bufotenine was first isolated, from toad skin, and named by the Austrian chemist Handovsky at the University of Prague during World War I. The structure of bufotenine was first confirmed in 1934 by Heinrich Wieland’s laboratory in Munich, and the first reported synthesis of bufotenine was by Toshio Hoshino in 1936. # Sources ## Toads Bufotenin is a chemical constituent in the venom and eggs of several species of toads belonging to the Bufo genus, including Bufo alvarius and Bufo marinus. Extracts of toad venom, containing bufotenin and other bioactive compounds, have been used in some traditional medicines such as ch’an su (probably derived from Bufo gargarizans), which has been used medicinally for centuries in China. The toad was "recurrently depicted in Mesoamerican art," which some authors have interpreted as indicating that the effects of ingesting Bufo secretions have been known in Mesoamerica for many years; however, others doubt that this art provides sufficient "ethnohistorical evidence" to support the claim. In addition to bufotenine, Bufo venoms also contain digoxin-like cardiac glycosides, and ingestion of the venom can be fatal. Ingestion of Bufo toad venom and eggs by humans has resulted in several reported cases of poisoning, some of which resulted in death. Contemporary reports indicate that bufotenine-containing toad venom has been used as a street drug; that is, as an aphrodisiac, ingested orally in the form of ch’an su, and as a hallucinogen, by smoking or orally ingesting Bufo toad venom or dried Bufo skins. The use of chan'su and love stone (a related toad venom preparation used as an aphrodisiac in the West Indies) has resulted in several cases of poisoning and at least one death. The practice of orally ingesting toad venom has been referred to in popular culture and in the scientific literature as toad licking and has drawn media attention. Albert Most, founder of the Church of the Toad of Light and a proponent of recreational use of Bufo alvarius venom, published a booklet titled Bufo avlarius: The Psychedelic Toad of the Sonoran Desert in 1983 which explained how to extract and smoke the secretions. Bufotenin is also present in the skin secretion of three arboreal amphibian species of the Osteocephalus genus (Osteocephalus taurinus, Osteocephalus oophagus, and Osteocephalus langsdorffii) from the Amazon and Atlantic rain forests. ## Anadenanthera Seeds Bufotenin is the primary active constituent Template:Disputable of the seeds of Anadenanthera colubrina and Anadenanthera peregrina trees. Anadenanthera seeds have been in use as hallucinogens Template:Disputable for over 4000 years. The use of these seeds have been historically linked to shamans in South America and in the Caribbean Islands.Template:Verify credibility Archeological evidence shows smoking as the original route of administration of Anadenanthera seeds. The seeds are smoked alone or often mixed with tobacco. Cigars sometimes used by shamans containing ground Anadenanthera seeds mixed with tobacco are estimated to contain up to 196 mg of bufotenin. Snuff and enema usage appears later in history. Snuff preparations eventually became the most widely accepted route of administration. The snuffs known as Vilca and Yopo (also known as Cohoba) are made from the seeds of the Anadenanthera colubrina and Anadenanthera peregrina trees, respectively. Cohoba was used by the tribe with whom Christopher Columbus made first contact, the Taino of Cuba and Hispaniola. Anadenanthera snuff is usually processed by toasting the seeds, removing the seed husks, and then grinding them to a fine powder. To improve the snuff's potency, most shamans usually add a natural form of calcium hydroxide (or calcium oxide) and a little water to the snuff. The mix is kneaded for several minutes and allowed to sit overnight. It is then dried and ground to a powder once more. Phenolic compounds such as bufotenine react with calcium hydroxide to form phenoxides. This processing with calcium hydroxide converts bufotenin (5-HO-DMT) into its phenoxide form: calcium bufotenoxide (Ca + 5-O-DMT, also known as calcium bufotenate), a compound with increased hallucinogenic properties.Template:Disputable A typical dose of snuff contains over 100 mg of bufoteninTemplate:Disputable. ## Mushrooms Bufotenine is also found in several species of Amanita mushrooms, including Amanita muscaria, Amanita citrina and Amanita porphyria. ## Other Sources Bufotenin has been identified as a component in the latex of the takini (Brosimum acutifolium) tree, which is used as a hallucinogen by South American shamans, and in the seeds of Mucuna pruriens DC # Pharmacology ## Uptake and Elimination In rats, subcutaneously administered bufotenin (1–100 μg/kg) distributes mainly to the lungs, heart, and blood, and to a much lesser extent, the brain (hypothalamus, brain stem, striatum, and cerebral cortex) and liver. It reaches peak concentrations at 1 hour and is nearly completely eliminated within 8 hours. In humans, bufotenine is rapidly absorbed following intravenous administration and is excreted in the urine predominantly (70%) in the form of 5-HIAA, an endogenous metabolite of serotonin, while roughly 4% is eliminated unmetabolized in the urine. Orally administered bufotenine undergoes extensive first-pass metabolism by the enzyme monoamine oxidase. ## Lethal Dose The acute toxicity of bufotenin in rodents has been calculated to have an LD50 of between 200 and 300 mg/kg, which by comparison, is comparable to the LD50 for intravenous morphine (200-300 mg/kg) in mice. Death occurs by respiratory arrest. ## Effects in Humans ### Fabing & Hawkins (1955) In 1955, Fabing and Hawkins administered bufotenin intravenously at doses of up to 16 mg to prison inmates at Ohio State Penitentiary. A troubling toxic blood circulation effect causing a purpling of the face was seen in these tests. A subject given 1 mg reported “a tight feeling in the chest” and prickling “as if he had been jabbed by needles.” This was accompanied by a “fleeting sensation of pain in both thighs and a mild nausea.” Another subject given 2 mg reported “tightness in his throat”. He had tightness in the stomach, tingling in pretibial areas, and developed a purplish hue in the face indicating blood circulation problems. He vomited after 3 minutes. Another subject given 4 mg complained of “chest oppression” and that “a load is pressing down from above and my body feels heavy.” The subject also reported “numbness of the entire body” and “a pleasant Martini feeling-my body is taking charge of my mind”. The subject reported he saw red spots passing before his eyes and red-purple spots on the floor, and the floor seemed very close to his face. Within 2 minutes these visual effects were gone, and replaced by a yellow haze, as if he were looking through a lens filter. Fabing and Hawkins commented that bufotenin’s hallucinogenic effects were "reminiscent of LSD and mescaline but develop and dispappear more quickly, indicating rapid central action and rapid degradation of the drug". ### Isbell (1956) In 1956, Dr. Harris S. Isbell at the Public Health Service Hospital in Lexington, Kentucky experimented with bufotenine as a snuff. He reported “no subjective or objective effects were observed after spraying with as much as 40 mg bufotenine”; however subjects who received 10-12 mg injected intramuscularly reported “elements of visual hallucinations consisting of a play of colors, lights, and patterns”. ### Turner & Merlis (1959) Turner and Merlis (1959) experimented with intravenous administration of bufotenine (as the water soluble creatinine sulfate salt) to schizophrenics at a New York state hospital. They reported that when one subject received 10 mg during a 50-second interval, “the peripheral nervous system effects were extreme: at 17 seconds, flushing of the face, at 22 seconds, maximal inhalation, followed by maximal hyperventilation for about 2 minutes, during which the patient was unresponsive to stimuli; her face was plum-colored. Finally, Turner and Merlis reported that: After pushing doses to the morally admissible limit without producing hallucinations, Turner and Merlis conservatively concluded: “We must reject bufotenine…as capable of producing the acute phase of Cohoba intoxication”. ### McLeod and Sitaram (1985) A 1985 study by McLeod and Sitaram in humans reported that bufotenine administered intranasally at a dose of 1-16 mg had no effect, other than intense local irritation. When given intravenously at low doses (2-4 mg), bufotenine oxalate caused anxiety but no other effects; however, a dose of 8 mg resulted in profound emotional and perceptual changes, involving extreme anxiety, a sense of imminent death, and visual disturbance associated with color reversal and distortion, and intense flushing of the cheeks and forehead. ### Ott (2001) In 2001, Jonathan Ott, an amateur ethnobotanist, published the results of a study in which he self-administered free base bufotenin intranasally (5-100 mg), sublingually (50 mg), intrarectally (30 mg), orally (100 mg) and via vaporization (2-8 mg). Ott reported “visionary effects" of intranasal bufotenine and that the "visionary threshold dose" by this route was 40 mg, with smaller doses eliciting perceptibly psychoactive effects. He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects". At 100 mg, effects began within 5 minutes, peaked at 35-40 minutes, and lasted up to 90 minutes. Higher doses produced effects that were described as hallucinogenic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque". Free base bufotenin taken sublingually was found to be identical to intranasal use. The potency, duration, and hallucinogenic action was the same. Ott found vaporized free base bufotenin active from 2-8 mg with 8 mg producing "ring-like, swirling, colored patterns with eyes closed". Ott noted that free base bufotenin taken intranasally and sublingually produced effects similar to those of Yopo without the toxic peripheral symptoms, such as facial flushing, observed in other studies in which the the drug was administered intravenously. ## Association With Schizophrenia and Other Mental Disorders A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects; however, subsequent research has failed to confirm these findings. Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders, such as infant autistic patients. Another study indicated that paranoid violent offenders or those who committed violent behaviour towards family members have higher bufotenin levels in their urine than other violent offenders. # Legal Status Bufotenine is regulated as a Schedule I drug (ID number 7403) by the U.S. Drug Enforcement Agency. It is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the government of Australia.	Bufotenin Bufotenin (also known as bufotenine), is a tryptamine related to the neurotransmitter serotonin. It is an alkaloid found in the skin of some species of toads; in mushrooms, higher plants, and mammals; and possibly in the brain, plasma, and urine of schizophrenics.[1] The name bufotenin originates from the Bufo genus of toads, which includes several species of psychoactive toads (such as Bufo alvarius and Bufo marinus) that secrete bufotoxins from their parotoid glands.[2] Bufotenin is very similar in chemical structure to the hallucinogen psilocin; the only structural difference is that the hydroxyl (-OH) group is located one carbon over on the indole ring. However, pharmacologically, it is more closely related to 5-MeO-DMT and DMT,[citation needed] chemicals that often occur in plant and animal species in which bufotenin is found. Whether bufotenine is also hallucingenic has been the subject of debate among researchers. # Nomenclature Bufotenin (bufotenine) is also known by the chemical names 5-hydroxy-dimethyltryptamine (5-OH-DMT), N,N-dimethyl-5-hydroxytryptamine, dimethyl serotonin,[3] and mappine.[3] # History Bufotenine was first isolated, from toad skin, and named by the Austrian chemist Handovsky at the University of Prague during World War I.[4] The structure of bufotenine was first confirmed in 1934 by Heinrich Wieland’s laboratory in Munich, and the first reported synthesis of bufotenine was by Toshio Hoshino in 1936.[4] # Sources ## Toads Template:Seealso Bufotenin is a chemical constituent in the venom and eggs of several species of toads belonging to the Bufo genus, including Bufo alvarius and Bufo marinus. Extracts of toad venom, containing bufotenin and other bioactive compounds, have been used in some traditional medicines such as ch’an su (probably derived from Bufo gargarizans), which has been used medicinally for centuries in China.[5] The toad was "recurrently depicted in Mesoamerican art,"[6] which some authors have interpreted as indicating that the effects of ingesting Bufo secretions have been known in Mesoamerica for many years; however, others doubt that this art provides sufficient "ethnohistorical evidence" to support the claim. [5] In addition to bufotenine, Bufo venoms also contain digoxin-like cardiac glycosides, and ingestion of the venom can be fatal. Ingestion of Bufo toad venom and eggs by humans has resulted in several reported cases of poisoning,[7][8][9] some of which resulted in death.[9][10][11] Contemporary reports indicate that bufotenine-containing toad venom has been used as a street drug; that is, as an aphrodisiac, ingested orally in the form of ch’an su,[9] and as a hallucinogen, by smoking or orally ingesting Bufo toad venom or dried Bufo skins. The use of chan'su and love stone (a related toad venom preparation used as an aphrodisiac in the West Indies) has resulted in several cases of poisoning and at least one death.[9][12] The practice of orally ingesting toad venom has been referred to in popular culture and in the scientific literature as toad licking and has drawn media attention[13][14]. Albert Most, founder of the Church of the Toad of Light and a proponent of recreational use of Bufo alvarius venom, published a booklet titled Bufo avlarius: The Psychedelic Toad of the Sonoran Desert[15][16] in 1983 which explained how to extract and smoke the secretions. Bufotenin is also present in the skin secretion of three arboreal amphibian species of the Osteocephalus genus (Osteocephalus taurinus, Osteocephalus oophagus, and Osteocephalus langsdorffii) from the Amazon and Atlantic rain forests.[17] ## Anadenanthera Seeds Template:Off-topic-other Template:Pagenumbers Bufotenin is the primary active constituent Template:Disputable of the seeds of Anadenanthera colubrina and Anadenanthera peregrina trees.[18] Anadenanthera seeds have been in use as hallucinogens Template:Disputable for over 4000 years.[18] The use of these seeds have been historically linked to shamans in South America and in the Caribbean Islands.[18][19]Template:Verify credibility Archeological evidence shows smoking as the original route of administration of Anadenanthera seeds. The seeds are smoked alone or often mixed with tobacco. Cigars sometimes used by shamans containing ground Anadenanthera seeds mixed with tobacco are estimated to contain up to 196 mg of bufotenin. Snuff and enema usage appears later in history.[18] Snuff preparations eventually became the most widely accepted route of administration.[18] The snuffs known as Vilca and Yopo (also known as Cohoba)[18][19][20] are made from the seeds of the Anadenanthera colubrina and Anadenanthera peregrina trees, respectively. Cohoba was used by the tribe with whom Christopher Columbus made first contact, the Taino of Cuba and Hispaniola.[21] Anadenanthera snuff is usually processed by toasting the seeds, removing the seed husks, and then grinding them to a fine powder. To improve the snuff's potency, most shamans usually add a natural form of calcium hydroxide (or calcium oxide) and a little water to the snuff. The mix is kneaded for several minutes and allowed to sit overnight. It is then dried and ground to a powder once more.[18] Phenolic compounds such as bufotenine react with calcium hydroxide to form phenoxides. This processing with calcium hydroxide converts bufotenin (5-HO-DMT) into its phenoxide form: calcium bufotenoxide (Ca + 5-O-DMT, also known as calcium bufotenate), a compound with increased hallucinogenic properties.Template:Disputable A typical dose of snuff contains over 100 mg of bufotenin[18]Template:Disputable. ## Mushrooms Bufotenine is also found in several species of Amanita mushrooms, including Amanita muscaria,[22] Amanita citrina[4] and Amanita porphyria.[4] ## Other Sources Bufotenin has been identified as a component in the latex of the takini (Brosimum acutifolium) tree, which is used as a hallucinogen by South American shamans,[23] and in the seeds of Mucuna pruriens DC [24] # Pharmacology ## Uptake and Elimination In rats, subcutaneously administered bufotenin (1–100 μg/kg) distributes mainly to the lungs, heart, and blood, and to a much lesser extent, the brain (hypothalamus, brain stem, striatum, and cerebral cortex) and liver. It reaches peak concentrations at 1 hour and is nearly completely eliminated within 8 hours.[25] In humans, bufotenine is rapidly absorbed following intravenous administration and is excreted in the urine predominantly (70%) in the form of 5-HIAA, an endogenous metabolite of serotonin, while roughly 4% is eliminated unmetabolized in the urine. Orally administered bufotenine undergoes extensive first-pass metabolism by the enzyme monoamine oxidase. ## Lethal Dose The acute toxicity of bufotenin in rodents has been calculated to have an LD50 of between 200 and 300 mg/kg, which by comparison, is comparable to the LD50 for intravenous morphine (200-300 mg/kg) in mice.[18] Death occurs by respiratory arrest.[18] ## Effects in Humans ### Fabing & Hawkins (1955) In 1955, Fabing and Hawkins administered bufotenin intravenously at doses of up to 16 mg to prison inmates at Ohio State Penitentiary. [26] A troubling toxic blood circulation effect causing a purpling of the face was seen in these tests. A subject given 1 mg reported “a tight feeling in the chest” and prickling “as if he had been jabbed by needles.” This was accompanied by a “fleeting sensation of pain in both thighs and a mild nausea.” [26] Another subject given 2 mg reported “tightness in his throat”. He had tightness in the stomach, tingling in pretibial areas, and developed a purplish hue in the face indicating blood circulation problems. He vomited after 3 minutes. [26] Another subject given 4 mg complained of “chest oppression” and that “a load is pressing down from above and my body feels heavy.” The subject also reported “numbness of the entire body” and “a pleasant Martini feeling-my body is taking charge of my mind”. The subject reported he saw red spots passing before his eyes and red-purple spots on the floor, and the floor seemed very close to his face. Within 2 minutes these visual effects were gone, and replaced by a yellow haze, as if he were looking through a lens filter. [26] Fabing and Hawkins commented that bufotenin’s hallucinogenic effects were "reminiscent of LSD and mescaline but develop and dispappear more quickly, indicating rapid central action and rapid degradation of the drug". ### Isbell (1956) In 1956, Dr. Harris S. Isbell at the Public Health Service Hospital in Lexington, Kentucky experimented with bufotenine as a snuff. He reported “no subjective or objective effects were observed after spraying with as much as 40 mg bufotenine”; however subjects who received 10-12 mg injected intramuscularly reported “elements of visual hallucinations consisting of a play of colors, lights, and patterns”.[4] ### Turner & Merlis (1959) Turner and Merlis (1959) [27] experimented with intravenous administration of bufotenine (as the water soluble creatinine sulfate salt) to schizophrenics at a New York state hospital. They reported that when one subject received 10 mg during a 50-second interval, “the peripheral nervous system effects were extreme: at 17 seconds, flushing of the face, at 22 seconds, maximal inhalation, followed by maximal hyperventilation for about 2 minutes, during which the patient was unresponsive to stimuli; her face was plum-colored. Finally, Turner and Merlis reported that: After pushing doses to the morally admissible limit without producing hallucinations, Turner and Merlis conservatively concluded: “We must reject bufotenine…as capable of producing the acute phase of Cohoba intoxication”.[4] ### McLeod and Sitaram (1985) A 1985 study by McLeod and Sitaram in humans reported that bufotenine administered intranasally at a dose of 1-16 mg had no effect, other than intense local irritation. When given intravenously at low doses (2-4 mg), bufotenine oxalate caused anxiety but no other effects; however, a dose of 8 mg resulted in profound emotional and perceptual changes, involving extreme anxiety, a sense of imminent death, and visual disturbance associated with color reversal and distortion, and intense flushing of the cheeks and forehead. [28] ### Ott (2001) In 2001, Jonathan Ott, an amateur ethnobotanist, published the results of a study in which he self-administered free base bufotenin intranasally (5-100 mg), sublingually (50 mg), intrarectally (30 mg), orally (100 mg) and via vaporization (2-8 mg).[29] Ott reported “visionary effects" of intranasal bufotenine and that the "visionary threshold dose" by this route was 40 mg, with smaller doses eliciting perceptibly psychoactive effects. He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects". At 100 mg, effects began within 5 minutes, peaked at 35-40 minutes, and lasted up to 90 minutes. Higher doses produced effects that were described as hallucinogenic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque". Free base bufotenin taken sublingually was found to be identical to intranasal use. The potency, duration, and hallucinogenic action was the same. Ott found vaporized free base bufotenin active from 2-8 mg with 8 mg producing "ring-like, swirling, colored patterns with eyes closed". Ott noted that free base bufotenin taken intranasally and sublingually produced effects similar to those of Yopo without the toxic peripheral symptoms, such as facial flushing, observed in other studies in which the the drug was administered intravenously. ## Association With Schizophrenia and Other Mental Disorders A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects;[30] however, subsequent research has failed to confirm these findings.[31][32][33][34] Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders,[35] such as infant autistic patients.[36] Another study indicated that paranoid violent offenders or those who committed violent behaviour towards family members have higher bufotenin levels in their urine than other violent offenders.[37] # Legal Status Bufotenine is regulated as a Schedule I drug (ID number 7403) by the U.S. Drug Enforcement Agency.[3] It is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the government of Australia.[38]	https://www.wikidoc.org/index.php/Bufotenin
36f802f825651857579f3da45679df9b5d9600a4	wikidoc	Bumblebee	Bumblebee Bumblebees (also spelled bumble bee, also known as humblebee) are flying insects of the genus Bombus in the family Apidae. Bumblebees are social insects that are characterized by black and yellow body hairs, often in bands, a commonality among the majority of the species of Bombus. However, some species are known to have orange or even red on their bodies, or may be entirely black. Another obvious (but not unique) characteristic is the soft nature of the long, branched setae, called pile, that covers their entire body, making them appear and feel fuzzy. They are best distinguished from similarly large, fuzzy bees by the form of the female hind leg, which is modified to form a corbicula; a shiny concave surface that is bare, but surrounded by a fringe of hairs used to transport pollen (in similar bees, the hind leg is completely hairy, and pollen grains are wedged into the hairs for transport). Like their relatives the honey bees, bumblebees feed on nectar and gather pollen to feed their young. # Biology ## Anatomy The blood or hemolymph, as in other arthropods, is carried in an open circulatory system. The body organs, heart, muscles, etc. are surrounded in a reservoir of blood. The heart does pulse blood through its long tube, though, so there is a circulation of sorts. In fertilised queens the ovaries are activated and when the queen lays her egg it passes along the oviduct to the vagina. In the vagina there is a container called the spermatheca. This is where the queen stored sperm from her mating. Before she lays the egg she will decide whether to use sperm from the spermatheca to fertilise it or not. Non-fertilised eggs grow into male bumblebees, and only fertilised eggs grow into females and queens. As in all animals hormones play a big role in the growth and development of the bumblebee. The hormones that stimulate the development of the ovaries are suppressed in the other female worker bees while the queen remains dominant. Salivary glands in the head secrete saliva which is mixed with the nectar and pollen. Saliva is also mixed into the nest materials to soften them. The bumblebee tongue is specialised to suck up nectar via capillary action. At rest or when flying the tongue is kept inside a sheath and folded under the head and thorax. The abdomen is covered with dorsal tergites and ventral sternites. Wax is secreted between these plates. The brightly-coloured pile of the bumble bee is a form of aposematic signal. Depending on the species and morph, these colours can range from entirely black, to bright yellow, red, orange, white, and pink. Thick pile can also act as insulation to keep the bee warm in cold weather. Further, when flying a bee builds up an electrostatic charge, and as flowers are usually well grounded, pollen is attracted to the bee's pile when it lands. When a pollen covered bee enters a flower, the charged pollen is preferentially attracted to the stigma because it is better grounded than the other parts of the flower. A bumblebee does not have ears, and it is not known whether or how a bumblebee can hear sound waves passing through the air, however they can feel the vibrations of sounds through wood and other materials. The heart, like that in most other insects, runs down the entire length of the body. The fat body is a nutritional store. Before hibernation queens eat as much as they can to enlarge their fat body. The fat in the cells is used up during hibernation. ## Habitat Bumblebees are typically found in higher latitudes and/or high altitudes, though exceptions exist (there are a few lowland tropical species). A few species (Bombus polaris and B. arcticus) range into very cold climates where other bees might not be found. One reason for this is that bumblebees can regulate their body temperature, via solar radiation, internal mechanisms of "shivering" and radiative cooling from the abdomen (called heterothermy). Other bees have similar physiology, but it has been best studied in bumblebees. ## Nests Bumblebees form colonies. However, their colonies are usually much less extensive than those of honey bees, because of the small physical size of the nest cavity, the fact that a single female is responsible for the initial construction and reproduction that happens within the nest, and the restriction to a single season (in most species). Often, mature bumblebee nests will hold fewer than 50 individuals, and may be within tunnels in the ground made by other animals, or in tussock grass. Bumblebees sometimes construct a wax canopy ("involucrum") over top of their nest for protection and insulation. Bumblebees mostly do not preserve their nests through the winter, though some tropical species live in their nests for several years (and their colonies can grow quite large, depending on the size of the nest cavity). The last generation of summer includes a number of queens who overwinter separately in protected spots. The queens can live up to one year, possibly longer in tropical species. ## Colony cycle Bumblebee nests are first constructed by over-wintered queens in the spring (in temperate areas). Upon emerging from hibernation, the queen collects pollen and nectar from flowers and searches for a suitable nest site. The characteristics of the nest site vary among bumble bee species, with some species preferring to nest in underground holes and others in tussock grass or directly on the ground. Once the queen has found a site, she prepares wax pots to store food and wax cells into which eggs are laid. These eggs then hatch into larvae, which cause the wax cells to expand isometrically into a clump of brood cells. These larvae need to be fed both nectar for carbohydrates and pollen for protein in order to develop. Bumblebees feed larvae nectar by chewing a small hole in the brood cell into which nectar is regurgitated. Larvae are fed pollen in two ways, depending on the bumblebee species. So called "pocket-maker" bumblebees create pockets of pollen at the base of the brood cell clump from which the larvae can feed themselves. Conversely, "pollen-storer" store pollen in separate wax pots and feed it to the larva in the same fashion as nectar. Bumble bees are incapable of trophallaxis. With proper care, the larvae progress through four instars, becoming successively larger with each molt. At the end of the fourth instar the larvae spin a silk cocoon under the wax covering the brood cell, changing it into a pupal cell. The larvae then undergo an intense period of cellular growth and differentiation and become pupae. These pupae then develop into adult bees, who chew their way out of the silk cocoon. When adult bumble bees first emerge from their cocoons, the hairs on their body are not yet fully pigmented and are a greyish-white colour. The bees are referred to as "callow" during this time, and they will not leave the colony for at least 24 hours. The entire process from egg to adult bee can take as long as five weeks, depending on the species and the environmental conditions. After the emergence of the first or second group of workers, workers take over the task of foraging and the queen spends most of her time laying eggs and caring for larvae. The colony grows progressively larger and at some point will begin to produce males and new queens. The point at which this occurs varies among species and is heavily dependant on resource availability and environmental factors. Unlike the workers of more advanced social insects, bumble bee workers are not physically reproductively sterile and are able to lay haploid eggs that develop into viable male bumble bees. Only fertilized queens can lay diploid eggs that mature into workers and new queens. Early in the colony cycle, the queen bumble bee compensates for potential reproductive competition from workers by suppressing their egg-laying by way of physical aggression and pheromonal signals. Thus, the queen will usually be the mother of all of the first males laid. Workers eventually begin to lay males later in the season when the queen's ability to suppress their reproduction diminishes. The reproductive competition between workers and the queen is one reason that bumble bees are considered "primitively eusocial". New queens and males leave the colony after maturation. Males in particular are forcibly driven out by the workers. Away from the colony, the new queens and males live off nectar and pollen and spend the night on flowers or in holes. The queens are eventually mated (often more than once) and search a for suitable location for diapause. ## Foraging behavior Bumblebees generally visit flowers exhibiting the bee pollination syndrome. They can visit patches of flowers up to 1-2 kilometres from their colony. Bumblebees will also tend to visit the same patches of flowers every day, as long as nectar and pollen continue to be available. While foraging, bumblebees can reach ground speeds of up to 15 m/s (54 kph). When bumblebees arrive at a flower, they extract nectar using their long tongue ("glossa") and store it in their crop. Many species of bumblebee also exhibit what is known as "nectar robbing": instead of inserting the mouthparts into the flower normally, these bees bite directly through the base of the corolla to extract nectar, avoiding pollen transfer. These bees obtain pollen from other species of flowers that they "legitimately" visit. Pollen is removed from flowers deliberately or incidentally by bumblebees. Incidental removal occurs when bumblebees come in contact with the anthers of a flower while collecting nectar. The bumblebee's body hairs receive a dusting of pollen from the anthers which is then groomed into the corbiculae ("pollen baskets"). Bumblebees are also capable of buzz pollination. In at least a few species, once a bumblebee has visited a flower, it leaves a scent mark on the flower. This scent mark deters visitation of the flower by other bumblebees until the scent degrades. Once they have collected nectar and pollen, bumblebees return to the nest and deposit the harvested nectar and pollen into brood cells, or into wax cells for storage. Unlike honey bees, bumblebees only store a few days' worth of food and so are much more vulnerable to food shortages. However, because bumblebees are much more opportunistic feeders than honey bees, these shortages may have less profound effects. Nectar is stored essentially in the form it was collected, rather than being processed into honey as is done in honey bees; it is therefore very dilute and watery, and is rarely consumed by humans. ## "Cuckoo" bumblebees Bumblebees of the sub genus Psithyrus (known as cuckoo bumblebees, and formerly considered a separate genus) are a lineage which has lost the ability to collect pollen, and live parasitically in the colonies of other bumblebees. Before finding and invading a host colony, a Psithyrus female (there is no caste system in these species) will feed directly from flowers. Once she has infiltrated a host colony, the Psithyrus female will kill or subdue the queen of that colony and forcibly (using pheromones and/or physical attacks) "enslave" the workers of that colony to feed her and her young. The female Psithyrus also has a number of morphological adaptations, such as larger mandibles and a larger venom sac that increase her chances of taking over a nest. Upon hatching, the male and female Psithyrus disperse and mate. Like non-parasitic bumblebee queens, female Psithyrus find suitable locations to spend the winter and enter diapause upon being mated. ## Reproduction In temperate zone species, in the autumn, young queens ("gynes") mate with males (drones) and diapause during the winter in a sheltered area, whether in the ground or in a man-made structure. In the early spring, the queen comes out of diapause and finds a suitable place to create her colony, and then builds wax cells in which to lay her fertilized eggs from the previous winter. The eggs that hatch develop into female workers, and in time the queen populates the colony, with workers feeding the young and performing other duties similar to honey bee workers. New reproductives are produced in autumn, and the queen and workers die, as do the males. # Sting Queen and worker bumblebees can sting, but, like virtually all bees, the sting is not barbed (only honey bees have a barbed sting), so they can sting more than once. Bumblebee species are non-aggressive, but will sting in defense of their nest, or if harmed. Female cuckoo bumblebees will aggressively attack host colony members, and sting the host queen, but will ignore other animals (including humans) unless disturbed. See Schmidt Sting Pain Index. # Bumblebees and people Bumblebees are important pollinators of both crops and wildflowers. ## Agricultural use Bumblebees are increasingly cultured for agricultural use as pollinators because they can pollinate plant species that other pollinators cannot by using a technique known as buzz pollination. For example, bumblebee colonies are often emplaced in greenhouse tomato production, because the frequency of buzzing that a bumblebee exhibits effectively releases tomato pollen. The agricultural use of bumblebees is limited to pollination. Because bumblebees do not overwinter the entire colony, they are not obliged to stockpile honey, and are therefore not useful as honey producers. ## Endangered status Bumblebees are in danger in many developed countries due to habitat destruction and collateral pesticide damage. In Britain, until relatively recently, 19 species of native true bumblebee were recognised along with six species of cuckoo bumblebees. Of these, three have already become extinct, eight are in serious decline and only six remain widespread. A decline in bumblebee numbers could cause large-scale sweeping changes to the countryside, due to inadequate pollination of certain plants. In response to this, a new organisation has recently been set up - The Bumblebee Conservation Trust aims to halt these declines through conservation and education (see links). ## Alias "Dumbledor" is an alternate name for the bumblebee. The bumblebee's buzzing sound is the quality for which they (as well as the cockchafer or scarab beetle) are given this name. Dor is applied in names like dorbeetle, dorbug, and dorfly, to refer to a humming or drone noise produced by the particular insect. ## In popular culture - The young Autobot Bumblebee is one of the characters of the Transformers series. - The Flight of the Bumblebee is a famous orchestral interlude written by Nikolai Rimsky-Korsakov for his opera The Tale of Tsar Saltan, composed in 1899-1900. - The character Bumblebee Man from The Simpsons is a Mexican slapstick comedian who dresses in a bumblebee costume. He is based on El Chapulín Colorado, a famous Mexican comedy character who dresses in a red grasshopper costume. - In the north-east of Scotland bumblebees are known as 'foggy bummers'. - Buck Bumblebee was a Nintendo 64 game starring the titular Bee in battle against villainous bugs. # Bumblebee myths ## Flight According to 20th century folklore, the laws of aerodynamics prove that the bumblebee should be incapable of flight, as it does not have the capacity (in terms of wing size or beat per second) to achieve flight with the degree of wing loading necessary. Not being aware of scientists 'proving' it cannot fly, the bumblebee succeeds under "the power of its own arrogance". The origin of this myth has been difficult to pin down with any certainty. John McMasters recounted an anecdote about an unnamed Swiss aerodynamicist at a dinner party who performed some rough calculations and concluded, presumably in jest, that according to the equations, bumblebees cannot fly. In later years McMasters has backed away from this origin, suggesting that there could be multiple sources, and that the earliest he has found was a reference in the 1934 French book Le vol des insectes by M. Magnan. Magnan is reported to have written that he and a Mr. Saint-Lague had applied the equations of air resistance to insects and found that their flight was impossible, but that "One shouldn't be surprised that the results of the calculations don't square with reality". It is believed that the calculations which purported to show that bumblebees cannot fly are based upon a simplified linear treatment of oscillating aerofoils. The method assumes small amplitude oscillations without flow separation. This ignores the effect of dynamic stall, an airflow separation inducing a large vortex above the wing, which briefly produces several times the lift of the aerofoil in regular flight. More sophisticated aerodynamic analysis shows that the bumblebee can fly because its wings encounter dynamic stall in every oscillation cycle. ## Buzz One common, yet incorrect, assumption is that the buzzing sound of bees is caused by the beating of their wings. The sound is the result of the bee vibrating its flight muscles, and this can be done while the muscles are decoupled from the wings, a feature known in bees but not possessed by other insects. This is especially pronounced in bumblebees, as they must warm up their bodies considerably to get airborne at low ambient temperatures. This is how bumblebees can sometimes reach an internal thoracic temperature of 30 degrees Celsius. # Selected species For a complete list, see List of world bumblebee species. - Bombus affinis - Bombus appositus - Bombus ashtoni - Bombus bifarius - Two-spotted Bumblebee, Bombus bimaculatus - Bombus borealis - Bombus citrinus - Cullum's bumblebee, Bombus cullumanus - Great Yellow bumblebee, Bombus distinguendus - Golden Northern Bumblebee, Bombus fervidus - Yellow-faced bumblebee, Bombus flavifrons - Bombus fraternus - Bombus frigidus - Grey-necked bumblebee, Bombus griseocollis - Small Garden bumblebee, Bombus hortorum - Frisky bumblebee Bombus impatiens - Bombus insularis - Bombus kirbyellus - Red-tailed bumblebee, Bombus lapidarius - Bombus lucorum - Orange-rumped Bumblebee, Bombus melanopygus - Blaeberry Bumblebee, Bombus monticola - Bombus occidentalis - Bombus pascuorum - Bombus pensylvanicus - Bombus perplexus - Northern bumblebee, Bombus polaris - Early Bumblebee, Bombus pratorum - Large Garden bumblebee, Bombus ruderatus - Bombus rufocinctus - Short-haired bumblebee, Bombus subterraneus - Shrill Carder bee, Bombus sylvarum - Bombus sylvicola - Orange-belted bumblebee Bombus ternarius - Buff-Tailed bumblebee, or Large Earth Bumblebee, Bombus terrestris - Bombus vagans # Associated parasites - Tracheal mites - Locustacarus buchneri - Protozoans- Crithidia bombi - Microsporidia- Nosema bombi	Bumblebee Bumblebees (also spelled bumble bee, also known as humblebee) are flying insects of the genus Bombus in the family Apidae. Bumblebees are social insects that are characterized by black and yellow body hairs, often in bands, a commonality among the majority of the species of Bombus. However, some species are known to have orange or even red on their bodies, or may be entirely black.[1] Another obvious (but not unique) characteristic is the soft nature of the long, branched setae, called pile, that covers their entire body, making them appear and feel fuzzy. They are best distinguished from similarly large, fuzzy bees by the form of the female hind leg, which is modified to form a corbicula; a shiny concave surface that is bare, but surrounded by a fringe of hairs used to transport pollen (in similar bees, the hind leg is completely hairy, and pollen grains are wedged into the hairs for transport). Like their relatives the honey bees, bumblebees feed on nectar and gather pollen to feed their young. # Biology Template:FixHTML Template:FixHTML Template:FixHTML Template:FixHTML Template:FixHTML Template:FixHTML ## Anatomy The blood or hemolymph, as in other arthropods, is carried in an open circulatory system. The body organs, heart, muscles, etc. are surrounded in a reservoir of blood. The heart does pulse blood through its long tube, though, so there is a circulation of sorts. In fertilised queens the ovaries are activated and when the queen lays her egg it passes along the oviduct to the vagina. In the vagina there is a container called the spermatheca. This is where the queen stored sperm from her mating. Before she lays the egg she will decide whether to use sperm from the spermatheca to fertilise it or not. Non-fertilised eggs grow into male bumblebees, and only fertilised eggs grow into females and queens. As in all animals hormones play a big role in the growth and development of the bumblebee. The hormones that stimulate the development of the ovaries are suppressed in the other female worker bees while the queen remains dominant. Salivary glands in the head secrete saliva which is mixed with the nectar and pollen. Saliva is also mixed into the nest materials to soften them. The bumblebee tongue is specialised to suck up nectar via capillary action. At rest or when flying the tongue is kept inside a sheath and folded under the head and thorax. The abdomen is covered with dorsal tergites and ventral sternites. Wax is secreted between these plates. The brightly-coloured pile of the bumble bee is a form of aposematic signal. Depending on the species and morph, these colours can range from entirely black, to bright yellow, red, orange, white, and pink. Thick pile can also act as insulation to keep the bee warm in cold weather. Further, when flying a bee builds up an electrostatic charge, and as flowers are usually well grounded, pollen is attracted to the bee's pile when it lands. When a pollen covered bee enters a flower, the charged pollen is preferentially attracted to the stigma because it is better grounded than the other parts of the flower. A bumblebee does not have ears, and it is not known whether or how a bumblebee can hear sound waves passing through the air, however they can feel the vibrations of sounds through wood and other materials. The heart, like that in most other insects, runs down the entire length of the body. The fat body is a nutritional store. Before hibernation queens eat as much as they can to enlarge their fat body. The fat in the cells is used up during hibernation. ## Habitat Bumblebees are typically found in higher latitudes and/or high altitudes, though exceptions exist (there are a few lowland tropical species). A few species (Bombus polaris and B. arcticus) range into very cold climates where other bees might not be found. One reason for this is that bumblebees can regulate their body temperature, via solar radiation, internal mechanisms of "shivering" and radiative cooling from the abdomen (called heterothermy). Other bees have similar physiology, but it has been best studied in bumblebees.[2] ## Nests Bumblebees form colonies. However, their colonies are usually much less extensive than those of honey bees, because of the small physical size of the nest cavity, the fact that a single female is responsible for the initial construction and reproduction that happens within the nest, and the restriction to a single season (in most species). Often, mature bumblebee nests will hold fewer than 50 individuals, and may be within tunnels in the ground made by other animals, or in tussock grass. Bumblebees sometimes construct a wax canopy ("involucrum") over top of their nest for protection and insulation. Bumblebees mostly do not preserve their nests through the winter, though some tropical species live in their nests for several years (and their colonies can grow quite large, depending on the size of the nest cavity). The last generation of summer includes a number of queens who overwinter separately in protected spots. The queens can live up to one year, possibly longer in tropical species. ## Colony cycle Bumblebee nests are first constructed by over-wintered queens in the spring (in temperate areas). Upon emerging from hibernation, the queen collects pollen and nectar from flowers and searches for a suitable nest site. The characteristics of the nest site vary among bumble bee species, with some species preferring to nest in underground holes and others in tussock grass or directly on the ground. Once the queen has found a site, she prepares wax pots to store food and wax cells into which eggs are laid. These eggs then hatch into larvae, which cause the wax cells to expand isometrically into a clump of brood cells. These larvae need to be fed both nectar for carbohydrates and pollen for protein in order to develop. Bumblebees feed larvae nectar by chewing a small hole in the brood cell into which nectar is regurgitated. Larvae are fed pollen in two ways, depending on the bumblebee species. So called "pocket-maker" bumblebees create pockets of pollen at the base of the brood cell clump from which the larvae can feed themselves. Conversely, "pollen-storer" store pollen in separate wax pots and feed it to the larva in the same fashion as nectar.[3] Bumble bees are incapable of trophallaxis. With proper care, the larvae progress through four instars, becoming successively larger with each molt. At the end of the fourth instar the larvae spin a silk cocoon under the wax covering the brood cell, changing it into a pupal cell. The larvae then undergo an intense period of cellular growth and differentiation and become pupae. These pupae then develop into adult bees, who chew their way out of the silk cocoon. When adult bumble bees first emerge from their cocoons, the hairs on their body are not yet fully pigmented and are a greyish-white colour. The bees are referred to as "callow" during this time, and they will not leave the colony for at least 24 hours. The entire process from egg to adult bee can take as long as five weeks, depending on the species and the environmental conditions. After the emergence of the first or second group of workers, workers take over the task of foraging and the queen spends most of her time laying eggs and caring for larvae. The colony grows progressively larger and at some point will begin to produce males and new queens. The point at which this occurs varies among species and is heavily dependant on resource availability and environmental factors. Unlike the workers of more advanced social insects, bumble bee workers are not physically reproductively sterile and are able to lay haploid eggs that develop into viable male bumble bees. Only fertilized queens can lay diploid eggs that mature into workers and new queens. Early in the colony cycle, the queen bumble bee compensates for potential reproductive competition from workers by suppressing their egg-laying by way of physical aggression and pheromonal signals.[4] Thus, the queen will usually be the mother of all of the first males laid. Workers eventually begin to lay males later in the season when the queen's ability to suppress their reproduction diminishes.[5] The reproductive competition between workers and the queen is one reason that bumble bees are considered "primitively eusocial". New queens and males leave the colony after maturation. Males in particular are forcibly driven out by the workers. Away from the colony, the new queens and males live off nectar and pollen and spend the night on flowers or in holes. The queens are eventually mated (often more than once) and search a for suitable location for diapause. ## Foraging behavior Template:FixHTML Template:FixHTML Bumblebees generally visit flowers exhibiting the bee pollination syndrome. They can visit patches of flowers up to 1-2 kilometres from their colony.[6] Bumblebees will also tend to visit the same patches of flowers every day, as long as nectar and pollen continue to be available.[7] While foraging, bumblebees can reach ground speeds of up to 15 m/s (54 kph).[8] When bumblebees arrive at a flower, they extract nectar using their long tongue ("glossa") and store it in their crop. Many species of bumblebee also exhibit what is known as "nectar robbing": instead of inserting the mouthparts into the flower normally, these bees bite directly through the base of the corolla to extract nectar, avoiding pollen transfer.[9] These bees obtain pollen from other species of flowers that they "legitimately" visit. Pollen is removed from flowers deliberately or incidentally by bumblebees. Incidental removal occurs when bumblebees come in contact with the anthers of a flower while collecting nectar. The bumblebee's body hairs receive a dusting of pollen from the anthers which is then groomed into the corbiculae ("pollen baskets"). Bumblebees are also capable of buzz pollination. In at least a few species, once a bumblebee has visited a flower, it leaves a scent mark on the flower. This scent mark deters visitation of the flower by other bumblebees until the scent degrades.[10] Once they have collected nectar and pollen, bumblebees return to the nest and deposit the harvested nectar and pollen into brood cells, or into wax cells for storage. Unlike honey bees, bumblebees only store a few days' worth of food and so are much more vulnerable to food shortages. However, because bumblebees are much more opportunistic feeders than honey bees, these shortages may have less profound effects. Nectar is stored essentially in the form it was collected, rather than being processed into honey as is done in honey bees; it is therefore very dilute and watery, and is rarely consumed by humans. ## "Cuckoo" bumblebees Bumblebees of the sub genus Psithyrus (known as cuckoo bumblebees, and formerly considered a separate genus) are a lineage which has lost the ability to collect pollen, and live parasitically in the colonies of other bumblebees. Before finding and invading a host colony, a Psithyrus female (there is no caste system in these species) will feed directly from flowers. Once she has infiltrated a host colony, the Psithyrus female will kill or subdue the queen of that colony and forcibly (using pheromones and/or physical attacks) "enslave" the workers of that colony to feed her and her young.[11] The female Psithyrus also has a number of morphological adaptations, such as larger mandibles and a larger venom sac that increase her chances of taking over a nest.[12] Upon hatching, the male and female Psithyrus disperse and mate. Like non-parasitic bumblebee queens, female Psithyrus find suitable locations to spend the winter and enter diapause upon being mated. ## Reproduction In temperate zone species, in the autumn, young queens ("gynes") mate with males (drones) and diapause during the winter in a sheltered area, whether in the ground or in a man-made structure. In the early spring, the queen comes out of diapause and finds a suitable place to create her colony, and then builds wax cells in which to lay her fertilized eggs from the previous winter. The eggs that hatch develop into female workers, and in time the queen populates the colony, with workers feeding the young and performing other duties similar to honey bee workers. New reproductives are produced in autumn, and the queen and workers die, as do the males. # Sting Queen and worker bumblebees can sting, but, like virtually all bees, the sting is not barbed (only honey bees have a barbed sting), so they can sting more than once.[13] Bumblebee species are non-aggressive, but will sting in defense of their nest, or if harmed. Female cuckoo bumblebees will aggressively attack host colony members, and sting the host queen, but will ignore other animals (including humans) unless disturbed. See Schmidt Sting Pain Index. # Bumblebees and people Bumblebees are important pollinators of both crops and wildflowers. ## Agricultural use Bumblebees are increasingly cultured for agricultural use as pollinators because they can pollinate plant species that other pollinators cannot by using a technique known as buzz pollination. For example, bumblebee colonies are often emplaced in greenhouse tomato production, because the frequency of buzzing that a bumblebee exhibits effectively releases tomato pollen.[14] The agricultural use of bumblebees is limited to pollination. Because bumblebees do not overwinter the entire colony, they are not obliged to stockpile honey, and are therefore not useful as honey producers. ## Endangered status Bumblebees are in danger in many developed countries due to habitat destruction and collateral pesticide damage. In Britain, until relatively recently, 19 species of native true bumblebee were recognised along with six species of cuckoo bumblebees. Of these, three have already become extinct,[15][16] eight are in serious decline and only six remain widespread. A decline in bumblebee numbers could cause large-scale sweeping changes to the countryside, due to inadequate pollination of certain plants. In response to this, a new organisation has recently been set up - The Bumblebee Conservation Trust aims to halt these declines through conservation and education (see links). ## Alias "Dumbledor" is an alternate name for the bumblebee. The bumblebee's buzzing sound is the quality for which they (as well as the cockchafer or scarab beetle) are given this name. Dor is applied in names like dorbeetle, dorbug, and dorfly, to refer to a humming or drone noise produced by the particular insect.[17] ## In popular culture - The young Autobot Bumblebee is one of the characters of the Transformers series. - The Flight of the Bumblebee is a famous orchestral interlude written by Nikolai Rimsky-Korsakov for his opera The Tale of Tsar Saltan, composed in 1899-1900. - The character Bumblebee Man from The Simpsons is a Mexican slapstick comedian who dresses in a bumblebee costume. He is based on El Chapulín Colorado, a famous Mexican comedy character who dresses in a red grasshopper costume. - In the north-east of Scotland bumblebees are known as 'foggy bummers'.[18] - Buck Bumblebee was a Nintendo 64 game starring the titular Bee in battle against villainous bugs. # Bumblebee myths ## Flight According to 20th century folklore, the laws of aerodynamics prove that the bumblebee should be incapable of flight, as it does not have the capacity (in terms of wing size or beat per second) to achieve flight with the degree of wing loading necessary. Not being aware of scientists 'proving' it cannot fly, the bumblebee succeeds under "the power of its own arrogance".[19] The origin of this myth has been difficult to pin down with any certainty. John McMasters recounted an anecdote about an unnamed Swiss aerodynamicist at a dinner party who performed some rough calculations and concluded, presumably in jest, that according to the equations, bumblebees cannot fly.[20] In later years McMasters has backed away from this origin, suggesting that there could be multiple sources, and that the earliest he has found was a reference in the 1934 French book Le vol des insectes by M. Magnan. Magnan is reported to have written that he and a Mr. Saint-Lague had applied the equations of air resistance to insects and found that their flight was impossible, but that "One shouldn't be surprised that the results of the calculations don't square with reality".[21] It is believed that the calculations which purported to show that bumblebees cannot fly are based upon a simplified linear treatment of oscillating aerofoils. The method assumes small amplitude oscillations without flow separation. This ignores the effect of dynamic stall, an airflow separation inducing a large vortex above the wing, which briefly produces several times the lift of the aerofoil in regular flight. More sophisticated aerodynamic analysis shows that the bumblebee can fly because its wings encounter dynamic stall in every oscillation cycle.[1] ## Buzz One common, yet incorrect, assumption is that the buzzing sound of bees is caused by the beating of their wings. The sound is the result of the bee vibrating its flight muscles, and this can be done while the muscles are decoupled from the wings, a feature known in bees but not possessed by other insects. This is especially pronounced in bumblebees, as they must warm up their bodies considerably to get airborne at low ambient temperatures.[2] This is how bumblebees can sometimes reach an internal thoracic temperature of 30 degrees Celsius. # Selected species For a complete list, see List of world bumblebee species. - Bombus affinis - Bombus appositus - Bombus ashtoni - Bombus bifarius - Two-spotted Bumblebee, Bombus bimaculatus - Bombus borealis - Bombus citrinus - Cullum's bumblebee, Bombus cullumanus - Great Yellow bumblebee, Bombus distinguendus - Golden Northern Bumblebee, Bombus fervidus - Yellow-faced bumblebee, Bombus flavifrons - Bombus fraternus - Bombus frigidus - Grey-necked bumblebee, Bombus griseocollis - Small Garden bumblebee, Bombus hortorum - Frisky bumblebee Bombus impatiens - Bombus insularis - Bombus kirbyellus - Red-tailed bumblebee, Bombus lapidarius - Bombus lucorum - Orange-rumped Bumblebee, Bombus melanopygus - Blaeberry Bumblebee, Bombus monticola[22][23] - Bombus occidentalis - Bombus pascuorum - Bombus pensylvanicus - Bombus perplexus - Northern bumblebee, Bombus polaris - Early Bumblebee, Bombus pratorum - Large Garden bumblebee, Bombus ruderatus - Bombus rufocinctus - Short-haired bumblebee, Bombus subterraneus - Shrill Carder bee, Bombus sylvarum - Bombus sylvicola - Orange-belted bumblebee Bombus ternarius - Buff-Tailed bumblebee, or Large Earth Bumblebee, Bombus terrestris - Bombus vagans # Associated parasites - Tracheal mites - Locustacarus buchneri - Protozoans- Crithidia bombi - Microsporidia- Nosema bombi	https://www.wikidoc.org/index.php/Bumblebee
270f6dfb679f5105fae8b84e1d8e8c7629fd57bb	wikidoc	Burosumab	Burosumab # 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 Burosumab is a fibroblast growth factor 23 (FGF23) blocking antibody that is FDA approved for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. Common adverse reactions include headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Burosumab is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. - The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks. - After initiation of treatment with burosumab, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose. Dose Decrease - Reassess fasting serum phosphorus level 2 weeks after dose adjustment. - Do not adjust burosumab more frequently than every 4 weeks. - If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks. The patient must have serum phosphorus below the normal range to be able to reinitiate burosumab. Once serum phosphorus is below the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3. Reassess serum phosphorus 2 weeks after any change in dose. - If a patient misses a dose, resume burosumab as soon as possible at the prescribed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding burosumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding burosumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Burosumab is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. - The recommended starting dose regimen is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. - After initiation of treatment with burosumab, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule below to maintain serum phosphorus within the reference range for age. Dose Adjustment - Reassess fasting serum phosphorus level 4 weeks after dose adjustment. - Do not adjust burosumab more frequently than every 4 weeks. - Dose Increase: If serum phosphorus is below the reference range for age, the dose may be increased stepwise up to approximately 2 mg/kg, administered every two weeks (maximum dose of 90 mg) according to the dosing schedule shown in Table 1. - Dose Decrease: If serum phosphorus is above 5 mg/dL, withhold the next dose and reassess the serum phosphorus level in 4 weeks. The patient must have serum phosphorus below the reference range for age to reinitiate burosumab. Once serum phosphorus is below the reference range for age, treatment may be restarted according to the dose schedule shown in Table 2. Reassess serum phosphorus level 4 weeks after dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted according to Table 1. - If a patient misses a dose, resume burosumab as soon as possible at the prescribed dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding burosumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding burosumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Do not use burosumab with oral phosphate and active vitamin D analogs. - Do not initiate burosumab treatment if serum phosphorus is within or above the normal range for age. - Burosumab is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism. # Warnings - Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with burosumab. Discontinue burosumab if serious hypersensitivity reactions occur and initiate appropriate medical treatment. - Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking burosumab, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels. - Administration of burosumab may result in local injection site reactions. Discontinue burosumab if severe injection site reactions occur and administer appropriate medical treatment. # 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 data described below reflect exposure to burosumab in 65 pediatric XLH patients that included 52 exposed for at least 64 weeks (Study 1) and 13 exposed for at least 40 weeks (Study 2). Overall, pediatric XLH patients have been exposed to burosumab for a mean duration of 108 weeks (min 40.9, max 150.0). Burosumab was studied in two pediatric open-label phase 2 studies (Study 1, ages 5 to 12 years, n = 52; Study 2, ages ≥ 1 to < 5 years, n = 13). Overall, the patient population was 1-12 years (mean age 7.4 years), 51% male, and 89% white/Caucasian and diagnosed with XLH. In Study 1, 26 of the patients received burosumab at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received burosumab every 4 weeks. In Study 2, patients received burosumab at a mean dose of 0.89 mg/kg (range 0.8 – 1.2 mg/kg) every 2 weeks at Week 40. Adverse reactions reported in more than 10% of burosumab-treated patients from Studies 1 and 2 are shown in Table 4. Hypersensitivity Reactions - In pediatric patients, the most frequent potential hypersensitivity events were rash (22%), injection site rash (6%), and urticaria (5%). Hyperphosphatemia - In pediatric studies, there were no events of hyperphosphatemia reported. Injection Site Reactions (ISR) - In pediatric studies, approximately 58% of the patients had a local reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of burosumab injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. - The safety data described below reflect exposure to burosumab in 68 adult XLH patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%). These patients were enrolled in a randomized, double-blind, placebo-controlled Phase 3 study in adults with XLH (Study 3: burosumab = 68, Placebo = 66), in which patients received burosumab at a mean dose of 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks at Week 24. Adverse reactions reported in more than 5% of burosumab-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 3 are shown in Table 5. Hypersensitivity Reactions - In the double-blind period of Study 3, approximately 6% of patients in both the burosumab and placebo treatment groups experienced a hypersensitivity event. The events were mild or moderate and did not require discontinuation. Hyperphosphatemia - In the double-blind period of Study 3, 7% of patients in the burosumab treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent. A single patient required a second dose reduction for continued hyperphosphatemia. Injection Site Reactions (ISR) - In the double-blind period of Study 3, approximately 12% of patients in both the burosumab and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. Restless Leg Syndrome (RLS) - In the double-blind period of Study 3, approximately 12% of the burosumab treatment group had worsening of baseline restless leg syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation. Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event. Spinal Stenosis - Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. In the burosumab phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 6 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if burosumab therapy exacerbates spinal stenosis or spinal cord compression. ### Immunogenicity - As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to burosumab-twza in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - Pre-existing anti-drug antibodies (ADA) have been detected in up to 10% of patients in clinical studies. ADA was not detected in patients who were antibody negative at the start of treatment. However, the assay used to measure ADA is subject to interference by serum burosumab-twza, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to burosumab-twza is not known. ## Postmarketing Experience There is limited information regarding Burosumab Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Burosumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data on burosumab use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to indicate clinical risk because they occurred at a drug exposure that was 64-fold higher, by AUC, than the human exposure at 1 mg/kg every 4 weeks and were accompanied in the non-XLH monkeys by maternal hyperphosphatemia and placental mineralization (see Data). Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657. - The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. - In a reproductive toxicity study in pregnant cynomolgus monkeys without XLH, burosumab-twza was administered intravenously once every two weeks from Day 20 of pregnancy to parturition or cesarean section on Day 133, which includes the period of organogenesis, at doses of 1-, 7- and 64-fold human exposure at the adult human dose of 1 mg/kg every 4 weeks. The treatment did not result in teratogenic effects in fetuses or offspring. An increase in late fetal loss, a shortened gestation period, and an increased incidence of preterm births were observed at 64-fold the human exposure at the adult human dose of 1 mg/kg every 4 weeks, concomitant with maternal hyperphosphatemia and placental mineralization. Burosumab-twza was detected in serum from fetuses indicating transport across the placenta. Hyperphosphatemia but no ectopic mineralization was present in fetuses and offspring of dams exposed to 64-fold human exposure at the 1 mg/kg dose every 4 weeks. Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Burosumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Burosumab during labor and delivery. ### Nursing Mothers - There is no information regarding the presence of burosumab-twza in human milk, or the effects of burosumab-twza on milk production or the breastfed infant. Maternal IgG is present in breast milk. However, the effects of local gastrointestinal exposure and limited systemic exposure to burosumab-twza in the breastfed infant are unknown. The lack of clinical data during lactation precludes a clear determination of the risk of burosumab to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for burosumab and any potential adverse effects on the breastfed infant from burosumab or from the underlying maternal condition. ### Pediatric Use - Safety and efficacy of burosumab have been established in pediatric patients 1 year and older. Efficacy in pediatric patients 1 year and older with XLH is based on open label studies of 52 pediatric patients 5 to 12 years of age with XLH (Study 1), and in 13 pediatric patients 1 to 4 years of age with XLH (Study 2) evaluating serum phosphorus and radiographic findings. Efficacy in adolescents is supported by studies in pediatric patients less than 13 years of age. Dosing in this age group was derived using modeling and simulation of adult and pediatric PK and PD data. - Safety and efficacy for burosumab in pediatric patients with XLH below the age of 1 have not been established. ### Geriatic Use - Clinical studies of burosumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 Burosumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Burosumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Burosumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Burosumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Burosumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Burosumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Injection sites should be rotated with each injection administered at a different anatomic location (upper arms, upper thighs, buttocks, or any quadrant of abdomen) than the previous injection. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. The maximum volume of burosumab per injection site is 1.5 mL. If more than 1.5 mL is required on a given dosing day, the total volume of burosumab should be split and administered at two different injection sites. Monitor for signs of reactions. - Visually inspect burosumab for particulate matter and discoloration prior to administration. Burosumab is a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution for subcutaneous injection. Do not use if the solution is discolored or cloudy or if the solution contains any particles or foreign particulate matter. ### Monitoring - Clinical improvement of hypophosphatemia may be indicative of efficacy. - Fasting serum phosphorus level: Prior to therapy initiation in all patients. - Fasting serum phosphorus level: Every 4 weeks for the first 3 months and then as clinically indicated in pediatric patients. - Fasting serum phosphorus level: Monthly, 2 weeks after dose is given, for the first 3 months and then as clinically indicated in adult patients. - Injection site reactions. # IV Compatibility There is limited information regarding the compatibility of Burosumab and IV administrations. # Overdosage - There have been no reports of overdose with burosumab. Burosumab has been administered in pediatric clinical trials without dose limiting toxicity using doses up to 2 mg/kg body weight with a maximal dose of 90 mg, administered every two weeks. In adult clinical trials, no dose limiting toxicity has been observed using doses up to 1 mg/kg or a maximal total dose of 128 mg every 4 weeks. In non-XLH rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were also observed at exposure greater than human exposure. - In case of overdose, it is recommended that serum phosphorus levels, serum calcium levels and renal function be measured immediately and monitored periodically until resolution to normal/baseline levels. In case of hyperphosphatemia, withhold burosumab and initiate appropriate medical treatment. # Pharmacology ## Mechanism of Action - X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D. ## Structure There is limited information regarding Burosumab Structure in the drug label. ## Pharmacodynamics - Following SC administration in XLH patients, higher burosumab-twza concentrations were associated with greater increase of serum phosphorus levels. The increase in serum phosphorus was reversible and returned to baseline with elimination of systemic burosumab-twza. - Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) showed dose-dependent increases from baseline. - Elevation in serum total FGF23 was observed after initiation of burosumab-twza treatment, however, the clinical implication is unknown. ## Pharmacokinetics - The following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified. - Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient). - The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in adult patients. - The burosumab-twza mean Tmax values ranged from 8 to 11 days. - The apparent volume of distribution of burosumab-twza is 8 L. - The apparent clearance is 0.290 L/day. The half-life of burosumab-twza is approximately 19 days. - The exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathways. - No clinical significant difference in burosumab-twza pharmacokinetics was observed based on age. - The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknown. Pediatric Patients - The steady-state trough concentration was 15.8 (± 9.4) mcg/mL in patients aged 5-12 years, and 11.2 (± 4.6) mcg/mL in patients aged 1-4 years. Body Weight - Clearance and volume of distribution of burosumab-twza increases with body weight. - No drug interaction studies have been conducted with burosumab. ## Nonclinical Toxicology - The carcinogenic potential of burosumab-twza has not been evaluated in long term animal studies. - Studies have not been performed to evaluate the mutagenic potential of burosumab-twza. - No specific fertility studies have been performed in animals to evaluate the effects of burosumab-twza. - Toxicology studies with burosumab-twza of up to 40 weeks duration in non-XLH cynomolgus monkeys did not show significant adverse effects on female reproductive organs at doses up to 65-fold human exposure at the dose of 1 mg/kg every 4 weeks. In male monkeys, minimal mineralization of the rete testis or seminiferous tubules associated with hyperphosphatemia was observed at 11- to 37-fold human exposure, but semen analysis did not show any adverse effects. - In rabbits and cynomolgus monkeys, inhibition of FGF23 signaling by burosumab-twza increased serum phosphate and 1,25 dihydroxy vitamin D. Ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels in the non-XLH animals. In a study in wild type (WT) and hypophosphatemic Hyp mice, a murine model of XLH, ectopic mineralization was markedly less in Hyp mice. - In adult cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or mineral density and cortical thickness at 37- to 65-fold human exposure at the dose of 1 mg/kg every 4 weeks. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were observed in adult male monkeys at 37- to 47-fold human exposure at the dose of 1 mg/kg every 4 weeks. - In juvenile cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or mineral density and/or cortical thickness at 0.5- to 5-fold clinical pediatric exposure. Bone mineralization was decreased in a male monkey at 5-fold pediatric exposure but there was no effect on bone strength. Burosumab-twza did not affect bone development in juvenile monkeys at doses up to 5-fold pediatric exposure. # Clinical Studies - Burosumab has been evaluated in 65 pediatric patients with XLH. - Study 1 (NCT 02163577) is a randomized, open-label study in 52 prepubescent XLH patients, 5 to 12 years old, which compared treatment with burosumab administered every 2 weeks versus every 4 weeks. Following an initial 16-week dose titration phase, patients completed 48-weeks of treatment with burosumab every 2 weeks. All 52 patients completed at least 64 weeks on study; no patient discontinued. Burosumab-twza dose was adjusted to target a fasting serum phosphorus concentration of 3.5 to 5.0 mg/dL based on the fasting phosphorus level the day of dosing. Twenty-six of 52 patients received burosumab every two weeks up to a maximum dose of 2 mg/kg. The average dose was 0.73 mg/kg (range: 0.3, 1.5) at week 16, 0.98 mg/kg (range: 0.4, 2.0) at week 40 and 1.04 mg/kg (range: 0.4, 2.0) at week 60. The remaining 26 patients received burosumab every four weeks. At study entry, the mean age of patients was 8.5 years and 46% were male. Ninety-six percent had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 7 (2.4) years. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Ninety-four percent of patients had radiographic evidence of rickets at baseline. - Study 2 (NCT 02750618) is a 64-week open-label study in 13 pediatric XLH patients, 1 to 4 years old. Patients received burosumab at a dose of 0.8 mg/kg every two weeks with titration up to 1.2 mg/kg based on serum phosphorus measurements. All patients completed at least 40 weeks on study; no patients discontinued. At study entry, the mean age of patients was 2.9 years and 69% were male. All patients had radiographic evidence of rickets at baseline and had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 16.9 (13.9) months. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Serum Phosphorus - In Study 1, burosumab increased mean (SD) serum phosphorus levels from 2.4 (0.40) at baseline to 3.3 (0.40) and 3.4 (0.45) mg/dL at week 40 and week 64 in the patients who received burosumab every 2 weeks (Figure 1). The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean (SD) of 2.2 (0.49) at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at week 40 and week 64. - In Study 2, burosumab increased mean (SD) serum phosphorus levels from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at week 40. Radiographic Evaluation of Rickets - Radiographs from 52 burosumab-treated XLH patients in Study 1 and 13 patients in Study 2 were examined to assess XLH-related rickets using the 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C). The RSS score is assigned based on images of the wrist and knee from a single timepoint, with higher scores indicating greater rickets severity. The RGI-C score is assigned based on side-by-side comparisons of wrist and knee radiographs from two timepoints, with higher scores indicating greater improvement in radiographic evidence of rickets. A RGI-C score of +2.0 was defined as radiographic evidence of substantial healing. - In Study 1, baseline mean (SD) RSS total score was 1.9 (1.17) in patients receiving burosumab every two weeks. After 40 weeks of treatment with burosumab, mean total RSS decreased from 1.9 to 0.8 (see Table 6). After 40 weeks of treatment with burosumab, the mean RGI-C Global score was +1.7 in patients receiving burosumab every two weeks. Eighteen out of 26 patients achieved an RGI-C score of ≥ +2.0. These findings were maintained at week 64 as shown in Table 6. - In Study 2, baseline mean (SD) total RSS was 2.9 (1.37) in 13 patients. After 40 weeks of treatment with burosumab, mean total RSS decreased from 2.9 to 1.2 and the mean (SE) RGI-C Global score was +2.3 (0.08). All 13 patients achieved a RGI-C global score ≥ +2.0. The mean (SE) lower limb deformity as assessed by RGI-C, using standing long leg radiographs, was +1.3 (0.14) (see Table 6). Serum Alkaline Phosphatase Activity - For Study 1, mean (SD) serum total alkaline phosphatase activity was 462 (110) U/L at baseline and decreased to 354 (73) U/L at Week 64 (-23%, p < 0.0001) in the patients who received burosumab every 2 weeks. - For Study 2, mean (SD) serum total alkaline phosphatase activity was 549 (194) U/L at baseline and decreased to 335 (88) U/L at Week 40 (mean change: -36%). Growth - In Study 1, burosumab treatment for 64 weeks increased standing mean (SD) height Z score from -1.72 (1.03) at baseline to -1.54 (1.13) in the patients who received burosumab every two weeks (LS mean change of +0.19 (95% CI: 0.09 to 0.29). - Study 3 (NCT 02526160) is a randomized, double-blind, placebo-controlled study in 134 adult XLH patients. The study comprises a 24-week placebo-controlled treatment phase. Burosumab was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% were male. All patients had skeletal pain associated with XLH/osteomalacia at baseline. The baseline mean (SD) serum phosphorus concentration was below the lower limit of normal at 1.98 (0.31) mg/dL. Oral phosphate and active vitamin D analogs were not allowed during the study. One patient in the burosumab group discontinued treatment. - Study 4 (NCT 02537431) is a 48-week, open-label, single-arm study in 14 adult XLH patients to assess the effects of burosumab on improvement of osteomalacia as determined by histologic and histomorphometric evaluation of iliac crest bone biopsies. Patients received 1 mg/kg burosumab every four weeks. At study entry, the mean age of patients was 40 years (range 25 to 52 years) and 43% were male. Oral phosphate and active vitamin D analogs were not allowed during the study. Serum Phosphorus - In Study 3 at baseline, mean (SD) serum phosphorus was 1.9 (0.32) and 2.0 (0.30) mg/dL in the placebo and burosumab groups respectively. During the initial 24 weeks of treatment, mean (SD) serum phosphorus across the midpoints of dose intervals (2 weeks post dose) was 2.1 (0.30) and 3.2 (0.53) mg/dL in the placebo and burosumab groups, and mean (SD) serum phosphorus across the ends of dose intervals was 2.0 (0.30) and 2.7 (0.45) mg/dL in the placebo and burosumab groups. - A total of 94% of patients treated with burosumab achieved a serum phosphorus level above the lower limit of normal (LLN) compared to 8% in the placebo group through week 24 (Table 7). - At baseline, the mean (SD) ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 1.60 (0.37) and 1.68 (0.40) mg/dL in the placebo and burosumab groups respectively. At week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 1.69 (0.37) and 2.73 (0.75) mg/dL in the placebo and burosumab groups. At week 24 (end of a dose interval), mean (SD) TmP/GFR was 1.73 (0.42) and 2.21 (0.48) mg/dL in the placebo and burosumab groups. Radiographic Evaluation of Osteomalacia - In Study 3, a skeletal survey was conducted at baseline to identify osteomalacia-related fractures and pseudofractures. Osteomalacia-related fractures are defined as atraumatic lucencies extending across both bone cortices and pseudofractures are defined as atraumatic lucencies extending across one cortex. There were 52% of patients who had either active (unhealed) fractures (12%) or active pseudofractures (47%) at baseline. The active fractures and pseudofractures were predominantly located in the femurs, tibia/fibula, and metatarsals of the feet. Assessment of these active fracture/pseudofracture sites at week 24 demonstrated a higher rate of complete healing in the burosumab group compared to placebo as shown in Table 8. During treatment through week 24, a total of 6 new fractures or pseudofractures appeared in 68 patients receiving burosumab, compared to 8 new abnormalities in 66 patients receiving placebo. Bone Histomorphometry - In Study 4, after 48 weeks of treatment, healing of osteomalacia was observed in ten patients as demonstrated by decreases in Osteoid volume/Bone volume (OV/BV) from a mean (SD) score of 26% (12.4) at baseline to 11% (6.5), a change of -57%. Osteoid thickness (O.Th) declined in eleven patients from a mean (SD) of 17 (4.1) micrometers to 12 (3.1) micrometers, a change of -33%. Mineralization lag time (MLt) declined in 6 patients from a mean (SD) of 594 (675) days to 156 (77) days, a change of -74%. # How Supplied - Burosumab (burosumab-twza) injection for subcutaneous administration is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution. The product is available as one single-dose vial per carton in the following strengths: - 10 mg/mL (NDC# 69794-102-01). - 20 mg/mL (NDC# 69794-203-01). - 30 mg/mL (NDC# 69794-304-01). ## Storage - Burosumab vials must be stored in the original carton until the time of use under refrigerated conditions at 36°F to 46°F (2°C to 8°C). Keep burosumab vial in the original carton to protect from light until time of use. - Do not freeze or shake burosumab. - Do not use burosumab beyond the expiration date stamped on the carton. - Burosumab vials are single-dose only. Discard any unused product. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that burosumab may cause hypersensitivity events such as rash, injection site rash and urticaria. Instruct the patients to contact their physician if such reactions occur. - Inform patients that injection site reactions (e.g. erythema, rash, swelling, bruising, pain, pruritus, urticaria, and hematoma) have occurred at the site of burosumab injection. Instruct the patients to contact their physician if such reactions occur. - Advise patients that burosumab can induce RLS or worsen the symptoms of existing RLS. Instruct the patients to contact their physician if such a reaction occurs. - Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657. # Precautions with Alcohol Alcohol-Burosumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Crysvita # Look-Alike Drug Names There is limited information regarding Burosumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Burosumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Burosumab is a fibroblast growth factor 23 (FGF23) blocking antibody that is FDA approved for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. Common adverse reactions include headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Burosumab is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. - The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks. - After initiation of treatment with burosumab, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose. Dose Decrease - Reassess fasting serum phosphorus level 2 weeks after dose adjustment. - Do not adjust burosumab more frequently than every 4 weeks. - If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks. The patient must have serum phosphorus below the normal range to be able to reinitiate burosumab. Once serum phosphorus is below the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3. Reassess serum phosphorus 2 weeks after any change in dose. - If a patient misses a dose, resume burosumab as soon as possible at the prescribed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding burosumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding burosumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Burosumab is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older. - The recommended starting dose regimen is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. - After initiation of treatment with burosumab, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule below to maintain serum phosphorus within the reference range for age. Dose Adjustment - Reassess fasting serum phosphorus level 4 weeks after dose adjustment. - Do not adjust burosumab more frequently than every 4 weeks. - Dose Increase: If serum phosphorus is below the reference range for age, the dose may be increased stepwise up to approximately 2 mg/kg, administered every two weeks (maximum dose of 90 mg) according to the dosing schedule shown in Table 1. - Dose Decrease: If serum phosphorus is above 5 mg/dL, withhold the next dose and reassess the serum phosphorus level in 4 weeks. The patient must have serum phosphorus below the reference range for age to reinitiate burosumab. Once serum phosphorus is below the reference range for age, treatment may be restarted according to the dose schedule shown in Table 2. Reassess serum phosphorus level 4 weeks after dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted according to Table 1. - If a patient misses a dose, resume burosumab as soon as possible at the prescribed dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding burosumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding burosumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Do not use burosumab with oral phosphate and active vitamin D analogs. - Do not initiate burosumab treatment if serum phosphorus is within or above the normal range for age. - Burosumab is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism. # Warnings - Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with burosumab. Discontinue burosumab if serious hypersensitivity reactions occur and initiate appropriate medical treatment. - Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking burosumab, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels. - Administration of burosumab may result in local injection site reactions. Discontinue burosumab if severe injection site reactions occur and administer appropriate medical treatment. # 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 data described below reflect exposure to burosumab in 65 pediatric XLH patients that included 52 exposed for at least 64 weeks (Study 1) and 13 exposed for at least 40 weeks (Study 2). Overall, pediatric XLH patients have been exposed to burosumab for a mean duration of 108 weeks (min 40.9, max 150.0). Burosumab was studied in two pediatric open-label phase 2 studies (Study 1, ages 5 to 12 years, n = 52; Study 2, ages ≥ 1 to < 5 years, n = 13). Overall, the patient population was 1-12 years (mean age 7.4 years), 51% male, and 89% white/Caucasian and diagnosed with XLH. In Study 1, 26 of the patients received burosumab at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received burosumab every 4 weeks. In Study 2, patients received burosumab at a mean dose of 0.89 mg/kg (range 0.8 – 1.2 mg/kg) every 2 weeks at Week 40. Adverse reactions reported in more than 10% of burosumab-treated patients from Studies 1 and 2 are shown in Table 4. Hypersensitivity Reactions - In pediatric patients, the most frequent potential hypersensitivity events were rash (22%), injection site rash (6%), and urticaria (5%). Hyperphosphatemia - In pediatric studies, there were no events of hyperphosphatemia reported. Injection Site Reactions (ISR) - In pediatric studies, approximately 58% of the patients had a local reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of burosumab injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. - The safety data described below reflect exposure to burosumab in 68 adult XLH patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%). These patients were enrolled in a randomized, double-blind, placebo-controlled Phase 3 study in adults with XLH (Study 3: burosumab = 68, Placebo = 66), in which patients received burosumab at a mean dose of 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks at Week 24. Adverse reactions reported in more than 5% of burosumab-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 3 are shown in Table 5. Hypersensitivity Reactions - In the double-blind period of Study 3, approximately 6% of patients in both the burosumab and placebo treatment groups experienced a hypersensitivity event. The events were mild or moderate and did not require discontinuation. Hyperphosphatemia - In the double-blind period of Study 3, 7% of patients in the burosumab treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL [the upper limit of normal] on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent. A single patient required a second dose reduction for continued hyperphosphatemia. Injection Site Reactions (ISR) - In the double-blind period of Study 3, approximately 12% of patients in both the burosumab and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. Restless Leg Syndrome (RLS) - In the double-blind period of Study 3, approximately 12% of the burosumab treatment group had worsening of baseline restless leg syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation. Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event. Spinal Stenosis - Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. In the burosumab phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 6 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if burosumab therapy exacerbates spinal stenosis or spinal cord compression. ### Immunogenicity - As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to burosumab-twza in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - Pre-existing anti-drug antibodies (ADA) have been detected in up to 10% of patients in clinical studies. ADA was not detected in patients who were antibody negative at the start of treatment. However, the assay used to measure ADA is subject to interference by serum burosumab-twza, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to burosumab-twza is not known. ## Postmarketing Experience There is limited information regarding Burosumab Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Burosumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data on burosumab use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to indicate clinical risk because they occurred at a drug exposure that was 64-fold higher, by AUC, than the human exposure at 1 mg/kg every 4 weeks and were accompanied in the non-XLH monkeys by maternal hyperphosphatemia and placental mineralization (see Data). Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657. - The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. - In a reproductive toxicity study in pregnant cynomolgus monkeys without XLH, burosumab-twza was administered intravenously once every two weeks from Day 20 of pregnancy to parturition or cesarean section on Day 133, which includes the period of organogenesis, at doses of 1-, 7- and 64-fold human exposure at the adult human dose of 1 mg/kg every 4 weeks. The treatment did not result in teratogenic effects in fetuses or offspring. An increase in late fetal loss, a shortened gestation period, and an increased incidence of preterm births were observed at 64-fold the human exposure at the adult human dose of 1 mg/kg every 4 weeks, concomitant with maternal hyperphosphatemia and placental mineralization. Burosumab-twza was detected in serum from fetuses indicating transport across the placenta. Hyperphosphatemia but no ectopic mineralization was present in fetuses and offspring of dams exposed to 64-fold human exposure at the 1 mg/kg dose every 4 weeks. Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Burosumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Burosumab during labor and delivery. ### Nursing Mothers - There is no information regarding the presence of burosumab-twza in human milk, or the effects of burosumab-twza on milk production or the breastfed infant. Maternal IgG is present in breast milk. However, the effects of local gastrointestinal exposure and limited systemic exposure to burosumab-twza in the breastfed infant are unknown. The lack of clinical data during lactation precludes a clear determination of the risk of burosumab to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for burosumab and any potential adverse effects on the breastfed infant from burosumab or from the underlying maternal condition. ### Pediatric Use - Safety and efficacy of burosumab have been established in pediatric patients 1 year and older. Efficacy in pediatric patients 1 year and older with XLH is based on open label studies of 52 pediatric patients 5 to 12 years of age with XLH (Study 1), and in 13 pediatric patients 1 to 4 years of age with XLH (Study 2) evaluating serum phosphorus and radiographic findings. Efficacy in adolescents is supported by studies in pediatric patients less than 13 years of age. Dosing in this age group was derived using modeling and simulation of adult and pediatric PK and PD data. - Safety and efficacy for burosumab in pediatric patients with XLH below the age of 1 have not been established. ### Geriatic Use - Clinical studies of burosumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 Burosumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Burosumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Burosumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Burosumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Burosumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Burosumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Injection sites should be rotated with each injection administered at a different anatomic location (upper arms, upper thighs, buttocks, or any quadrant of abdomen) than the previous injection. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. The maximum volume of burosumab per injection site is 1.5 mL. If more than 1.5 mL is required on a given dosing day, the total volume of burosumab should be split and administered at two different injection sites. Monitor for signs of reactions. - Visually inspect burosumab for particulate matter and discoloration prior to administration. Burosumab is a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution for subcutaneous injection. Do not use if the solution is discolored or cloudy or if the solution contains any particles or foreign particulate matter. ### Monitoring - Clinical improvement of hypophosphatemia may be indicative of efficacy. - Fasting serum phosphorus level: Prior to therapy initiation in all patients. - Fasting serum phosphorus level: Every 4 weeks for the first 3 months and then as clinically indicated in pediatric patients. - Fasting serum phosphorus level: Monthly, 2 weeks after dose is given, for the first 3 months and then as clinically indicated in adult patients. - Injection site reactions. # IV Compatibility There is limited information regarding the compatibility of Burosumab and IV administrations. # Overdosage - There have been no reports of overdose with burosumab. Burosumab has been administered in pediatric clinical trials without dose limiting toxicity using doses up to 2 mg/kg body weight with a maximal dose of 90 mg, administered every two weeks. In adult clinical trials, no dose limiting toxicity has been observed using doses up to 1 mg/kg or a maximal total dose of 128 mg every 4 weeks. In non-XLH rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were also observed at exposure greater than human exposure. - In case of overdose, it is recommended that serum phosphorus levels, serum calcium levels and renal function be measured immediately and monitored periodically until resolution to normal/baseline levels. In case of hyperphosphatemia, withhold burosumab and initiate appropriate medical treatment. # Pharmacology ## Mechanism of Action - X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D. ## Structure There is limited information regarding Burosumab Structure in the drug label. ## Pharmacodynamics - Following SC administration in XLH patients, higher burosumab-twza concentrations were associated with greater increase of serum phosphorus levels. The increase in serum phosphorus was reversible and returned to baseline with elimination of systemic burosumab-twza. - Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) showed dose-dependent increases from baseline. - Elevation in serum total FGF23 was observed after initiation of burosumab-twza treatment, however, the clinical implication is unknown. ## Pharmacokinetics - The following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified. - Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient). - The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in adult patients. - The burosumab-twza mean Tmax values ranged from 8 to 11 days. - The apparent volume of distribution of burosumab-twza is 8 L. - The apparent clearance is 0.290 L/day. The half-life of burosumab-twza is approximately 19 days. - The exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathways. - No clinical significant difference in burosumab-twza pharmacokinetics was observed based on age. - The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknown. Pediatric Patients - The steady-state trough concentration was 15.8 (± 9.4) mcg/mL in patients aged 5-12 years, and 11.2 (± 4.6) mcg/mL in patients aged 1-4 years. Body Weight - Clearance and volume of distribution of burosumab-twza increases with body weight. - No drug interaction studies have been conducted with burosumab. ## Nonclinical Toxicology - The carcinogenic potential of burosumab-twza has not been evaluated in long term animal studies. - Studies have not been performed to evaluate the mutagenic potential of burosumab-twza. - No specific fertility studies have been performed in animals to evaluate the effects of burosumab-twza. - Toxicology studies with burosumab-twza of up to 40 weeks duration in non-XLH cynomolgus monkeys did not show significant adverse effects on female reproductive organs at doses up to 65-fold human exposure at the dose of 1 mg/kg every 4 weeks. In male monkeys, minimal mineralization of the rete testis or seminiferous tubules associated with hyperphosphatemia was observed at 11- to 37-fold human exposure, but semen analysis did not show any adverse effects. - In rabbits and cynomolgus monkeys, inhibition of FGF23 signaling by burosumab-twza increased serum phosphate and 1,25 dihydroxy vitamin D. Ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels in the non-XLH animals. In a study in wild type (WT) and hypophosphatemic Hyp mice, a murine model of XLH, ectopic mineralization was markedly less in Hyp mice. - In adult cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or mineral density and cortical thickness at 37- to 65-fold human exposure at the dose of 1 mg/kg every 4 weeks. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were observed in adult male monkeys at 37- to 47-fold human exposure at the dose of 1 mg/kg every 4 weeks. - In juvenile cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or mineral density and/or cortical thickness at 0.5- to 5-fold clinical pediatric exposure. Bone mineralization was decreased in a male monkey at 5-fold pediatric exposure but there was no effect on bone strength. Burosumab-twza did not affect bone development in juvenile monkeys at doses up to 5-fold pediatric exposure. # Clinical Studies - Burosumab has been evaluated in 65 pediatric patients with XLH. - Study 1 (NCT 02163577) is a randomized, open-label study in 52 prepubescent XLH patients, 5 to 12 years old, which compared treatment with burosumab administered every 2 weeks versus every 4 weeks. Following an initial 16-week dose titration phase, patients completed 48-weeks of treatment with burosumab every 2 weeks. All 52 patients completed at least 64 weeks on study; no patient discontinued. Burosumab-twza dose was adjusted to target a fasting serum phosphorus concentration of 3.5 to 5.0 mg/dL based on the fasting phosphorus level the day of dosing. Twenty-six of 52 patients received burosumab every two weeks up to a maximum dose of 2 mg/kg. The average dose was 0.73 mg/kg (range: 0.3, 1.5) at week 16, 0.98 mg/kg (range: 0.4, 2.0) at week 40 and 1.04 mg/kg (range: 0.4, 2.0) at week 60. The remaining 26 patients received burosumab every four weeks. At study entry, the mean age of patients was 8.5 years and 46% were male. Ninety-six percent had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 7 (2.4) years. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Ninety-four percent of patients had radiographic evidence of rickets at baseline. - Study 2 (NCT 02750618) is a 64-week open-label study in 13 pediatric XLH patients, 1 to 4 years old. Patients received burosumab at a dose of 0.8 mg/kg every two weeks with titration up to 1.2 mg/kg based on serum phosphorus measurements. All patients completed at least 40 weeks on study; no patients discontinued. At study entry, the mean age of patients was 2.9 years and 69% were male. All patients had radiographic evidence of rickets at baseline and had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 16.9 (13.9) months. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Serum Phosphorus - In Study 1, burosumab increased mean (SD) serum phosphorus levels from 2.4 (0.40) at baseline to 3.3 (0.40) and 3.4 (0.45) mg/dL at week 40 and week 64 in the patients who received burosumab every 2 weeks (Figure 1). The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean (SD) of 2.2 (0.49) at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at week 40 and week 64. - In Study 2, burosumab increased mean (SD) serum phosphorus levels from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at week 40. Radiographic Evaluation of Rickets - Radiographs from 52 burosumab-treated XLH patients in Study 1 and 13 patients in Study 2 were examined to assess XLH-related rickets using the 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C). The RSS score is assigned based on images of the wrist and knee from a single timepoint, with higher scores indicating greater rickets severity. The RGI-C score is assigned based on side-by-side comparisons of wrist and knee radiographs from two timepoints, with higher scores indicating greater improvement in radiographic evidence of rickets. A RGI-C score of +2.0 was defined as radiographic evidence of substantial healing. - In Study 1, baseline mean (SD) RSS total score was 1.9 (1.17) in patients receiving burosumab every two weeks. After 40 weeks of treatment with burosumab, mean total RSS decreased from 1.9 to 0.8 (see Table 6). After 40 weeks of treatment with burosumab, the mean RGI-C Global score was +1.7 in patients receiving burosumab every two weeks. Eighteen out of 26 patients achieved an RGI-C score of ≥ +2.0. These findings were maintained at week 64 as shown in Table 6. - In Study 2, baseline mean (SD) total RSS was 2.9 (1.37) in 13 patients. After 40 weeks of treatment with burosumab, mean total RSS decreased from 2.9 to 1.2 and the mean (SE) RGI-C Global score was +2.3 (0.08). All 13 patients achieved a RGI-C global score ≥ +2.0. The mean (SE) lower limb deformity as assessed by RGI-C, using standing long leg radiographs, was +1.3 (0.14) (see Table 6). Serum Alkaline Phosphatase Activity - For Study 1, mean (SD) serum total alkaline phosphatase activity was 462 (110) U/L at baseline and decreased to 354 (73) U/L at Week 64 (-23%, p < 0.0001) in the patients who received burosumab every 2 weeks. - For Study 2, mean (SD) serum total alkaline phosphatase activity was 549 (194) U/L at baseline and decreased to 335 (88) U/L at Week 40 (mean change: -36%). Growth - In Study 1, burosumab treatment for 64 weeks increased standing mean (SD) height Z score from -1.72 (1.03) at baseline to -1.54 (1.13) in the patients who received burosumab every two weeks (LS mean change of +0.19 (95% CI: 0.09 to 0.29). - Study 3 (NCT 02526160) is a randomized, double-blind, placebo-controlled study in 134 adult XLH patients. The study comprises a 24-week placebo-controlled treatment phase. Burosumab was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% were male. All patients had skeletal pain associated with XLH/osteomalacia at baseline. The baseline mean (SD) serum phosphorus concentration was below the lower limit of normal at 1.98 (0.31) mg/dL. Oral phosphate and active vitamin D analogs were not allowed during the study. One patient in the burosumab group discontinued treatment. - Study 4 (NCT 02537431) is a 48-week, open-label, single-arm study in 14 adult XLH patients to assess the effects of burosumab on improvement of osteomalacia as determined by histologic and histomorphometric evaluation of iliac crest bone biopsies. Patients received 1 mg/kg burosumab every four weeks. At study entry, the mean age of patients was 40 years (range 25 to 52 years) and 43% were male. Oral phosphate and active vitamin D analogs were not allowed during the study. Serum Phosphorus - In Study 3 at baseline, mean (SD) serum phosphorus was 1.9 (0.32) and 2.0 (0.30) mg/dL in the placebo and burosumab groups respectively. During the initial 24 weeks of treatment, mean (SD) serum phosphorus across the midpoints of dose intervals (2 weeks post dose) was 2.1 (0.30) and 3.2 (0.53) mg/dL in the placebo and burosumab groups, and mean (SD) serum phosphorus across the ends of dose intervals was 2.0 (0.30) and 2.7 (0.45) mg/dL in the placebo and burosumab groups. - A total of 94% of patients treated with burosumab achieved a serum phosphorus level above the lower limit of normal (LLN) compared to 8% in the placebo group through week 24 (Table 7). - At baseline, the mean (SD) ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 1.60 (0.37) and 1.68 (0.40) mg/dL in the placebo and burosumab groups respectively. At week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 1.69 (0.37) and 2.73 (0.75) mg/dL in the placebo and burosumab groups. At week 24 (end of a dose interval), mean (SD) TmP/GFR was 1.73 (0.42) and 2.21 (0.48) mg/dL in the placebo and burosumab groups. Radiographic Evaluation of Osteomalacia - In Study 3, a skeletal survey was conducted at baseline to identify osteomalacia-related fractures and pseudofractures. Osteomalacia-related fractures are defined as atraumatic lucencies extending across both bone cortices and pseudofractures are defined as atraumatic lucencies extending across one cortex. There were 52% of patients who had either active (unhealed) fractures (12%) or active pseudofractures (47%) at baseline. The active fractures and pseudofractures were predominantly located in the femurs, tibia/fibula, and metatarsals of the feet. Assessment of these active fracture/pseudofracture sites at week 24 demonstrated a higher rate of complete healing in the burosumab group compared to placebo as shown in Table 8. During treatment through week 24, a total of 6 new fractures or pseudofractures appeared in 68 patients receiving burosumab, compared to 8 new abnormalities in 66 patients receiving placebo. Bone Histomorphometry - In Study 4, after 48 weeks of treatment, healing of osteomalacia was observed in ten patients as demonstrated by decreases in Osteoid volume/Bone volume (OV/BV) from a mean (SD) score of 26% (12.4) at baseline to 11% (6.5), a change of -57%. Osteoid thickness (O.Th) declined in eleven patients from a mean (SD) of 17 (4.1) micrometers to 12 (3.1) micrometers, a change of -33%. Mineralization lag time (MLt) declined in 6 patients from a mean (SD) of 594 (675) days to 156 (77) days, a change of -74%. # How Supplied - Burosumab (burosumab-twza) injection for subcutaneous administration is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution. The product is available as one single-dose vial per carton in the following strengths: - 10 mg/mL (NDC# 69794-102-01). - 20 mg/mL (NDC# 69794-203-01). - 30 mg/mL (NDC# 69794-304-01). ## Storage - Burosumab vials must be stored in the original carton until the time of use under refrigerated conditions at 36°F to 46°F (2°C to 8°C). Keep burosumab vial in the original carton to protect from light until time of use. - Do not freeze or shake burosumab. - Do not use burosumab beyond the expiration date stamped on the carton. - Burosumab vials are single-dose only. Discard any unused product. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients that burosumab may cause hypersensitivity events such as rash, injection site rash and urticaria. Instruct the patients to contact their physician if such reactions occur. - Inform patients that injection site reactions (e.g. erythema, rash, swelling, bruising, pain, pruritus, urticaria, and hematoma) have occurred at the site of burosumab injection. Instruct the patients to contact their physician if such reactions occur. - Advise patients that burosumab can induce RLS or worsen the symptoms of existing RLS. Instruct the patients to contact their physician if such a reaction occurs. - Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657. # Precautions with Alcohol Alcohol-Burosumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Crysvita # Look-Alike Drug Names There is limited information regarding Burosumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Burosumab
5cf01641164b53d607bdee4f9324bea2cd3aad0a	wikidoc	Buserelin	Buserelin # Overview Buserelin (INN) is a gonadotropin-releasing hormone agonist (GnRH agonist). The drug's effects are dependent on the frequency and time course of administration. GnRH is released in a pulsatile fashion in the postpubertal adult. Initial interaction of any GnRH agonist, such as buserelin, with the GnRH receptor induces release of FSH and LH by gonadotrophes. Long-term exposure to constant levels of buserelin, rather than endogenous pulses, leads to downregulation of the GnRH receptors and subsequent suppression of the pituitary release of LH and FSH. Like other GnRH agonists, buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. It is normally delivered via a nasal spray, but is also available as an injection. Buserelin acetate is marketed by Sanofi-Aventis under the brand name Suprefact and a generic form of Buserelin is now produced by CinnaGen under the brand name CinnaFact. Buserelin is also marketed under the brand name Metrelef. Metrelef is approved to treat patients with endometriosis by suppression of ovarian hormone production. In ovulation induction Metrelef is used as a pituitary blockade as an adjunct to gonadotrophin administration.	Buserelin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Overview Buserelin (INN) is a gonadotropin-releasing hormone agonist (GnRH agonist). The drug's effects are dependent on the frequency and time course of administration. GnRH is released in a pulsatile fashion in the postpubertal adult. Initial interaction of any GnRH agonist, such as buserelin, with the GnRH receptor induces release of FSH and LH by gonadotrophes. Long-term exposure to constant levels of buserelin, rather than endogenous pulses, leads to downregulation of the GnRH receptors and subsequent suppression of the pituitary release of LH and FSH. Like other GnRH agonists, buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. It is normally delivered via a nasal spray, but is also available as an injection. Buserelin acetate is marketed by Sanofi-Aventis under the brand name Suprefact and a generic form of Buserelin is now produced by CinnaGen under the brand name CinnaFact. Buserelin is also marketed under the brand name Metrelef. Metrelef is approved to treat patients with endometriosis by suppression of ovarian hormone production. In ovulation induction Metrelef is used as a pituitary blockade as an adjunct to gonadotrophin administration.	https://www.wikidoc.org/index.php/Buserelin
9e8b4859c0f49952e32d0da2b3436ff27813a39c	wikidoc	Buspirone	Buspirone # 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 Buspirone is an anti anxiety drug that is FDA approved for the treatment of anxiety disorders or the short-term relief of the symptoms of anxiety. Common adverse reactions include nausea, dizziness, headache, somnolence and feeling nervous. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Anxiety Disorders Dosing information - Recommended initial dose:15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 to 30 mg per day were commonly employed. - The bioavailability of buspirone is increased when given with food as compared to the fasted state . Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. - When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the precaution drug interaction section should be followed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of buspirone in adult patients. ### Non–Guideline-Supported Use # Depression Dosing information - 5 mg administered 3 times daily for 4 weeks # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Buspirone 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 buspirone in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of buspirone in pediatric patients. # Contraindications - Buspirone hydrochloride ablets, USP are contraindicated in patients hypersensitive to buspirone hydrochloride. # Warnings - The administration of buspirone to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when buspirone hydrochloride has been added to a regimen including an MAOI. Therefore, it is recommended that buspirone not be used concomitantly with an MAOI. - Because buspirone has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment. ## PRECAUTIONS ### General - Interference with Cognitive and Motor Performance - Studies indicate that buspirone is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about operating an automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. - While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. - Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug-Dependent Patients - Because buspirone does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with buspirone, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination. - The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. - Possible Concerns Related to Buspirone’s Binding to Dopamine Receptors - Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (e.g., dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central nor adrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (i.e., represent akathisia). # Adverse Reactions ## Clinical Trials Experience ## Commonly Observed - The more commonly observed untoward events associated with the use of buspirone not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. ## Associated with Discontinuation of Treatment - One guide to the relative clinical importance of adverse events associated with buspirone is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the buspirone premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. ## Incidence in Controlled Clinical Trials - The table that follows enumerates adverse events that occurred at a frequency of 1% or more among buspirone hydrochloride patients who participated in 4 week, controlled trials comparing buspirone with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures 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 which 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. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and non drug factors to the side-effect incidence rate in the population studied. ## Other Events Observed During the Entire Premarketing Evaluation of Buspirone - During its premarketing assessment, buspirone was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of buspirone in the dose range for which buspirone is being recommended (i.e., the modal daily dose of buspirone fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to buspirone varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to buspirone hydrochloride treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. - The following enumeration by organ system describes events in terms of their relative frequency of reporting in this data base. - The following definitions of frequency are used: frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. ## Cardiovascular - Frequent was non specific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. ## Central Nervous System - Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria , akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. ## ENT - Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. ## Endocrine - Rare were galactorrhea and thyroid abnormality. ## Gastrointestinal - Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. ## Genitourinary - Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. ## Musculoskeletal - Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. ## Respiratory - Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. ## Sexual Function - Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. ## Skin - Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. ## Clinical Laboratory - Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. ## Miscellaneous - Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. ## Postmarketing Experience - Postmarketing experience has shown an adverse experience profile similar to that given above. voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes (including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone treatment has not been determined. # Drug Interactions # Psychotropic Agents MAO inhibitors - It is recommended that buspirone not be used concomitantly with MAO inhibitors. Amitriptyline - After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed. Diazepam - After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol - In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone Trazodone - There is one report suggesting that the concomitant use of trazodone hydrochloride and buspirone may have caused 3 to 6 fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/flurazepam - Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other psychotropics - Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 - Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and verapamil - In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and Cmax of buspirone 3.4 fold while diltiazem increased AUC and Cmax 5.5 fold and 4 fold, respectively). Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5 fold increase in Cmax and 6 fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit juice - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3 fold increase in Cmax; 9.2 fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13 fold increase in Cmax and 19 fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone - In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in Cmax and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5 mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects receiving buspirone 5 mg b.i.d. and nefazodone 250 mg b.i.d. experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Rifampin - In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other inhibitors and inducers of CYP3A4 - Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. # Other Drugs Cimetidine - Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2 fold), but had minimal effects on the AUC of buspirone. Protein Binding - In vitro, buspirone does not displace tightly bound drugs like phenytoin, propanolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and levothyroxine sodium. In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. - Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol , thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well-controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - The effect of buspirone on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. ### Labor and Delivery There is no FDA guidance on use of Buspirone during labor and delivery. ### Nursing Mothers - The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. Buspirone administration to nursing women should be avoided if clinically possible. ### Pediatric Use - The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6 week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5 mg to 30 mg b.i.d. (15 to 60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population. ### Geriatic Use - In one study of 6632 patients who received buspirone for the treatment of anxiety, 605 patients were ≥ 65 years old and 41 were ≥ 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). Review of spontaneously reported adverse clinical events has not identified differences between elderly and younger patients, but greater sensitivity of some older patients can not be ruled out.There were no effects of age on the pharmacokinetics of buspirone ### Gender There is no FDA guidance on the use of Buspirone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Buspirone with respect to specific racial populations. ### Renal Impairment - Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of buspirone hydrochloride tablets, USP to patients with severe hepatic or renal impairment cannot be recommended. ### Hepatic Impairment - Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of buspirone hydrochloride tablets, USP to patients with severe hepatic or renal impairment cannot be recommended. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Buspirone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Buspirone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - FDA package insert for buspirone contains no information regarding drug monitoring. # IV Compatibility - There is limited information about the IV compatibility. # Overdosage ## Signs and Symptoms - In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete recovery as the usual outcome. No deaths have been reported following overdosage with buspirone alone. Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. ## Recommended Overdose Treatment - General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. # Pharmacology ## Mechanism of Action - The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. ## Structure - Buspirone hydrochloride is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. - Buspirone hydrochloride is a white crystalline, water soluble compound. Chemically, buspirone hydrochloride is N-butyl]-1,1-cyclopentanediacetamide monohydrochloride, which can be represented by the following structural formula: - Each tablet, for oral administration, contains 5 mg, 10 mg, 15 mg or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 9.1 mg, 13.7 mg and 27.4 mg of buspirone free base respectively). The 5 mg and 10 mg tablets are scored so they can be bisected. Thus, the 5 mg tablet can also provide a 2.5 mg dose, and the 10 mg tablet can provide a 5 mg dose. The 15 mg tablets are scored such that they may be bisected or trisected. Thus, a single tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two-thirds of a tablet), 7.5 mg (one-half of a tablet), or 5 mg (one-third of a tablet). The 30 mg tablets are scored such that they may be bisected or trisected. Thus, a single tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two-thirds of a tablet), 15 mg (one-half of a tablet), or 10 mg (one-third of a tablet). Buspirone hydrochloride tablets, USP contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. ## Pharmacodynamics - Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. - Buspirone is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged buspirone are very low and variable between subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. - The effects of food upon the bioavailability of buspirone have been studied in eight subjects. They were given a 20 mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone. - A multiple-dose study conducted in 15 subjects suggests that buspirone has non linear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. - An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin. ## Pharmacokinetics - Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of buspirone, but is present in up to 20 fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to buspirone hydrochloride do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of buspirone without signs of toxicity. - In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged buspirone after single doses of 10 to 40 mg is about 2 to 3 hours. # Special Populations Age and Gender Effects - After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women. Hepatic Impairment - After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13 fold compared with healthy subjects. Renal Impairment - After multiple-dose administration of buspirone to renally impaired (Clcr = 10 to 70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4 fold compared with healthy (Clcr ≥ 80 mL/min/1.73 m2) subjects. Race Effects - The effects of race on the pharmacokinetics of buspirone have not been studied. ## Nonclinical Toxicology - No evidence of carcinogenic potential was observed in rats during a 24 month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18 month study at approximately 167 times the maximum recommended human oral dose. - With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. # Clinical Studies - There is limited information about the clinical studies. # How Supplied - Buspirone Hydrochloride Tablets, USP are available as: - Buspirone Hydrochloride Tablets, USP 5 mg are white ovoid-rectangular, uncoated tablets, with score line on one side and plain on other side. Tablets are packed in the bottles of 100 having NDC 64380-741-06. - Buspirone Hydrochloride Tablets, USP 10 mg are white ovoid-rectangular, uncoated tablets, with score line on one side and plain on other side. Tablets are packed in the bottles of 100 having NDC 64380-742-06. - Buspirone Hydrochloride Tablets, USP 15 mg are white rectangular, uncoated tablets, with trisected score lines on both sides. The 15 mg tablet is in xx tablet design and scored so that it can be either bisected or trisected. Tablets are packed in bottles of 60 having NDC 64380-743-03, 100 having NDC 64380-743-06 and 180 having NDC 64380-743-18. - Buspirone Hydrochloride Tablets, USP 30 mg are white rectangular, uncoated tablets that can either be bisected or trisected. Tablets are packed in bottles of 60 having NDC 64380-744-03. ## Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° C to 30° C (59° F to 86° F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - To assure safe and effective use of buspirone hydrochloride tablets, USP the following information and instructions should be given to patients: 1. Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with buspirone. 2. Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking buspirone. 3. Inform your physician if you are breast-feeding an infant. 4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. 5. You should take buspirone consistently, either always with or always without food. 6. During your treatment with buspirone, avoid drinking large amounts of grapefruit juice. # Precautions with Alcohol - While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. # Brand Names - Buspar - Buspar Dividose - Vanspar # Look-Alike Drug Names - Buspirone - Bupropion # Drug Shortage Status # Price	Buspirone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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 Buspirone is an anti anxiety drug that is FDA approved for the treatment of anxiety disorders or the short-term relief of the symptoms of anxiety. Common adverse reactions include nausea, dizziness, headache, somnolence and feeling nervous. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Anxiety Disorders Dosing information - Recommended initial dose:15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 to 30 mg per day were commonly employed. - The bioavailability of buspirone is increased when given with food as compared to the fasted state . Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. - When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the precaution drug interaction section should be followed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of buspirone in adult patients. ### Non–Guideline-Supported Use # Depression Dosing information - 5 mg administered 3 times daily for 4 weeks # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Buspirone 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 buspirone in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of buspirone in pediatric patients. # Contraindications - Buspirone hydrochloride ablets, USP are contraindicated in patients hypersensitive to buspirone hydrochloride. # Warnings - The administration of buspirone to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when buspirone hydrochloride has been added to a regimen including an MAOI. Therefore, it is recommended that buspirone not be used concomitantly with an MAOI. - Because buspirone has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment. ## PRECAUTIONS ### General - Interference with Cognitive and Motor Performance - Studies indicate that buspirone is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about operating an automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. - While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. - Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug-Dependent Patients - Because buspirone does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with buspirone, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination. - The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. - Possible Concerns Related to Buspirone’s Binding to Dopamine Receptors - Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (e.g., dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central nor adrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (i.e., represent akathisia). # Adverse Reactions ## Clinical Trials Experience ## Commonly Observed - The more commonly observed untoward events associated with the use of buspirone not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. ## Associated with Discontinuation of Treatment - One guide to the relative clinical importance of adverse events associated with buspirone is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the buspirone premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. ## Incidence in Controlled Clinical Trials - The table that follows enumerates adverse events that occurred at a frequency of 1% or more among buspirone hydrochloride patients who participated in 4 week, controlled trials comparing buspirone with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures 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 which 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. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and non drug factors to the side-effect incidence rate in the population studied. ## Other Events Observed During the Entire Premarketing Evaluation of Buspirone - During its premarketing assessment, buspirone was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of buspirone in the dose range for which buspirone is being recommended (i.e., the modal daily dose of buspirone fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to buspirone varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to buspirone hydrochloride treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. - The following enumeration by organ system describes events in terms of their relative frequency of reporting in this data base. - The following definitions of frequency are used: frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. ## Cardiovascular - Frequent was non specific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. ## Central Nervous System - Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria , akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. ## ENT - Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. ## Endocrine - Rare were galactorrhea and thyroid abnormality. ## Gastrointestinal - Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. ## Genitourinary - Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. ## Musculoskeletal - Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. ## Respiratory - Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. ## Sexual Function - Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. ## Skin - Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. ## Clinical Laboratory - Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. ## Miscellaneous - Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. ## Postmarketing Experience - Postmarketing experience has shown an adverse experience profile similar to that given above. voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes (including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone treatment has not been determined. # Drug Interactions # Psychotropic Agents MAO inhibitors - It is recommended that buspirone not be used concomitantly with MAO inhibitors. Amitriptyline - After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed. Diazepam - After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol - In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone Trazodone - There is one report suggesting that the concomitant use of trazodone hydrochloride and buspirone may have caused 3 to 6 fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/flurazepam - Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other psychotropics - Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 [CYP3A4] - Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and verapamil - In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and Cmax of buspirone 3.4 fold while diltiazem increased AUC and Cmax 5.5 fold and 4 fold, respectively). Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5 fold increase in Cmax and 6 fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit juice - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d. for 2 days) increased plasma buspirone concentrations (4.3 fold increase in Cmax; 9.2 fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole - In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13 fold increase in Cmax and 19 fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone - In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in Cmax and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5 mg b.i.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects receiving buspirone 5 mg b.i.d. and nefazodone 250 mg b.i.d. experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg q.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Rifampin - In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other inhibitors and inducers of CYP3A4 - Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. # Other Drugs Cimetidine - Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2 fold), but had minimal effects on the AUC of buspirone. Protein Binding - In vitro, buspirone does not displace tightly bound drugs like phenytoin, propanolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and levothyroxine sodium. In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. - Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol , thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well-controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - The effect of buspirone on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. ### Labor and Delivery There is no FDA guidance on use of Buspirone during labor and delivery. ### Nursing Mothers - The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. Buspirone administration to nursing women should be avoided if clinically possible. ### Pediatric Use - The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6 week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5 mg to 30 mg b.i.d. (15 to 60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population. ### Geriatic Use - In one study of 6632 patients who received buspirone for the treatment of anxiety, 605 patients were ≥ 65 years old and 41 were ≥ 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). Review of spontaneously reported adverse clinical events has not identified differences between elderly and younger patients, but greater sensitivity of some older patients can not be ruled out.There were no effects of age on the pharmacokinetics of buspirone ### Gender There is no FDA guidance on the use of Buspirone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Buspirone with respect to specific racial populations. ### Renal Impairment - Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of buspirone hydrochloride tablets, USP to patients with severe hepatic or renal impairment cannot be recommended. ### Hepatic Impairment - Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of buspirone hydrochloride tablets, USP to patients with severe hepatic or renal impairment cannot be recommended. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Buspirone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Buspirone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - FDA package insert for buspirone contains no information regarding drug monitoring. # IV Compatibility - There is limited information about the IV compatibility. # Overdosage ## Signs and Symptoms - In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete recovery as the usual outcome. No deaths have been reported following overdosage with buspirone alone. Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. ## Recommended Overdose Treatment - General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. # Pharmacology ## Mechanism of Action - The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. ## Structure - Buspirone hydrochloride is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. - Buspirone hydrochloride is a white crystalline, water soluble compound. Chemically, buspirone hydrochloride is N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,1-cyclopentanediacetamide monohydrochloride, which can be represented by the following structural formula: - Each tablet, for oral administration, contains 5 mg, 10 mg, 15 mg or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 9.1 mg, 13.7 mg and 27.4 mg of buspirone free base respectively). The 5 mg and 10 mg tablets are scored so they can be bisected. Thus, the 5 mg tablet can also provide a 2.5 mg dose, and the 10 mg tablet can provide a 5 mg dose. The 15 mg tablets are scored such that they may be bisected or trisected. Thus, a single tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two-thirds of a tablet), 7.5 mg (one-half of a tablet), or 5 mg (one-third of a tablet). The 30 mg tablets are scored such that they may be bisected or trisected. Thus, a single tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two-thirds of a tablet), 15 mg (one-half of a tablet), or 10 mg (one-third of a tablet). Buspirone hydrochloride tablets, USP contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. ## Pharmacodynamics - Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. - Buspirone is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged buspirone are very low and variable between subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. - The effects of food upon the bioavailability of buspirone have been studied in eight subjects. They were given a 20 mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone. - A multiple-dose study conducted in 15 subjects suggests that buspirone has non linear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. - An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin. ## Pharmacokinetics - Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of buspirone, but is present in up to 20 fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to buspirone hydrochloride do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of buspirone without signs of toxicity. - In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged buspirone after single doses of 10 to 40 mg is about 2 to 3 hours. # Special Populations Age and Gender Effects - After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women. Hepatic Impairment - After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13 fold compared with healthy subjects. Renal Impairment - After multiple-dose administration of buspirone to renally impaired (Clcr = 10 to 70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4 fold compared with healthy (Clcr ≥ 80 mL/min/1.73 m2) subjects. Race Effects - The effects of race on the pharmacokinetics of buspirone have not been studied. ## Nonclinical Toxicology - No evidence of carcinogenic potential was observed in rats during a 24 month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18 month study at approximately 167 times the maximum recommended human oral dose. - With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. # Clinical Studies - There is limited information about the clinical studies. # How Supplied - Buspirone Hydrochloride Tablets, USP are available as: - Buspirone Hydrochloride Tablets, USP 5 mg are white ovoid-rectangular, uncoated tablets, with score line on one side and plain on other side. Tablets are packed in the bottles of 100 having NDC 64380-741-06. - Buspirone Hydrochloride Tablets, USP 10 mg are white ovoid-rectangular, uncoated tablets, with score line on one side and plain on other side. Tablets are packed in the bottles of 100 having NDC 64380-742-06. - Buspirone Hydrochloride Tablets, USP 15 mg are white rectangular, uncoated tablets, with trisected score lines on both sides. The 15 mg tablet is in xx tablet design and scored so that it can be either bisected or trisected. Tablets are packed in bottles of 60 having NDC 64380-743-03, 100 having NDC 64380-743-06 and 180 having NDC 64380-743-18. - Buspirone Hydrochloride Tablets, USP 30 mg are white rectangular, uncoated tablets that can either be bisected or trisected. Tablets are packed in bottles of 60 having NDC 64380-744-03. ## Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° C to 30° C (59° F to 86° F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - To assure safe and effective use of buspirone hydrochloride tablets, USP the following information and instructions should be given to patients: 1. Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with buspirone. 2. Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking buspirone. 3. Inform your physician if you are breast-feeding an infant. 4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. 5. You should take buspirone consistently, either always with or always without food. 6. During your treatment with buspirone, avoid drinking large amounts of grapefruit juice. # Precautions with Alcohol - While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. # Brand Names - Buspar - Buspar Dividose - Vanspar # Look-Alike Drug Names - Buspirone - Bupropion[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Buspar_Dividose
64c699cba889a3e1c46d3f9deba6d3bdd24ebb14	wikidoc	Butterbur	Butterbur The plants commonly referred to as Butterbur are found in the daisy family Asteraceae in the genus Petasites. They are mostly quite robust plants with thick, creeping underground rhizomes and large Rhubarb-like leaves during the growing season. Another common name for many species of this genus is Sweet Coltsfoot. The short spikes of flowers are produced just before these leaves in Spring, emerging with only a few elongated basal bracts and are usually green, flesh coloured or dull white depending on species. Butterburs are found in the temperate zone of the Northern Hemisphere. They prefer moist environments such as riverbanks, marshes and ditches. Petasites is very closely related to the genus Tussilago (Coltsfoot), and also related to the huge genus Senecio. # Medicinal uses Butterbur was used by native Americans as a remedy for headache and inflammation. Some Butterbur contains petasin and isopetasin, with the highest concentrations occurring in the root. The best-documented beneficial effect of Butterbur extracts are as a treatment of migraine headaches. Several mainstream double-blind studies have shown that extracts of Butterbur petasin and/or isopetasin are effective both in preventing and in relieving migraine, with the best results coming in more severe cases . Additionally, a peer-reviewed journal published a Swiss study showing Butterbur extract to be an effective treament for hay fever without the sedative effect of the antihistamine cetirizine . Butterbur naturally contains components called pyrrolizidine alkaloids. They are toxic to the liver and may cause cancers. The concentrations are often highest in the rhizomes and stalks and lowest in the leaves and may vary depending on where the plants are grown. Butterbur extract should be taken only when prepared by a reputable laboratory. Long-term health effects and interaction with other drugs have not been studied. # Selected species - Petasites albus White Butterbur - Petasites amplus - Petasites doerfleri - Petasites formosanus - Petasites fragrans Winter Heliotrope - Petasites frigidus (syn. P. speciosa) Arctic Butterbur or Arctic Sweet Coltsfoot - Petasites hybridus Common Butterbur - Petasites japonicus Giant Butterbur, or Fuki - Petasites kablikianus - Petasites paradoxus - Petasites radiatus - Petasites sagittatus - Petasites sibiricus - Petasites spurius - Petasites tatewakianus - Petasites tricholobus # Hybrids - Petasites x vitifolius # In popular culture In the manga Shaman King, the young Ainu shaman Horohoro dreams of planting a vast field of Butterbur from the east to the west coast of Hokkaidō.	Butterbur The plants commonly referred to as Butterbur are found in the daisy family Asteraceae in the genus Petasites. They are mostly quite robust plants with thick, creeping underground rhizomes and large Rhubarb-like leaves during the growing season. Another common name for many species of this genus is Sweet Coltsfoot. The short spikes of flowers are produced just before these leaves in Spring, emerging with only a few elongated basal bracts and are usually green, flesh coloured or dull white depending on species. Butterburs are found in the temperate zone of the Northern Hemisphere. They prefer moist environments such as riverbanks, marshes and ditches. Petasites is very closely related to the genus Tussilago (Coltsfoot), and also related to the huge genus Senecio. # Medicinal uses Butterbur was used by native Americans as a remedy for headache and inflammation. Some Butterbur contains petasin[1] and isopetasin, with the highest concentrations occurring in the root. The best-documented beneficial effect of Butterbur extracts are as a treatment of migraine headaches.[1] Several mainstream double-blind studies have shown that extracts of Butterbur petasin and/or isopetasin are effective both in preventing and in relieving migraine, with the best results coming in more severe cases [2]. Additionally, a peer-reviewed journal published a Swiss study showing Butterbur extract to be an effective treament for hay fever without the sedative effect of the antihistamine cetirizine [3]. Butterbur naturally contains components called pyrrolizidine alkaloids. They are toxic to the liver and may cause cancers. The concentrations are often highest in the rhizomes and stalks and lowest in the leaves and may vary depending on where the plants are grown. Butterbur extract should be taken only when prepared by a reputable laboratory. Long-term health effects and interaction with other drugs have not been studied. # Selected species - Petasites albus White Butterbur - Petasites amplus - Petasites doerfleri - Petasites formosanus - Petasites fragrans Winter Heliotrope - Petasites frigidus (syn. P. speciosa) Arctic Butterbur or Arctic Sweet Coltsfoot - Petasites hybridus Common Butterbur - Petasites japonicus Giant Butterbur, or Fuki - Petasites kablikianus - Petasites paradoxus - Petasites radiatus - Petasites sagittatus - Petasites sibiricus - Petasites spurius - Petasites tatewakianus - Petasites tricholobus # Hybrids - Petasites x vitifolius # In popular culture In the manga Shaman King, the young Ainu shaman Horohoro dreams of planting a vast field of Butterbur from the east to the west coast of Hokkaidō.	https://www.wikidoc.org/index.php/Butterbur
ee34d301902e425b1f791389b5df90e08b2d8261	wikidoc	Exenatide	Exenatide # 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 Exenatide is a GLP-1 receptor agonist that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include injection site mass, injection site pruritus, injection site reaction, hypoglycemia, constipation, diarrhea, indigestion, nausea, vomiting, antibody development, asthenia, dizziness, nervousness, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Type 2 Diabetes Mellitus - Dosing information - 5 mg injection SC bid at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart) - Exenatide should not be administered after a meal. - Based on clinical response, the dose of Exenatide can be increased to 10 mcg SC injection bid after 1 month of therapy. - Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Exenatide with insulin. Do not transfer Exenatide from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Exenatide. ### Important limitations of use - Exenatide is not a substitute for insulin. Exenatide should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. - The concurrent use of Exenatide with prandial insulin has not been studied and cannot be recommended. - Based on post marketing data Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Exenatide has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Exenatide. Other anti diabetic therapies should be considered in patients with a history of pancreatitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of exenatide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of exenatide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Exenatide have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of exenatide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of exenatide in pediatric patients. # Contraindications ### Hypersensitivity Exenatide is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components. # Warnings ### Never Share a Exenatide Pen between Patients Exenatide pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. ### Acute Pancreatitis - Based on post marketing data, Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. - After initiation of Exenatide, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). - If pancreatitis is suspected, Exenatide should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Exenatide should not be restarted. - Consider anti diabetic therapies other than Exenatide in patients with a history of pancreatitis. ### Use with Medications Known to Cause Hypoglycemia - The risk of hypoglycemia is increased when Exenatide is used in combination with a sulfonylurea. Therefore, patients receiving Exenatide and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia. - When Exenatide is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin. - The concurrent use of Exenatide with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Exenatide with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia. ### Renal Impairment - Exenatide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation . - In patients with end-stage renal disease receiving dialysis, single doses of Exenatide 5 mcg were not well tolerated due to gastrointestinal side effects. - Because Exenatide may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). - There have been post marketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. - Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. - Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Exenatide. - Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. ### Gastrointestinal Disease - Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. - Because Exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Exenatide is not recommended in patients with severe gastrointestinal disease. ### Immunogenicity - Patients may develop antibodies to exenatide following treatment with Exenatide. - Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. - In 3%, 4%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. - If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative anti diabetic therapy should be considered. ### Hypersensitivity - There have been post marketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with Exenatide. - If a hypersensitivity reaction occurs, the patient should discontinue Exenatide and other suspect medications and promptly seek medical advice. ### Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Exenatide or any other anti diabetic 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 practice. ### Hypoglycemia Table 1 summarizes the incidence and rate of hypoglycemia with Exenatide in six placebo-controlled clinical trials. ### Immunogenicity - Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. In the 30-week controlled trials of Exenatide add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. - The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. - The level of glycemic control (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. - Of these patients, 32 (3% overall) had an attenuated glycemic response to Exenatide; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies. - In the 16-week trial of Exenatide add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. - The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. - Of these patients, 4 (4% overall) had an attenuated glycemic response to Exenatide; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. - In the 24-week trial of Exenatide used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. - The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. - Of these patients, 1 (1% overall) had an attenuated glycemic response to Exenatide; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies. - Antibodies to exenatide were not assessed in the 30-week trial of Exenatide used in combination with insulin glargine. - Two hundred and ten patients with antibodies to exenatide in the Exenatide clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. - No treatment-emergent cross-reactive antibodies were observed across the range of titers. ### Other Adverse Reactions Monotherapy For the 24-week placebo-controlled study of Exenatide used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Exenatide, nausea, occurred in a dose-dependent fashion. Two of the 155 patients treated with Exenatide withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions. Combination Therapy Add-On to Metformin and/or Sulfonylurea In the three 30-week controlled trials of Exenatide add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients ] are summarized in Table 3. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials. The most common adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting. Add-On to Thiazolidinedione with or without Metformin For the 16-week placebo-controlled study of Exenatide add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in Exenatide-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Exenatide arm. No serious adverse events were reported in the placebo arm. The most common adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea. Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione For the 30-week placebo-controlled study of Exenatide as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. The most frequently reported adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting. ## Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Exenatide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction . Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding. Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death. Neurologic: dysgeusia; somnolence. Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction. Skin and Subcutaneous Tissue Disorders: alopecia. # Drug Interactions ### Orally Administered Drugs The effect of Exenatide to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Exenatide should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before Exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Exenatide is not administered . ### Warfarin There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Exenatide . In a drug interaction study, Exenatide did not have a significant effect on INR . In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Exenatide therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of Exenatide use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Pregnancy Registry A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Exenatide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Exenatide during labor and delivery. ### Nursing Mothers It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Exenatide is administered to a nursing woman. ### Pediatric Use Safety and effectiveness of Exenatide have not been established in pediatric patients. ### Geriatic Use Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide. Exenatide was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function. ### Gender There is no FDA guidance on the use of Exenatide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Exenatide with respect to specific racial populations. ### Renal Impairment Exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of Exenatide is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) ### Hepatic Impairment No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of eventide. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Exenatide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Exenatide in patients who are immunocompromised. # Administration and Monitoring ### Administration Injection SC ### Monitoring FDA package insert for abcixmab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage In a clinical study of Exenatide, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. # Pharmacology ## Mechanism of Action Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below. ## Structure Exenatide (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors. Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below. H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Exenatide is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID). ## Pharmacodynamics Glucose-Dependent Insulin Secretion Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Exenatide does not impair the normal glucagon response to hypoglycemia. First-Phase Insulin Response In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Exenatide compared with saline (p<0.001 for both). Glucagon Secretion In patients with type 2 diabetes, Exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. Gastric Emptying Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation. Food Intake In both animals and humans, administration of exenatide has been shown to reduce food intake. Postprandial Glucose In patients with type 2 diabetes, Exenatide reduces postprandial plasma glucose concentrations (Figure 2). Fasting Glucose In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Exenatide. Plasma glucose concentrations were significantly reduced with Exenatide compared with placebo (Figure 3). Cardiac Electrophysiology The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec. Thus, Exenatide (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval. ## Pharmacokinetics Absorption Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Exenatide. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Exenatide in the abdomen, thigh, or upper arm. Distribution The mean apparent volume of distribution of exenatide following SC administration of a single dose of Exenatide is 28.3 L. Metabolism and Elimination Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose. Drug Interactions Acetaminophen When 1000 mg acetaminophen elixir was given with 10 mcg Exenatide (0 hour) and 1 hour, 2 hours, and 4 hours after Exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before Exenatide injection. Digoxin Administration of repeated doses of Exenatide (10 mcg BID) 30 minutes before oral digoxin (0.25 mg once daily) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed. Lovastatin Administration of Exenatide (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of Exenatide, the use of Exenatide in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline. Lisinopril In patients with mild to moderate hypertension stabilized on lisinopril (5-20 mg/day), Exenatide (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic blood pressure. Oral Contraceptives The effect of Exenatide (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Exenatide administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Exenatide administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Exenatide did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Exenatide administration injection as compared to when the OC was given alone. The effect of Exenatide on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Exenatide injection. warfarin Administration of warfarin (25 mg) 35 minutes after repeated doses of Exenatide (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Exenatide did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin . Specific Populations Renal Impairment Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function. Hepatic Impairment No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Age Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide . Gender Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide. Race Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide. Body Mass Index Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC). In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay. In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. ### Reproductive and Developmental Toxicology In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. # Clinical Studies Exenatide has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione. ### Monotherapy In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Exenatide 5 mcg BID (n=77), Exenatide 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to Exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian. The primary endpoint was the change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, Exenatide 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 6). ### Combination Therapy with Oral Antihyperglycemic Medicines Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Exenatide in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where Exenatide was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive Exenatide 5 mcg bid, Exenatide 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. In the placebo-controlled trial of 16 weeks duration, Exenatide (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to Exenatide or placebo was stratified based on whether the patients were receiving metformin. Exenatide treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. Exenatide or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline HbA1c values were 7.9% for Exenatide and placebo. The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials. HbA1c The addition of Exenatide to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 7). In the 16-week trial of Exenatide add-on to thiazolidinediones, with or without metformin, Exenatide resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo (Table 7). Postprandial Glucose Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, Exenatide reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of Exenatide at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID (n=42), −71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44). ### Combination with Insulin Glargine A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of Exenatide (n=137) versus placebo (n=122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to Exenatide had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA1c ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA1c ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins. The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo, Exenatide 10 mcg bid resulted in statistically significant reductions in HbA1c from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine. # How Supplied Exenatide is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide. The following packages are available: 5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07 10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01 ## Storage - Prior to first use, Exenatide must be stored refrigerated at 36°F to 46°F (2°C to 8°C). - After first use, Exenatide can be kept at a temperature not to exceed 77°F (25°C). - Do not freeze. Do not use Exenatide if it has been frozen. - Exenatide should be protected from light. - The pen should be discarded 30 days after first use, even if some drug remains in the pen. - Use a puncture-resistant container to discard the needles. Do not reuse or share needles. - Exenatide should not be used past the expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Exenatide - Bydureon # Look-Alike Drug Names There is limited information about the Look-alike drug names. # Drug Shortage Status # Price	Exenatide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Exenatide is a GLP-1 receptor agonist that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include injection site mass, injection site pruritus, injection site reaction, hypoglycemia, constipation, diarrhea, indigestion, nausea, vomiting, antibody development, asthenia, dizziness, nervousness, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Type 2 Diabetes Mellitus - Dosing information - 5 mg injection SC bid at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart) - Exenatide should not be administered after a meal. - Based on clinical response, the dose of Exenatide can be increased to 10 mcg SC injection bid after 1 month of therapy. - Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Exenatide with insulin. Do not transfer Exenatide from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Exenatide. ### Important limitations of use - Exenatide is not a substitute for insulin. Exenatide should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. - The concurrent use of Exenatide with prandial insulin has not been studied and cannot be recommended. - Based on post marketing data Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Exenatide has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Exenatide. Other anti diabetic therapies should be considered in patients with a history of pancreatitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of exenatide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of exenatide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Exenatide have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of exenatide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of exenatide in pediatric patients. # Contraindications ### Hypersensitivity Exenatide is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components. # Warnings ### Never Share a Exenatide Pen between Patients Exenatide pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. ### Acute Pancreatitis - Based on post marketing data, Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. - After initiation of Exenatide, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). - If pancreatitis is suspected, Exenatide should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Exenatide should not be restarted. - Consider anti diabetic therapies other than Exenatide in patients with a history of pancreatitis. ### Use with Medications Known to Cause Hypoglycemia - The risk of hypoglycemia is increased when Exenatide is used in combination with a sulfonylurea. Therefore, patients receiving Exenatide and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia. - When Exenatide is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin. - The concurrent use of Exenatide with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Exenatide with other glucose-independent insulin secretagogues (e.g., meglitinides) could increase the risk of hypoglycemia. ### Renal Impairment - Exenatide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation . - In patients with end-stage renal disease receiving dialysis, single doses of Exenatide 5 mcg were not well tolerated due to gastrointestinal side effects. - Because Exenatide may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). - There have been post marketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. - Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. - Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Exenatide. - Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. ### Gastrointestinal Disease - Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. - Because Exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Exenatide is not recommended in patients with severe gastrointestinal disease. ### Immunogenicity - Patients may develop antibodies to exenatide following treatment with Exenatide. - Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. - In 3%, 4%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. - If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative anti diabetic therapy should be considered. ### Hypersensitivity - There have been post marketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with Exenatide. - If a hypersensitivity reaction occurs, the patient should discontinue Exenatide and other suspect medications and promptly seek medical advice. ### Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Exenatide or any other anti diabetic 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 practice. ### Hypoglycemia Table 1 summarizes the incidence and rate of hypoglycemia with Exenatide in six placebo-controlled clinical trials. ### Immunogenicity - Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. In the 30-week controlled trials of Exenatide add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. - The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. - The level of glycemic control (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. - Of these patients, 32 (3% overall) had an attenuated glycemic response to Exenatide; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies. - In the 16-week trial of Exenatide add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. - The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. - Of these patients, 4 (4% overall) had an attenuated glycemic response to Exenatide; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. - In the 24-week trial of Exenatide used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. - The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. - Of these patients, 1 (1% overall) had an attenuated glycemic response to Exenatide; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies. - Antibodies to exenatide were not assessed in the 30-week trial of Exenatide used in combination with insulin glargine. - Two hundred and ten patients with antibodies to exenatide in the Exenatide clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. - No treatment-emergent cross-reactive antibodies were observed across the range of titers. ### Other Adverse Reactions Monotherapy For the 24-week placebo-controlled study of Exenatide used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Exenatide, nausea, occurred in a dose-dependent fashion. Two of the 155 patients treated with Exenatide withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions. Combination Therapy Add-On to Metformin and/or Sulfonylurea In the three 30-week controlled trials of Exenatide add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients ] are summarized in Table 3. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials. The most common adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting. Add-On to Thiazolidinedione with or without Metformin For the 16-week placebo-controlled study of Exenatide add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in Exenatide-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Exenatide arm. No serious adverse events were reported in the placebo arm. The most common adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea. Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione For the 30-week placebo-controlled study of Exenatide as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients. The most frequently reported adverse reactions leading to withdrawal for Exenatide-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting. ## Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Exenatide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction . Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding. Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death. Neurologic: dysgeusia; somnolence. Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction. Skin and Subcutaneous Tissue Disorders: alopecia. # Drug Interactions ### Orally Administered Drugs The effect of Exenatide to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Exenatide should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before Exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Exenatide is not administered . ### Warfarin There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Exenatide . In a drug interaction study, Exenatide did not have a significant effect on INR . In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Exenatide therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of Exenatide use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Pregnancy Registry A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Exenatide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Exenatide during labor and delivery. ### Nursing Mothers It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Exenatide is administered to a nursing woman. ### Pediatric Use Safety and effectiveness of Exenatide have not been established in pediatric patients. ### Geriatic Use Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide. Exenatide was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function. ### Gender There is no FDA guidance on the use of Exenatide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Exenatide with respect to specific racial populations. ### Renal Impairment Exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of Exenatide is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) ### Hepatic Impairment No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of eventide. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Exenatide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Exenatide in patients who are immunocompromised. # Administration and Monitoring ### Administration Injection SC ### Monitoring FDA package insert for abcixmab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage In a clinical study of Exenatide, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. # Pharmacology ## Mechanism of Action Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below. ## Structure Exenatide (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors. Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below. H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Exenatide is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID). ## Pharmacodynamics Glucose-Dependent Insulin Secretion Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Exenatide does not impair the normal glucagon response to hypoglycemia. First-Phase Insulin Response In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Exenatide compared with saline (p<0.001 for both). Glucagon Secretion In patients with type 2 diabetes, Exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. Gastric Emptying Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation. Food Intake In both animals and humans, administration of exenatide has been shown to reduce food intake. Postprandial Glucose In patients with type 2 diabetes, Exenatide reduces postprandial plasma glucose concentrations (Figure 2). Fasting Glucose In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Exenatide. Plasma glucose concentrations were significantly reduced with Exenatide compared with placebo (Figure 3). Cardiac Electrophysiology The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec. Thus, Exenatide (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval. ## Pharmacokinetics Absorption Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Exenatide. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Exenatide in the abdomen, thigh, or upper arm. Distribution The mean apparent volume of distribution of exenatide following SC administration of a single dose of Exenatide is 28.3 L. Metabolism and Elimination Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose. Drug Interactions Acetaminophen When 1000 mg acetaminophen elixir was given with 10 mcg Exenatide (0 hour) and 1 hour, 2 hours, and 4 hours after Exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before Exenatide injection. Digoxin Administration of repeated doses of Exenatide (10 mcg BID) 30 minutes before oral digoxin (0.25 mg once daily) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed. Lovastatin Administration of Exenatide (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of Exenatide, the use of Exenatide in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline. Lisinopril In patients with mild to moderate hypertension stabilized on lisinopril (5-20 mg/day), Exenatide (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic blood pressure. Oral Contraceptives The effect of Exenatide (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Exenatide administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Exenatide administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Exenatide did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Exenatide administration injection as compared to when the OC was given alone. The effect of Exenatide on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Exenatide injection. warfarin Administration of warfarin (25 mg) 35 minutes after repeated doses of Exenatide (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Exenatide did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)]. Specific Populations Renal Impairment Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function. Hepatic Impairment No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Age Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)]. Gender Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide. Race Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide. Body Mass Index Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC). In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay. In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. ### Reproductive and Developmental Toxicology In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. # Clinical Studies Exenatide has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione. ### Monotherapy In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Exenatide 5 mcg BID (n=77), Exenatide 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA1c ranging from 6.5% to 10%. All patients assigned to Exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian. The primary endpoint was the change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, Exenatide 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA1c from baseline at Week 24 (Table 6). ### Combination Therapy with Oral Antihyperglycemic Medicines Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Exenatide in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where Exenatide was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive Exenatide 5 mcg bid, Exenatide 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. In the placebo-controlled trial of 16 weeks duration, Exenatide (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to Exenatide or placebo was stratified based on whether the patients were receiving metformin. Exenatide treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. Exenatide or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline HbA1c values were 7.9% for Exenatide and placebo. The primary endpoint in each study was the mean change in HbA1c from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials. HbA1c The addition of Exenatide to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo added to these agents in the three controlled trials (Table 7). In the 16-week trial of Exenatide add-on to thiazolidinediones, with or without metformin, Exenatide resulted in statistically significant reductions from baseline in HbA1c compared with patients receiving placebo (Table 7). Postprandial Glucose Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, Exenatide reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of Exenatide at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID (n=42), −71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44). ### Combination with Insulin Glargine A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of Exenatide (n=137) versus placebo (n=122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to Exenatide had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA1c ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA1c ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins. The primary endpoint was the change in HbA1c from baseline to Week 30. Compared to placebo, Exenatide 10 mcg bid resulted in statistically significant reductions in HbA1c from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine. # How Supplied Exenatide is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide. The following packages are available: 5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07 10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01 ## Storage - Prior to first use, Exenatide must be stored refrigerated at 36°F to 46°F (2°C to 8°C). - After first use, Exenatide can be kept at a temperature not to exceed 77°F (25°C). - Do not freeze. Do not use Exenatide if it has been frozen. - Exenatide should be protected from light. - The pen should be discarded 30 days after first use, even if some drug remains in the pen. - Use a puncture-resistant container to discard the needles. Do not reuse or share needles. - Exenatide should not be used past the expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Exenatide - Bydureon # Look-Alike Drug Names There is limited information about the Look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Byetta
3e6813fa7b7f8856d8b4ac02b8cebb0d4649afbf	wikidoc	Nebivolol	Nebivolol ## Hypertension - Dosing information - The dose of Nebivolol must be individualized to the needs of the patient. - Recommended starting dosage: 5 mg PO qd, with or without food, as monotherapy or in combination with other agents. - For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial. ## Patients with a history of MI or ACS and reduced ejection fraction (EF) - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level B - Dosing Information - Not applicable ## Congestive heart failure - Dosing information - 1.25 mg PO qd - 10 mg PO qd ## Prophylaxis of Migraine - Dosing information - 5 mg/day - Severe bradycardia. - Heart block greater than first degree. - Patients with cardiogenic shock. - Decompensated cardiac failure - Sick sinus syndrome (unless a permanent pacemaker is in place). - Patients with severe hepatic impairment (Child-Pugh B). - Patients who are hypersensitive to any component of this product. Do not abruptly discontinue Nebivolol therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, carefully observe and advise patients to minimize physical activity. Taper Nebivolol over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, re-start Nebivolol promptly, at least temporarily. # Angina and Acute Myocardial Infarction Nebivolol was not studied in patients with angina pectoris or who had a recent MI. # Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers. # Anesthesia and Major Surgery Because beta-blocker withdrawal has been associated with an increased risk of myocardial infarction and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If Nebivolol is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. # Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. # Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. # Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. # Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents. # Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 . The dose of Nebivolol may need to be reduced. # Impaired Renal Function Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol has not been studied in patients receiving dialysis. # Impaired Hepatic Function Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. Nebivolol has not been studied in patients with severe hepatic impairment. # Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. # Pheochromocytoma In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker. The data described below reflect worldwide clinical trial exposure to Nebivolol in 6545 patients, including 5038 patients treated for hypertensionand the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received Nebivolol for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. HYPERTENSION: In placebo-controlled clinical trials comparing Nebivolol with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of Nebivolol were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 20-40 mg of Nebivolol and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with Nebivolol in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. # Laboratory Abnormalities In controlled monotherapy trials of hypertensive patients, Nebivolol was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.). # Hypotensive Agents Do not use Nebivolol with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, discontinue Nebivolol for several days before the gradual tapering of clonidine. # Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. # Calcium Channel Blockers Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine and benzothiazepine classes), or antiarrhythmic agents, such as disopyramide. Drugs that inhibit CYP2D6 can be expected to increase plasma levels of nebivolol. When Nebivolol is co-administered with an inhibitor or an inducer of this enzyme, monitor patients closely and adjust the nebivolol dose according to blood pressure response. In vitro studies have demonstrated that at therapeutically relevant concentrations, d- and l-nebivolol do not inhibit any cytochrome P450 pathways. Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol. Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. Diuretics: No pharmacokinetic interactions were observed in healthy adults between nebivolol (10 mg daily for 10 days) and furosemide (40 mg single dose),hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days). Ramipril: Concomitant administration of Nebivolol (10 mg once daily) and ramipril (5 mg once daily) for 10 days in 15 healthy adult volunteers produced no pharmacokinetic interactions. Losartan: Concomitant administration of Nebivolol (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions. Fluoxetine: Fluoxetine, a CYP2D6 inhibitor, administered at 20 mg per day for 21 days prior to a single 10 mg dose of nebivolol to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in Cmax for d-nebivolol. Histamine-2 Receptor Antagonists: The pharmacokinetics of nebivolol (5 mg single dose) were not affected by the co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol. Charcoal: The pharmacokinetics of nebivolol (10 mg single dose) were not affected by repeated co-administration (4, 8, 12, 16, 22, 28, 36, and 48 hours after nebivolol administration) of activated charcoal (Actidose-Aqua®). Sildenafil: The co-administration of nebivolol and sildenafil decreased AUC and Cmax of sildenafil by 21 and 23% respectively. The effect on the Cmax and AUC for d-nebivolol was also small (< 20%). The effect on vital signs (e.g., pulse and blood pressure) was approximately the sum of the effects of sildenafil and nebivolol. Other Concomitant Medications: Utilizing population pharmacokinetic analyses, derived from hypertensive patients, the following drugs were observed not to have an effect on the pharmacokinetics of nebivolol: acetaminophen, acetylsalicylic acid, atorvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). No studies of nebivolol were conducted in pregnant women. Use Nebivolol during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, Nebivolol is not recommended during nursing. The largest known ingestion of Nebivolol worldwide involved a patient who ingested up to 500 mg of Nebivolol along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhydrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping Nebivolol, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short acting inhaled β2-agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12-19 hours. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment. Nebivolol hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, and methylbenzene. Plasma levels of d–nebivolol increase in proportion to dose in extensive metabolizers (EMs) and poor metabolizers (PMs) for doses up to 20mg. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1000-fold higher than l-nebivolol. For the same dose, PMs attain a 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol than do EMs. d-Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs. Absorption of Nebivolol is similar to an oral solution. The absolute bioavailability has not been determined. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. Nebivolol may be administered without regard to meals. ## Distribution The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations. ## Metabolism Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to the pharmacologic activity. ## Elimination After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates. # Pharmacokinetics in Special Populations ## Hepatic Disease d-Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic impairment (Child-Pugh Class B). No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients. ## Renal Disease The apparent clearance of nebivolol was unchanged following a single 5 mg dose of Nebivolol in patients with mild renal impairment (ClCr 50 to 80 mL/min, n=7), and it was reduced negligibly in patients with moderate (ClCr 30 to 50 mL/min, n=9), but clearance was reduced by 53% in patients with severe renal impairment (ClCr <30 mL/min, n=5). No studies have been conducted in patients on dialysis. In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man. A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone. Effects on spermatogenesis were seen in male rats and mice at ≥ 40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible. Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests). The antihypertensive effectiveness of Nebivolol as monotherapy has been demonstrated in three randomized, double-blind, multi-center, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2, and 3). A fourth placebo-controlled trial demonstrated additional antihypertensive effects of Nebivolol at doses ranging from 5 to 20 mg when administered concomitantly with up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) in patients with inadequate blood pressure control. The three monotherapy trials included a total of 2016 patients (1811 Nebivolol, 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg. Patients received either Nebivolol or placebo once daily for twelve weeks. Two of these monotherapy trials (Studies 1 and 2) studied 1716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as PMs. The third monotherapy trial (Study 3) studied 300 Black patients with a mean age of 51 years, 45% males, 14% diabetics, and 3% as PMs. Placebo-subtracted blood pressure reductions by dose for each study are presented in Table 2. Most studies showed increasing response to doses above 5 mg. Study 4 enrolled 669 patients with a mean age of 54 years, 55% males, 54% Caucasians, 29% Blacks, 15% Hispanics, 1% Asians, 14% diabetics, and 5% PMs. Nebivolol, 5 mg to 20 mg, administered once daily concomitantly with stable doses of up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) resulted in significant additional antihypertensive effects over placebo compared to baseline blood pressure. Effectiveness was similar in subgroups analyzed by age and sex. Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians. The blood pressure lowering effect of Nebivolol was seen within two weeks of treatment and was maintained over the 24-hour dosing interval. There are no trials of Nebivolol demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. Nebivolol tablets are triangular-shaped, biconvex, unscored, differentiated by color and are engraved with “FL” on one side and the number of mg (2 ½, 5, 10, or 20) on the other side. Nebivolol tablets are supplied in the following strengths and package configurations: Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Advise patients to take Nebivolol regularly and continuously, as directed. Nebivolol can be taken with or without food. If a dose is missed, take the next scheduled dose only (without doubling it). Do not interrupt or discontinue Nebivolol without consulting the physician. Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness. Advise patients to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia. Caution patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. - ↑ Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J; et al. (2005). "Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)". Eur Heart J. 26 (3): 215–25. doi:10.1093/eurheartj/ehi115. PMID 15642700.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} - ↑ Dobre D, van Veldhuisen DJ, Mordenti G, Vintila M, Haaijer-Ruskamp FM, Coats AJ; et al. (2007). "Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial". Am Heart J. 154 (1): 109–15. doi:10.1016/j.ahj.2007.03.025. PMID 17584562.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Schellenberg R, Lichtenthal A, Wöhling H, Graf C, Brixius K (2008). "Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment?". Headache. 48 (1): 118–25. doi:10.1111/j.1526-4610.2007.00785.x. PMID 18184294.CS1 maint: Multiple names: authors list (link)	Nebivolol ### Hypertension - Dosing information - The dose of Nebivolol must be individualized to the needs of the patient. - Recommended starting dosage: 5 mg PO qd, with or without food, as monotherapy or in combination with other agents. - For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial. ### Patients with a history of MI or ACS and reduced ejection fraction (EF) - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level B - Dosing Information - Not applicable ### Congestive heart failure - Dosing information - 1.25 mg PO qd [1] - 10 mg PO qd [2] ### Prophylaxis of Migraine - Dosing information - 5 mg/day [3] - Severe bradycardia. - Heart block greater than first degree. - Patients with cardiogenic shock. - Decompensated cardiac failure - Sick sinus syndrome (unless a permanent pacemaker is in place). - Patients with severe hepatic impairment (Child-Pugh B). - Patients who are hypersensitive to any component of this product. Do not abruptly discontinue Nebivolol therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, carefully observe and advise patients to minimize physical activity. Taper Nebivolol over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, re-start Nebivolol promptly, at least temporarily. ## Angina and Acute Myocardial Infarction Nebivolol was not studied in patients with angina pectoris or who had a recent MI. ## Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers. ## Anesthesia and Major Surgery Because beta-blocker withdrawal has been associated with an increased risk of myocardial infarction and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If Nebivolol is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of Nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. ## Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. ## Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. ## Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. ## Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents. ## Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 . The dose of Nebivolol may need to be reduced. ## Impaired Renal Function Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol has not been studied in patients receiving dialysis. ## Impaired Hepatic Function Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. Nebivolol has not been studied in patients with severe hepatic impairment. ## Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. ## Pheochromocytoma In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker. The data described below reflect worldwide clinical trial exposure to Nebivolol in 6545 patients, including 5038 patients treated for hypertensionand the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received Nebivolol for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. HYPERTENSION: In placebo-controlled clinical trials comparing Nebivolol with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of Nebivolol were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 20-40 mg of Nebivolol and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with Nebivolol in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. ## Laboratory Abnormalities In controlled monotherapy trials of hypertensive patients, Nebivolol was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.). ## Hypotensive Agents Do not use Nebivolol with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of Nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, discontinue Nebivolol for several days before the gradual tapering of clonidine. ## Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. ## Calcium Channel Blockers Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. Drugs that inhibit CYP2D6 can be expected to increase plasma levels of nebivolol. When Nebivolol is co-administered with an inhibitor or an inducer of this enzyme, monitor patients closely and adjust the nebivolol dose according to blood pressure response. In vitro studies have demonstrated that at therapeutically relevant concentrations, d- and l-nebivolol do not inhibit any cytochrome P450 pathways. Digoxin: Concomitant administration of Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol. Warfarin: Administration of Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. Diuretics: No pharmacokinetic interactions were observed in healthy adults between nebivolol (10 mg daily for 10 days) and furosemide (40 mg single dose),hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days). Ramipril: Concomitant administration of Nebivolol (10 mg once daily) and ramipril (5 mg once daily) for 10 days in 15 healthy adult volunteers produced no pharmacokinetic interactions. Losartan: Concomitant administration of Nebivolol (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions. Fluoxetine: Fluoxetine, a CYP2D6 inhibitor, administered at 20 mg per day for 21 days prior to a single 10 mg dose of nebivolol to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in Cmax for d-nebivolol. Histamine-2 Receptor Antagonists: The pharmacokinetics of nebivolol (5 mg single dose) were not affected by the co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol. Charcoal: The pharmacokinetics of nebivolol (10 mg single dose) were not affected by repeated co-administration (4, 8, 12, 16, 22, 28, 36, and 48 hours after nebivolol administration) of activated charcoal (Actidose-Aqua®). Sildenafil: The co-administration of nebivolol and sildenafil decreased AUC and Cmax of sildenafil by 21 and 23% respectively. The effect on the Cmax and AUC for d-nebivolol was also small (< 20%). The effect on vital signs (e.g., pulse and blood pressure) was approximately the sum of the effects of sildenafil and nebivolol. Other Concomitant Medications: Utilizing population pharmacokinetic analyses, derived from hypertensive patients, the following drugs were observed not to have an effect on the pharmacokinetics of nebivolol: acetaminophen, acetylsalicylic acid, atorvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). No studies of nebivolol were conducted in pregnant women. Use Nebivolol during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, Nebivolol is not recommended during nursing. The largest known ingestion of Nebivolol worldwide involved a patient who ingested up to 500 mg of Nebivolol along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhydrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping Nebivolol, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short acting inhaled β2-agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12-19 hours. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment. Nebivolol hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, and methylbenzene. Plasma levels of d–nebivolol increase in proportion to dose in extensive metabolizers (EMs) and poor metabolizers (PMs) for doses up to 20mg. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1000-fold higher than l-nebivolol. For the same dose, PMs attain a 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol than do EMs. d-Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs. Absorption of Nebivolol is similar to an oral solution. The absolute bioavailability has not been determined. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. Nebivolol may be administered without regard to meals. ### Distribution The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations. ### Metabolism Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to the pharmacologic activity. ### Elimination After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates. ## Pharmacokinetics in Special Populations ### Hepatic Disease d-Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic impairment (Child-Pugh Class B). No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients. ### Renal Disease The apparent clearance of nebivolol was unchanged following a single 5 mg dose of Nebivolol in patients with mild renal impairment (ClCr 50 to 80 mL/min, n=7), and it was reduced negligibly in patients with moderate (ClCr 30 to 50 mL/min, n=9), but clearance was reduced by 53% in patients with severe renal impairment (ClCr <30 mL/min, n=5). No studies have been conducted in patients on dialysis. In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man. A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone. Effects on spermatogenesis were seen in male rats and mice at ≥ 40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible. Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests). The antihypertensive effectiveness of Nebivolol as monotherapy has been demonstrated in three randomized, double-blind, multi-center, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2, and 3). A fourth placebo-controlled trial demonstrated additional antihypertensive effects of Nebivolol at doses ranging from 5 to 20 mg when administered concomitantly with up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) in patients with inadequate blood pressure control. The three monotherapy trials included a total of 2016 patients (1811 Nebivolol, 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg. Patients received either Nebivolol or placebo once daily for twelve weeks. Two of these monotherapy trials (Studies 1 and 2) studied 1716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as PMs. The third monotherapy trial (Study 3) studied 300 Black patients with a mean age of 51 years, 45% males, 14% diabetics, and 3% as PMs. Placebo-subtracted blood pressure reductions by dose for each study are presented in Table 2. Most studies showed increasing response to doses above 5 mg. Study 4 enrolled 669 patients with a mean age of 54 years, 55% males, 54% Caucasians, 29% Blacks, 15% Hispanics, 1% Asians, 14% diabetics, and 5% PMs. Nebivolol, 5 mg to 20 mg, administered once daily concomitantly with stable doses of up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) resulted in significant additional antihypertensive effects over placebo compared to baseline blood pressure. Effectiveness was similar in subgroups analyzed by age and sex. Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians. The blood pressure lowering effect of Nebivolol was seen within two weeks of treatment and was maintained over the 24-hour dosing interval. There are no trials of Nebivolol demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. Nebivolol tablets are triangular-shaped, biconvex, unscored, differentiated by color and are engraved with “FL” on one side and the number of mg (2 ½, 5, 10, or 20) on the other side. Nebivolol tablets are supplied in the following strengths and package configurations: Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Advise patients to take Nebivolol regularly and continuously, as directed. Nebivolol can be taken with or without food. If a dose is missed, take the next scheduled dose only (without doubling it). Do not interrupt or discontinue Nebivolol without consulting the physician. Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness. Advise patients to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia. Caution patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. - ↑ Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J; et al. (2005). "Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)". Eur Heart J. 26 (3): 215–25. doi:10.1093/eurheartj/ehi115. PMID 15642700.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} - ↑ Dobre D, van Veldhuisen DJ, Mordenti G, Vintila M, Haaijer-Ruskamp FM, Coats AJ; et al. (2007). "Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial". Am Heart J. 154 (1): 109–15. doi:10.1016/j.ahj.2007.03.025. PMID 17584562.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Schellenberg R, Lichtenthal A, Wöhling H, Graf C, Brixius K (2008). "Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment?". Headache. 48 (1): 118–25. doi:10.1111/j.1526-4610.2007.00785.x. PMID 18184294.CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Bystolic
cda9135eef327a305bfdd7cfe4d6c14f7a36c76c	wikidoc	C-peptide	C-peptide # Overview C-peptide is a peptide which is made when proinsulin is split into insulin and C-peptide. They split when proinsulin is released from the pancreas into the blood in response to a rise in serum glucose - one C-peptide for each insulin molecule. - In proinsulin, C-peptide is an amino-acid chain connecting A and B chains of insulin - The level of C-peptide in the body is indicative of how much insulin is being produced in the body - Reference range: 0.33-1.20 nmol/l # Etymology and History C-peptide is the abbreviation for "connecting peptide", although its name was probably also inspired by the fact that insulin is also composed of an "A" chain and a "B" chain. C-peptide was discovered in 1967. The first documented use of the C-peptide test was in 1972. It should not to be confused with c-reactive protein or Protein C. # Function C-peptide functions in repair of the muscular layer of the arteries. C-peptide also exerts beneficial therapeutic effects on many complications associated with diabetes mellitus , , such as for instance diabetic neuropathy and other diabetes-induced ailments. In the kidneys, C-peptide prevents diabetic nephropathy , , and in the heart blood flow is improved in diabetic patients. In spite of these physiological functions, C-peptide is actually removed from pharmaceutical preparations of insulin sold by drug companies when they manufacture the synthetic human insulin that is in widescale clinical usage today. # Uses - Newly diagnosed diabetes patients often get their C-peptide levels measured, to find if they are type 1 diabetes or type 2 diabetes. The reason that the C-peptide levels are measured instead of the insulin levels themselves is because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it (the plasma), but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin and they will therefore usually have a decreased level of C-peptide, while C-peptide levels in type 2 patients is normal or higher than normal. Measuring C-peptide in patients injecting insulin can help to determine how much of their own natural insulin these patients are still producing. - C peptide is also used for determining the possibility of gastrinomas associated with Multiple endocrine neoplasia (MEN). Since a significant amount of gastrinomas also include MEN which include pancreatic, parathyroid, and pituitary adenomas, higher levels of c-protein in addition to a gastrinoma may suggest other organs than just the stomach may include neoplasms. - Can be used for identifying malingering: hypoglycemia with low C-peptide level may indicate abuse of insulin. C-peptide levels are also checked to determine how insulin resistant women with Polycystic Ovarian Syndrome may be. # Differential Diagnosis ## Decreased - Low insulin production - With elevated serum insulin: drug-induced hypoglycemia ## Increased - Insulinoma ### Normal Values in Patients with Injections of Insulin - Patient is still producing insulin	C-peptide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview C-peptide is a peptide which is made when proinsulin is split into insulin and C-peptide. They split when proinsulin is released from the pancreas into the blood in response to a rise in serum glucose - one C-peptide for each insulin molecule. - In proinsulin, C-peptide is an amino-acid chain connecting A and B chains of insulin - The level of C-peptide in the body is indicative of how much insulin is being produced in the body [1] - Reference range: 0.33-1.20 nmol/l # Etymology and History C-peptide is the abbreviation for "connecting peptide", although its name was probably also inspired by the fact that insulin is also composed of an "A" chain and a "B" chain. C-peptide was discovered in 1967. The first documented use of the C-peptide test was in 1972. It should not to be confused with c-reactive protein or Protein C. # Function C-peptide functions in repair of the muscular layer of the arteries. C-peptide also exerts beneficial therapeutic effects on many complications associated with diabetes mellitus [2] , [3], such as for instance diabetic neuropathy[4] and other diabetes-induced ailments. In the kidneys, C-peptide prevents diabetic nephropathy [5], [6], and in the heart [7] blood flow is improved in diabetic patients. In spite of these physiological functions, C-peptide is actually removed from pharmaceutical preparations of insulin sold by drug companies when they manufacture the synthetic human insulin that is in widescale clinical usage today. # Uses - Newly diagnosed diabetes patients often get their C-peptide levels measured, to find if they are type 1 diabetes or type 2 diabetes. The reason that the C-peptide levels are measured instead of the insulin levels themselves is because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it (the plasma), but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin and they will therefore usually have a decreased level of C-peptide, while C-peptide levels in type 2 patients is normal or higher than normal. Measuring C-peptide in patients injecting insulin can help to determine how much of their own natural insulin these patients are still producing. - C peptide is also used for determining the possibility of gastrinomas associated with Multiple endocrine neoplasia (MEN). Since a significant amount of gastrinomas also include MEN which include pancreatic, parathyroid, and pituitary adenomas, higher levels of c-protein in addition to a gastrinoma may suggest other organs than just the stomach may include neoplasms. - Can be used for identifying malingering: hypoglycemia with low C-peptide level may indicate abuse of insulin. C-peptide levels are also checked to determine how insulin resistant women with Polycystic Ovarian Syndrome may be. # Differential Diagnosis ## Decreased - Low insulin production - With elevated serum insulin: drug-induced hypoglycemia ## Increased - Insulinoma ### Normal Values in Patients with Injections of Insulin - Patient is still producing insulin	https://www.wikidoc.org/index.php/C-Peptide
878aa8d00578e27427776bd0fcfbc69b7c045f55	wikidoc	C10orf118	C10orf118 C10orf118 is a protein that in humans is encoded by the C10orf118 gene The C10orf118 (CCDC186) gene is also known as the CTCL-tumor associated antigen with accession number NM_018017. # Gene ## Location C10orf118 has the chromosome location of 10q25.3 and is 53,750 bases in size oriented on the minus strand. PSORTII Protein k-NN Prediction indicated that C10orf118 is 65.2% of the time nuclear, 17.4% cytosolic, 8.7% mitochondrial, 4.3% vesicles of secretory system, and 4.3% endoplasmic reticulum. ## Expression Analysis of gene expression in humans and other species indicates C10orf118 is ubiquitously expressed in all tissue types at varying developmental stages. An EST profile from NCBI displayed the greatest expression in bone marrow, kidneys, and the prostate cell lines. Breakdown by health state indicates high expression of C10orf118 in bladder carcinoma and prostate cancer. # Protein ## General Properties The protein of CCDC186 (NP_060487) is 898 amino acids in length. The predicted molecular weight is 103.7kdal and the isoelectric point is predicted to be 5.92. ## Composition A serine rich region is observed in amino acids 710-747. A compositional analysis revealed that C10orf118 is Proline (1.1%) poor and Glutamic acid (14.1%) and Lysine (12.0%) rich. ## Interactions C10orf118 protein was found to interact with proteins PLEKAH5, Ezra, GAMMAHV.ORF23, and SMAD3. ## Homology Orthologous sequences of C10orf118 were not found to be in bacteria, archea, protist, or plants. C10orf118 has no human paralogs. The date of divergence for the orthologous sequences highly correlates with the sequences similarity in that the percent identity decreases as you go back in time. Closely related orthologs include mammals and birds and moderately related orthologs include other vertebrates such as fish, reptiles, and amphibians. Distantly related orthologous sequences are primarily observed in invertebrates. ## Motifs ## Post Translational Modification C10orf118 is predicted to undergo multiple posttranslational modifications including predicted O-beta-GlcNAc attachment, phosphorylation, a nuclear export signal, glycation of lysines, GlcNAc O-glycosylation, N-glycosylation, and NetCorona sites. ## Clinical significance Prior research indicates that the open reading frame of C10orf118 is linked to cutaneous T-cell lymphoma by a tumor antigen L14-2. The protein C10orf118 is also found at higher than normal levels in the breast cancer cell line BC 8701.	C10orf118 C10orf118 is a protein that in humans is encoded by the C10orf118 gene [2] The C10orf118 (CCDC186) gene is also known as the CTCL-tumor associated antigen with accession number NM_018017.[3] # Gene ## Location C10orf118 has the chromosome location of 10q25.3 and is 53,750 bases in size oriented on the minus strand. PSORTII Protein k-NN Prediction indicated that C10orf118 is 65.2% of the time nuclear, 17.4% cytosolic, 8.7% mitochondrial, 4.3% vesicles of secretory system, and 4.3% endoplasmic reticulum.[4] ## Expression Analysis of gene expression in humans and other species indicates C10orf118 is ubiquitously expressed in all tissue types at varying developmental stages. An EST profile from NCBI displayed the greatest expression in bone marrow, kidneys, and the prostate cell lines. Breakdown by health state indicates high expression of C10orf118 in bladder carcinoma and prostate cancer.[7] # Protein ## General Properties The protein of CCDC186 (NP_060487) is 898 amino acids in length. The predicted molecular weight is 103.7kdal and the isoelectric point is predicted to be 5.92.[8] ## Composition A serine rich region is observed in amino acids 710-747. A compositional analysis revealed that C10orf118 is Proline (1.1%) poor and Glutamic acid (14.1%) and Lysine (12.0%) rich.[8] ## Interactions C10orf118 protein was found to interact with proteins PLEKAH5, Ezra, GAMMAHV.ORF23, and SMAD3.[9][10] ## Homology Orthologous sequences of C10orf118 were not found to be in bacteria, archea, protist, or plants. C10orf118 has no human paralogs. The date of divergence for the orthologous sequences highly correlates with the sequences similarity in that the percent identity decreases as you go back in time. Closely related orthologs include mammals and birds and moderately related orthologs include other vertebrates such as fish, reptiles, and amphibians. Distantly related orthologous sequences are primarily observed in invertebrates.[8][12] ## Motifs ## Post Translational Modification C10orf118 is predicted to undergo multiple posttranslational modifications including predicted O-beta-GlcNAc attachment, phosphorylation, a nuclear export signal, glycation of lysines, GlcNAc O-glycosylation, N-glycosylation, and NetCorona sites.[14] ## Clinical significance Prior research indicates that the open reading frame of C10orf118 is linked to cutaneous T-cell lymphoma by a tumor antigen L14-2.[15] The protein C10orf118 is also found at higher than normal levels in the breast cancer cell line BC 8701.[16]	https://www.wikidoc.org/index.php/C10orf118
ef6faf9eb092afed9fb0e014241638ddae9aa306	wikidoc	C14orf159	C14orf159 UPF0317 protein C14orf159, mitochondrial is a protein that in humans is encoded by the C14orf159 gene (chromosome 14 open reading frame 159). # Orthologs The human gene, c14orf159 mRNA, is highly conserved in mammals and birds. Orthologs gathered from BLAST and BLAT searches reveal that the human c14orf159 mRNA sequence is conserved with a sequence identity of 98% in chimpanzees, 88% in mice, and 81% in platypus and chicken. The following table contains a list orthologs that were gathered from BLAST searches. Sequence alignments were performed using blastn to derive sequence identity, score, and E-values between the human c14orf159 variant 1 mRNA and its orthologs. The protein that the human gene c14orf159 encodes has been found to be highly conserved among mammals, birds, amphibians, fish, tunicates, cnidarians, and echinoderms. However, no protein orthologs have been found in nematodes, arthropods, fungi, protists, plants, bacteria, or archea. Fungi and bacteria contain the DUF1445 conserved domain which is found in human c14orf159 and its orthologs. BLAST and BLAT searches have been utilized to find orthologs to the c14orf159 protein. The following table lists protein orthologs for the human protein with sequence identity, sequence similarity, scores, and E-values derived from blastp sequence comparisons. # Post-translational modification The protein product of the C14orf159 gene is predicted and was found to be translocated to mitochondrion. Post-translational modifications are predicted for the protein c14orf159. All predicted sites in human c14orf159 were compared to orthologs using multiple sequence alignments to determine likelihood of modification. # Regulation Estrogen receptor alpha, in the presence of estradiol, binds to the C14orf159 gene and likely regulates its expression.	C14orf159 UPF0317 protein C14orf159, mitochondrial is a protein that in humans is encoded by the C14orf159 gene (chromosome 14 open reading frame 159).[1] # Orthologs The human gene, c14orf159 mRNA, is highly conserved in mammals and birds.[2] Orthologs gathered from BLAST and BLAT searches reveal that the human c14orf159 mRNA sequence is conserved with a sequence identity of 98% in chimpanzees, 88% in mice, and 81% in platypus and chicken.[3][4] The following table contains a list orthologs that were gathered from BLAST searches. Sequence alignments were performed using blastn to derive sequence identity, score, and E-values between the human c14orf159 variant 1 mRNA and its orthologs. The protein that the human gene c14orf159 encodes has been found to be highly conserved among mammals, birds, amphibians, fish, tunicates, cnidarians, and echinoderms. However, no protein orthologs have been found in nematodes, arthropods, fungi, protists, plants, bacteria, or archea. Fungi and bacteria contain the DUF1445 conserved domain which is found in human c14orf159 and its orthologs. BLAST and BLAT searches have been utilized to find orthologs to the c14orf159 protein. The following table lists protein orthologs for the human protein with sequence identity, sequence similarity, scores, and E-values derived from blastp sequence comparisons.[5] # Post-translational modification The protein product of the C14orf159 gene is predicted[1] and was found[6][7] to be translocated to mitochondrion. Post-translational modifications are predicted for the protein c14orf159. All predicted sites in human c14orf159 were compared to orthologs using multiple sequence alignments to determine likelihood of modification.[8][9][10][11] [12] # Regulation Estrogen receptor alpha, in the presence of estradiol, binds to the C14orf159 gene and likely regulates its expression.[13]	https://www.wikidoc.org/index.php/C14orf159
7e2121a3173f10380d64a9e53d8e65873b442f71	wikidoc	C20orf111	C20orf111 Chromosome 20 open reading frame 111, or C20orf111, is the hypothetical protein that in humans is encoded by the C20orf111 gene. C20orf111 is also known as Perit1 (peroxide inducible transcript 1), HSPC207, and dJ1183I21.1. It was originally located using genomic sequencing of chromosome 20. The National Center for Biotechnology Information, or NCBI, shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website shows that it is at location q13.12, and within a million base pairs of the adenosine deaminase locus. It was also found to have an increase in expression in cells undergoing hydrogen peroxide(H2O2)-induced apoptosis. After analyzing the amino acid content of C20orf111, it was found to be rich in serine residues. # Gene C20orf111 a valid, protein coding gene that is found on the minus strand of chromosome 20 at q13.12 by searching the UCSC Genome Browser, but q13.11 according to Refseq on NCBI. ## Gene neighborhood A few of the known genes near C20orf111 are given in the box below with their known function. # Transcript ## General properties - Genomic DNA Length:14,968 base pairs (bp) - Most common mRNA Length: 2,260 bp with 4 exons. Has 10 splice isoforms. - 5' untranslated region 252 bp long. - 3' untranslated region 1,129 bp long. ## Transcript variants 10 splice isoforms that encode good proteins, altogether 8 different isoforms, 2 of which are complete isoforms. The image below shows the 10 isoforms that are predicted. Of these 10 splice isoforms, 8 have varying peptide lengths, however all of these proteins are only hypothetical with no extensive research done on them. ## Transcription regulation When looking at the predicted promoter sequence, there are no RNA Polymerase II binding sites, however there is a binding site for core promoter element for TATA-less promoters. In this same region of the promoter, there is also a TATA-binding factor sequence, which helps in the positioning of RNA polymerase II for transcription. # Protein ## General properties - Contains a highly conserved domain of unknown function 776 (DUF776),which composes 62% of the entire protein. - Molecular weight 31.8 kilodaltons - Isoelectric point 8.57 - Predicted to be a nuclear protein ## Function The function of C20orf111 is not well understood by the scientific community. It does contain a domain of unknown function, DUF776, which has a large segment that is conserved well conserved through Xenopus tropicalus. It is also shown to have an increase in expression in rat cardiomyocytes undergoing hydrogen peroxide induced apoptosis. ## Expression When looking at the EST Profiles in humans, normal tissue (non-cancerous), expresses at a level of 82 transcripts per million. C20orf111 has been shown to increase in expression in rat cardiac myocytes undergoing \|H\|2\|O\|2\|-induced apoptosis, suggesting a role in cell death. In bladder, cervical, head and neck, non-neoplasia, pancreatic, and prostate cancer cells, there are expression levels lower than normal. ## Homology C20orf111 gene has no clear paralogs in the human genome. However, it has many orthologs in other organisms, and is conserved highly in organisms such as Xenopus tropicalis and is semi-conserved in the proto-animal Trichoplax adherens at the C-terminus. The following table presents a select number of the orthologs found. ## Conservation The image below is a multiple sequence alignment comparing the conservation of the C20orf111 protein amongst other organisms. The protein is highly conserved in the DUF776 region amongst vertebrates, and also at the C-terminus in eukaryotes. ## Predicted post-translational modification Using tools at ExPASy the following are predicted post-translational modifications for C20orf111. - Predicted propeptide cleavage site in protein between position R81 and S82. - 30 predicted Serine phosphorylation sites - 5 predicted Threonine phosphorylation sites - 3 predicted Tyrosine phosphorylation sites ## Predicted secondary structure PELE (Protein Secondary Structure Prediction) was used to predict the secondary structure of C20orf111. There is little in the way of β-strand or α-helix secondary structure, but a large part of the protein appears to exist as random coils. This is shown on the image of the C20orf111 images to the right.	C20orf111 Chromosome 20 open reading frame 111, or C20orf111, is the hypothetical protein that in humans is encoded by the C20orf111 gene.[1] C20orf111 is also known as Perit1 (peroxide inducible transcript 1), HSPC207, and dJ1183I21.1.[2] It was originally located using genomic sequencing of chromosome 20.[3] The National Center for Biotechnology Information, or NCBI,[1] shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website[4] shows that it is at location q13.12, and within a million base pairs of the adenosine deaminase locus.[5] It was also found to have an increase in expression in cells undergoing hydrogen peroxide(H2O2)-induced apoptosis.[6] After analyzing the amino acid content of C20orf111, it was found to be rich in serine residues. # Gene C20orf111 a valid, protein coding gene that is found on the minus strand of chromosome 20 at q13.12 by searching the UCSC Genome Browser,[4] but q13.11 according to Refseq on NCBI.[1] ## Gene neighborhood A few of the known genes near C20orf111 are given in the box below with their known function. # Transcript ## General properties [10] - Genomic DNA Length:14,968 base pairs (bp) - Most common mRNA Length: 2,260 bp with 4 exons. Has 10 splice isoforms. - 5' untranslated region 252 bp long. - 3' untranslated region 1,129 bp long. ## Transcript variants 10 splice isoforms that encode good proteins, altogether 8 different isoforms, 2 of which are complete isoforms. The image below shows the 10 isoforms that are predicted.[11] Of these 10 splice isoforms, 8 have varying peptide lengths, however all of these proteins are only hypothetical with no extensive research done on them.[11] ## Transcription regulation When looking at the predicted promoter sequence,[12] there are no RNA Polymerase II binding sites, however there is a binding site for core promoter element for TATA-less promoters.[13] In this same region of the promoter, there is also a TATA-binding factor sequence, which helps in the positioning of RNA polymerase II for transcription.[14] # Protein ## General properties [15] - Contains a highly conserved domain of unknown function 776 (DUF776),which composes 62% of the entire protein. - Molecular weight 31.8 kilodaltons - Isoelectric point 8.57 - Predicted to be a nuclear protein[16] ## Function The function of C20orf111 is not well understood by the scientific community. It does contain a domain of unknown function, DUF776, which has a large segment that is conserved well conserved through Xenopus tropicalus. It is also shown to have an increase in expression in rat cardiomyocytes undergoing hydrogen peroxide induced apoptosis.[6] ## Expression When looking at the EST Profiles in humans, normal tissue (non-cancerous), expresses at a level of 82 transcripts per million.[17] C20orf111 has been shown to increase in expression in rat cardiac myocytes undergoing \|H\|2\|O\|2\|-induced apoptosis, suggesting a role in cell death.[6] In bladder, cervical, head and neck, non-neoplasia, pancreatic, and prostate cancer cells, there are expression levels lower than normal. ## Homology C20orf111 gene has no clear paralogs in the human genome. However, it has many orthologs in other organisms, and is conserved highly in organisms such as Xenopus tropicalis and is semi-conserved in the proto-animal Trichoplax adherens at the C-terminus. The following table presents a select number of the orthologs found.[18] ## Conservation The image below is a multiple sequence alignment comparing the conservation of the C20orf111 protein amongst other organisms. The protein is highly conserved in the DUF776 region amongst vertebrates, and also at the C-terminus in eukaryotes. ## Predicted post-translational modification Using tools at ExPASy[19] the following are predicted post-translational modifications for C20orf111. - Predicted propeptide cleavage site in protein between position R81 and S82.[20] - 30 predicted Serine phosphorylation sites - 5 predicted Threonine phosphorylation sites - 3 predicted Tyrosine phosphorylation sites[21] ## Predicted secondary structure PELE (Protein Secondary Structure Prediction) was used to predict the secondary structure of C20orf111. There is little in the way of β-strand or α-helix secondary structure, but a large part of the protein appears to exist as random coils. This is shown on the image of the C20orf111 images to the right.	https://www.wikidoc.org/index.php/C20orf111
c368a72bb3fa3a96f2f32de4e090d254e693932d	wikidoc	CAMP test	CAMP test Synonyms and keywords: CAMP reaction; Christie Atkins Munch–Petersen reaction; Christie-Atkins-Munch–Petersen reaction # Overview The CAMP test is a test to identify Group B β-streptococci based on their formation of a substance (CAMP factor) that enlarges the area of hemolysis formed by β-hemolysin from Staphylococcus aureus. It is frequently used to identify Listeria species. The name has no relationship to cyclic adenosine monophosphate (cAMP). # Historical Perspective It is an acronym for R. Christie, N. E. Atkins, and E. Munch-Peterson, for the three researchers who discovered the phenomenon. It is often incorrectly reported as the product of four people (counting Munch-Petersen as two people). # CAMP factor Although usually used to identify group "B", there is some evidence that the CAMP factor gene is present in several groups of streptococci, including group "A". A similar factor has been identified in Bartonella henselae. # Uses It can be used to identify Streptococcus agalactiae. Though not strongly beta-hemolytic on its own, it presents with a wedge-shape in the presence of Staphylococcus aureus.	CAMP test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: CAMP reaction; Christie Atkins Munch–Petersen reaction; Christie-Atkins-Munch–Petersen reaction # Overview The CAMP test is a test to identify Group B β-streptococci[1][2] based on their formation of a substance (CAMP factor[3]) that enlarges the area of hemolysis formed by β-hemolysin from Staphylococcus aureus. It is frequently used to identify Listeria species. The name has no relationship to cyclic adenosine monophosphate (cAMP). # Historical Perspective It is an acronym for R. Christie, N. E. Atkins, and E. Munch-Peterson,[4][5][6] for the three researchers who discovered the phenomenon.[7] It is often incorrectly reported as the product of four people (counting Munch-Petersen as two people).[8] # CAMP factor Although usually used to identify group "B", there is some evidence that the CAMP factor gene is present in several groups of streptococci, including group "A".[9] A similar factor has been identified in Bartonella henselae.[10] # Uses It can be used to identify Streptococcus agalactiae. Though not strongly beta-hemolytic on its own,[11] it presents with a wedge-shape in the presence of Staphylococcus aureus.[12]	https://www.wikidoc.org/index.php/CAMP_reaction
390db1fbc732f8acf2e915f1eb1d5cb711e2966c	wikidoc	Caspase 1	Caspase 1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells. # Cellular expression Caspase-1 is evolutionarily conserved in many eukaryotes of the Kingdom Animalia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the liver, kidney, spleen, and blood (neutrophils). Following infection, the inflammatory response increases expression of Caspase-1, by a positive feedback mechanism that amplifies the response. # Structure Caspase-1 is produced as a zymogen that can then be cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the active enzyme. Active Caspase 1 contains two heterodimers of p20 and p10. It contains a catalytic domain with an active site that spans both the p20 and p10 subunits, as well as a noncatalytic Caspase Activation and Recruitment Domain (CARD) . It interacts with other CARD containing proteins such as Apoptosis-Associated Speck-like Protein Containing a CARD (ASC) and Nod-Like Receptor (NLR) Family CARD Domain-Containing Protein 4 (NLRC4) through CARD-CARD interactions in the formation of inflammasomes. # Regulation ## Activation Caspase-1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous inflammasome complex by autoproteolysis into the p10 and p20 subunits. The inflammasome complex is a ring complex composed of trimers of a signal specific sensor protein such as those of the NLR family and the AIM-1 (Absent in Melanoma) like receptors, an adaptor protein such as ASC, and a caspase, in this case Caspase-1. In some cases, where the signaling proteins contain their own CARDs, like in NLRP1 and NLRC4, the CARD –CARD interaction is direct, meaning there is no adaptor protein in the complex. There are a variety of sensor and adaptor proteins, the various combinations of which confer the inflammasomes' responses to specific signals. This allows the cell to have varying degrees of inflammatory responses based on the severity of the danger signal received. ## Inhibition CARD only proteins (COPs) as their name implies, are proteins that only contain the non-catalytic CARDs. Owing to the importance of CARD-CARD interactions in inflammasome formation, many COPs are known inhibitors of Caspase activation. For Caspase-1, genes for specific COPs—ICEBERG, COP1 (ICE/Pseudo-ICE), and INCA (Inhibitory Card)—are all found near its locus, and are thus thought to have emerged from gene duplication events and subsequent deletions of the catalytic domains. Though they all interact with the inflammasomes using CARD–CARD interactions, they differ in the way they carry out their inhibitory functions as well as in their effectiveness at doing so. For example, ICEBERG nucleates the formation of Caspase-1 filaments and is thus incorporated into the filaments, but lacks the ability to inhibit the activation of inflammasomes. Instead, it is thought to inhibit Caspase-1 activation by interfering with the interaction of Caspase-1 with other important CARD containing proteins. INCA, on the other hand, directly blocks inflammasome assembly by capping Caspase-1 CARD oligomers, thus blocking further polymerization into the inflammasome filaments. Similarly, some POPs (Pyrin only proteins) are also known to regulate Caspase-1 activation through inhibition of inflammasome activation by binding to and blocking PYD interactions, which also play a role in the formation of the inflammasomes, though the exact mechanisms are not yet well established. - Belnacasan (VX-765) - Pralnacasan (VX-740) # Function ## Proteolytic cleavage Activated Caspase 1 proteolytically cleaves pro IL-1β and pro IL-18 into their active forms, IL-1β and IL-18. The active cytokines lead to a downstream inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis. ## Inflammatory response Once matured, the cytokines initiate downstream signaling events to induce a proinflammatory response as well as to activate the expression of antiviral genes. The speed, specificity and types of response are dependent on the signal received as well as the sensor protein that received it. Signals that can be received by the inflammasomes include viral double stranded RNA, urea, free radicals, and other signals associated with cellular danger, even byproducts of other immune response pathways. The mature cytokines themselves do not contain the necessary sorting sequences to enter the ER-Golgi secretory pathway, and thus are not excreted from the cell by conventional methods. However, it is theorized that the release of these proinflammatory cytokines is not reliant on cellular rupture via pyroptosis, and is in fact, an active process. There exists evidence both for and against this hypothesis. The fact that for many cell types, the cytokines are secreted despite them showing absolutely no signs of pyroptosis, supports this hypothesis. However, some experiments show that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them, indicating pyroptosis may in fact be necessary for secretion in some way. ## Pyroptosis response Following the inflammatory response, an activated Caspase-1 can induce pyroptosis, a lytic form of cell death, depending on the signal received as well as the specific inflammasome sensor domain protein that received it. Though pyroptosis may or may not be required for the full inflammatory response, the inflammatory response is fully required before pyroptosis can occur. In order to induce pyroptosis, Caspase-1 cleaves Gasdermin D, which either directly or through some signaling cascade leads to pyroptosis. The exact mechanism is not known. ## Other roles Caspase-1 has also been shown to induce necrosis and may also function in various developmental stages. Studies of a similar protein in mice suggest a role in the pathogenesis of Huntington's disease. Alternative splicing of the gene results in five transcript variants encoding distinct isoforms. Recent studies implicated caspase-1 in promoting CD4 T-cell death and inflammation by HIV, two signature events that fuel HIV disease progression to AIDS. Caspase-1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria and immune complexes.	Caspase 1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides.[1][2][3] It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.[4] # Cellular expression Caspase-1 is evolutionarily conserved in many eukaryotes of the Kingdom Animalia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the liver, kidney, spleen, and blood (neutrophils).[5][6] Following infection, the inflammatory response increases expression of Caspase-1, by a positive feedback mechanism that amplifies the response.[6] # Structure Caspase-1 is produced as a zymogen that can then be cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the active enzyme. Active Caspase 1 contains two heterodimers of p20 and p10. It contains a catalytic domain with an active site that spans both the p20 and p10 subunits,[7] as well as a noncatalytic Caspase Activation and Recruitment Domain (CARD) . It interacts with other CARD containing proteins such as Apoptosis-Associated Speck-like Protein Containing a CARD (ASC) and Nod-Like Receptor (NLR) Family CARD Domain-Containing Protein 4 (NLRC4) through CARD-CARD interactions in the formation of inflammasomes.[3][8] # Regulation ## Activation Caspase-1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous inflammasome complex by autoproteolysis into the p10 and p20 subunits.[9][10] The inflammasome complex is a ring complex composed of trimers of a signal specific sensor protein such as those of the NLR family and the AIM-1 (Absent in Melanoma) like receptors, an adaptor protein such as ASC, and a caspase, in this case Caspase-1. In some cases, where the signaling proteins contain their own CARDs, like in NLRP1 and NLRC4, the CARD –CARD interaction is direct, meaning there is no adaptor protein in the complex. There are a variety of sensor and adaptor proteins, the various combinations of which confer the inflammasomes' responses to specific signals. This allows the cell to have varying degrees of inflammatory responses based on the severity of the danger signal received.[11][12] ## Inhibition CARD only proteins (COPs) as their name implies, are proteins that only contain the non-catalytic CARDs. Owing to the importance of CARD-CARD interactions in inflammasome formation, many COPs are known inhibitors of Caspase activation. For Caspase-1, genes for specific COPs—ICEBERG, COP1 (ICE/Pseudo-ICE), and INCA (Inhibitory Card)—are all found near its locus, and are thus thought to have emerged from gene duplication events and subsequent deletions of the catalytic domains. Though they all interact with the inflammasomes using CARD–CARD interactions, they differ in the way they carry out their inhibitory functions as well as in their effectiveness at doing so.[10][13][14] For example, ICEBERG nucleates the formation of Caspase-1 filaments and is thus incorporated into the filaments, but lacks the ability to inhibit the activation of inflammasomes. Instead, it is thought to inhibit Caspase-1 activation by interfering with the interaction of Caspase-1 with other important CARD containing proteins.[10][13][14] INCA, on the other hand, directly blocks inflammasome assembly by capping Caspase-1 CARD oligomers, thus blocking further polymerization into the inflammasome filaments.[13][14][15][8] Similarly, some POPs (Pyrin only proteins) are also known to regulate Caspase-1 activation through inhibition of inflammasome activation by binding to and blocking PYD interactions, which also play a role in the formation of the inflammasomes, though the exact mechanisms are not yet well established.[14][16] - Belnacasan (VX-765) [17] - Pralnacasan (VX-740) [18] # Function ## Proteolytic cleavage Activated Caspase 1 proteolytically cleaves pro IL-1β and pro IL-18 into their active forms, IL-1β and IL-18. The active cytokines lead to a downstream inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis.[8] ## Inflammatory response Once matured, the cytokines initiate downstream signaling events to induce a proinflammatory response as well as to activate the expression of antiviral genes. The speed, specificity and types of response are dependent on the signal received as well as the sensor protein that received it. Signals that can be received by the inflammasomes include viral double stranded RNA, urea, free radicals, and other signals associated with cellular danger, even byproducts of other immune response pathways.[19] The mature cytokines themselves do not contain the necessary sorting sequences to enter the ER-Golgi secretory pathway, and thus are not excreted from the cell by conventional methods. However, it is theorized that the release of these proinflammatory cytokines is not reliant on cellular rupture via pyroptosis, and is in fact, an active process. There exists evidence both for and against this hypothesis. The fact that for many cell types, the cytokines are secreted despite them showing absolutely no signs of pyroptosis, supports this hypothesis.[12][20] However, some experiments show that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them, indicating pyroptosis may in fact be necessary for secretion in some way.[21] ## Pyroptosis response Following the inflammatory response, an activated Caspase-1 can induce pyroptosis, a lytic form of cell death, depending on the signal received as well as the specific inflammasome sensor domain protein that received it. Though pyroptosis may or may not be required for the full inflammatory response, the inflammatory response is fully required before pyroptosis can occur.[12] In order to induce pyroptosis, Caspase-1 cleaves Gasdermin D, which either directly or through some signaling cascade leads to pyroptosis. The exact mechanism is not known.[12] ## Other roles Caspase-1 has also been shown to induce necrosis and may also function in various developmental stages. Studies of a similar protein in mice suggest a role in the pathogenesis of Huntington's disease. Alternative splicing of the gene results in five transcript variants encoding distinct isoforms.[22] Recent studies implicated caspase-1 in promoting CD4 T-cell death and inflammation by HIV, two signature events that fuel HIV disease progression to AIDS.[23][24] Caspase-1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria[25] and immune complexes.[26]	https://www.wikidoc.org/index.php/CASP1
17ad80fad07304fc6ce0a593cfb0f90488e16f3d	wikidoc	Caspase 2	Caspase 2 Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. # Function Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. The proteolytic cleavage of this protein is induced by a variety of apoptotic stimuli. Caspase 2 proteolytically cleaves other proteins. It belongs to a family of cysteine proteases called caspases that cleave proteins only at an amino acid following an aspartic acid residue. Within this family, caspase 2 is part of the Ich-1 subfamily. It is one of the most conserved caspases in different species of animal. Caspase 2 has a similar amino acid sequence to initiator caspases, including caspase 1, caspase 4, caspase 5, and caspase 9. It is produced as a zymogen, which contains a long pro-domain that is similar to that of caspase 9 and contains a protein interaction domain known as a CARD domain. Pro-caspase-2 contains two subunits, p19 and p12. It has been shown to associate with several proteins involved in apoptosis using its CARD domain, including RIP-associated Ich-1/Ced-3-homologue protein with a death domain (RAIDD), apoptosis repressor with caspase recruitment domain (ARC), and death effector filament-forming Ced-4-like apoptosis protein (DEFCAP). Together with RAIDD and p53-induced protein with a death domain ()(LRDD), caspase 2 has been shown to form the so-called PIDDosome, which may serve as an activation platform for the protease, although it may also be activated in the absence of PIDD. Overall, caspase 2 appears to be a very versatile caspase with multiple functions beyond cell death induction. # Interactions Caspase 2 has been shown to interact with: - BH3 interacting domain death agonist, - CRADD, and - Caspase 8.	Caspase 2 Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene.[1] CASP2 orthologs [2] have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. # Function Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. The proteolytic cleavage of this protein is induced by a variety of apoptotic stimuli.[3] Caspase 2 proteolytically cleaves other proteins. It belongs to a family of cysteine proteases called caspases that cleave proteins only at an amino acid following an aspartic acid residue. Within this family, caspase 2 is part of the Ich-1 subfamily. It is one of the most conserved caspases in different species of animal. Caspase 2 has a similar amino acid sequence to initiator caspases, including caspase 1, caspase 4, caspase 5, and caspase 9. It is produced as a zymogen, which contains a long pro-domain that is similar to that of caspase 9 and contains a protein interaction domain known as a CARD domain. Pro-caspase-2 contains two subunits, p19 and p12. It has been shown to associate with several proteins involved in apoptosis using its CARD domain, including RIP-associated Ich-1/Ced-3-homologue protein with a death domain (RAIDD), apoptosis repressor with caspase recruitment domain (ARC), and death effector filament-forming Ced-4-like apoptosis protein (DEFCAP).[4] Together with RAIDD and p53-induced protein with a death domain ([PIDD])(LRDD), caspase 2 has been shown to form the so-called PIDDosome,[5] which may serve as an activation platform for the protease, although it may also be activated in the absence of PIDD.[6] Overall, caspase 2 appears to be a very versatile caspase with multiple functions beyond cell death induction.[7][8] # Interactions Caspase 2 has been shown to interact with: - BH3 interacting domain death agonist,[9][10] - CRADD,[5][11][12] and - Caspase 8.[9][13]	https://www.wikidoc.org/index.php/CASP2
33b36ef931b404e6bcedbd69829ba531b275beb9	wikidoc	Caspase 6	Caspase 6 Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene. CASP6 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis, early immune response and neurodegeneration in Huntington's and Alzheimer's disease. # Function This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Caspase 6 can also undergo self-processing without other members of the caspase family. Alternative splicing of this gene results in two transcript variants that encode different isoforms. Caspase-6 plays a role in the early immune response via de-repression. It reduces the expression of the immunosuppressant cytokine interleukin-10 and cleaves the macrophage suppressing IRAK-M. With respect to neurodegeneration, caspase-6 cleaves HTT in Huntington's and APP in Alzheimer's disease. Resulting in both cases in protein aggregation of the fragments. # Interactions Caspase 6 has been shown to interact with Caspase 8.	Caspase 6 Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene.[1][2] CASP6 orthologs [3] have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis[4], early immune response[5][6] and neurodegeneration in Huntington's and Alzheimer's disease.[7] # Function This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis.[4] Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Caspase 6 can also undergo self-processing without other members of the caspase family.[8] Alternative splicing of this gene results in two transcript variants that encode different isoforms.[9] Caspase-6 plays a role in the early immune response via de-repression. It reduces the expression of the immunosuppressant cytokine interleukin-10[5] and cleaves the macrophage suppressing IRAK-M.[6] With respect to neurodegeneration, caspase-6 cleaves HTT in Huntington's and APP in Alzheimer's disease. Resulting in both cases in protein aggregation of the fragments.[7] # Interactions Caspase 6 has been shown to interact with Caspase 8.[10][11][12]	https://www.wikidoc.org/index.php/CASP6
a18de3cf8cb76931789e8f8b91d0d85ae865496e	wikidoc	Caspase 7	Caspase 7 Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. # Function Caspase-7 is a member of the caspase (cysteine aspartate protease) family of proteins, and has been shown to be an executioner protein of apoptosis. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing by upstream caspases (caspase-8, -9) at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme in the form of a heterotetramer. The precursor of this caspase is cleaved by caspase 3, caspase 10, and caspase 9. It is activated upon cell death stimuli and induces apoptosis. Alternative splicing results in four transcript variants, encoding three distinct isoforms. # Interactions Caspase 7 has been shown to interact with: - Caspase 8, - Survivin and - XIAP.	Caspase 7 Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs [1] have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. # Function Caspase-7 is a member of the caspase (cysteine aspartate protease) family of proteins, and has been shown to be an executioner protein of apoptosis. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing by upstream caspases (caspase-8, -9) at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme in the form of a heterotetramer. The precursor of this caspase is cleaved by caspase 3, caspase 10, and caspase 9. It is activated upon cell death stimuli and induces apoptosis. Alternative splicing results in four transcript variants, encoding three distinct isoforms.[2] # Interactions Caspase 7 has been shown to interact with: - Caspase 8,[3][4] - Survivin[5][6] and - XIAP.[7][8][9][10]	https://www.wikidoc.org/index.php/CASP7
2a86edd169470116d57481c88c3bcdc9bc5955bf	wikidoc	Caspase 8	Caspase 8 Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds. # Function The CASP8 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. # Clinical significance A very rare genetic disorder of the immune system can also be caused by mutations in this gene. This disease, called CEDS, stands for “Caspase eight deficiency state.” CEDS has features similar to ALPS, another genetic disease of apoptosis, with the addition of an immunodeficient phenotype. Thus, the clinical manifestations include splenomegaly and lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus, persistent warts and molluscum contagiosum infections, and hypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease in parenchymal organs, but autoimmunity is minimal and lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner. The clinical phenotype of CEDS patients represented a paradox since caspase-8 was considered to be chiefly a proapoptotic protease, that was mainly involved in signal transduction from Tumor necrosis factor receptor family death receptors such as Fas. The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in lymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (NF-κB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for the induction of nuclear translocation of NF-κB. Moreover, the biochemical form of caspase-8 differed in the two pathways. For the death pathway, the caspase-8 zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein. # Interactions Caspase-8 has been shown to interact with: - BCAP31, - BID, - Bcl-2, - CFLAR, - Caspase-10, - Caspase-2, - Caspase-3, - Caspase-6, - Caspase-7, - Caspase-9, - DEDD, - FADD, - FasL, - FasR, - IFT57, - NOL3, - PEA15, - RIPK1, - TNFRSF10B, and - TRAF1. # Additional photos	Caspase 8 Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs[1] have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds. # Function The CASP8 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined.[2] # Clinical significance A very rare genetic disorder of the immune system can also be caused by mutations in this gene. This disease, called CEDS, stands for “Caspase eight deficiency state.” CEDS has features similar to ALPS, another genetic disease of apoptosis, with the addition of an immunodeficient phenotype. Thus, the clinical manifestations include splenomegaly and lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus, persistent warts and molluscum contagiosum infections, and hypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease in parenchymal organs, but autoimmunity is minimal and lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner.[3] The clinical phenotype of CEDS patients represented a paradox since caspase-8 was considered to be chiefly a proapoptotic protease, that was mainly involved in signal transduction from Tumor necrosis factor receptor family death receptors such as Fas. The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in lymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (NF-κB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells.[3] Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for the induction of nuclear translocation of NF-κB. Moreover, the biochemical form of caspase-8 differed in the two pathways. For the death pathway, the caspase-8 zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein.[3] # Interactions Caspase-8 has been shown to interact with: - BCAP31,[4] - BID,[5][6] - Bcl-2,[6][7] - CFLAR,[8][9][10][11][12][13][14] - Caspase-10,[5][6][8][15] - Caspase-2,[6][15] - Caspase-3,[6][15] - Caspase-6,[6][15][16] - Caspase-7,[6][15] - Caspase-9,[6][15] - DEDD,[17][18][19] - FADD,[5][8][11][20][21][22][23] - FasL,[5][8] - FasR,[5][9][24] - IFT57,[25] - NOL3,[26] - PEA15,[27][28] - RIPK1,[20][29][30] - TNFRSF10B,[5][24] and - TRAF1.[8][31] # Additional photos	https://www.wikidoc.org/index.php/CASP8
162d0be119d9caca28b8e29febcef26841ab48c5	wikidoc	Caspase-9	Caspase-9 Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes. Caspase-9 belongs to a family of caspases, cysteine-aspartic proteases involved in apoptosis and cytokine signalling. Apoptotic signals cause the release of cytochrome c from mitochondria and activation of apaf-1 (apoptosome), which then cleaves the pro-enzyme of caspase-9 into the active dimer form. Regulation of this enzyme occurs through phosphorylation by an allosteric inhibitor, inhibiting dimerization and inducing a conformational change. Correct caspase-9 function is required for apoptosis, leading to the normal development of the central nervous system. Without correct function, abnormal tissue development can occur leading to abnormal function, diseases and premature death. Certain diseases involving caspase-9 are treated with therapy by targeting this enzyme. Different protein isoforms of caspase-9 are produced due to alternative splicing. # Structure Similar to other caspases, caspase-9 has three domains: N-terminal pro-domain, large subunit, and a small subunit. The N-terminal pro-domain is also called the long pro-domain and this contains the caspase activation domain (CARD) motif. The pro-domain is linked to the catalytic domain by a linker loop. The caspase-9 monomer consists of one large and one small subunit, both comprising the catalytic domain. Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG. When dimerized, caspase-9 has two different active site conformations within each dimer. One site closely resembles the catalytic site of other caspases, whereas the second has no 'activation loop', disrupting the catalytic machinery in that particular active site. Surface loops around the active site are short, giving rise to broad substrate specificity as the substrate-binding cleft is more open. Within caspase-9's active site, in order for catalytic activity to occur there has to be specific amino acids in the right position. Amino acid Asp at position P1 is essential, with a preference for amino acid His at position P2. # Localization Within the cell, caspase-9 in humans is found in the mitochondria, cytosol, and nucleus. ## Protein expression Caspase-9 in humans is expressed in fetus and adult tissues. Tissue expression of caspase-9 is ubiquitous with the highest expression in the brain and heart, specifically at the developmental stage of an adult in the heart's muscle cells. The liver, pancreas, and skeletal muscle express this enzyme at a moderate level, and all other tissues express caspase-9 at low levels. # Mechanism Active caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating apoptosis. Once activated, caspase-9 goes on to cleave caspase-3, -6, and -7, initiating the caspase cascade as they cleave several other cellular targets. When caspase-9 is inactive, it exists in the cytosol as a zymogen, in its monomer form. It is then recruited and activated by the CARDs in apaf-1, recognizing the CARDs in caspase-9. ## Processing Before activation can occur, caspase-9 has to be processed. Initially, caspase-9 is made as an inactive single-chain zymogen. Processing occurs when the apoptosome binds to pro-caspase-9 as apaf-1 assists in the autoproteolytic processing of the zymogen. The processed caspase-9 stays bound to the apoptosome complex, forming a holoenzyme. ## Activation Activation occurs when caspase-9 dimerizes, and there are two different ways for which this can occur: - Caspase-9 is auto-activated when it binds to apaf-1(apoptosome), as apaf-1 oligomerizes the precursor molecules of pro-caspase-9. - Previously activated caspases can cleave caspase-9, causing its dimerization. ## Catalytic activity Caspase-9 has a preferred cleavage sequence of Leu-Gly-His-Asp-(cut)-X. # Regulation Negative regulation of caspase-9 occurs through phosphorylation. This is done by a serine-threonine kinase, Akt, on serine-196 which inhibits the activation and protease activity of caspase-9, suppressing caspase-9 and further activation of apoptosis. Akt acts as an allosteric inhibitor of caspase-9 because the site of phosphorylation of serine-196 is far from the catalytic site. The inhibitor affects the dimerization of caspase-9 and causes a conformational change that affects the substrate-binding cleft of caspase-9. Akt can act on both processed and unprocessed caspase-9 in-vitro, where phosphorylation on processed caspase-9 occurs on the large subunit. # Deficiencies and mutations A deficiency in caspase-9 largely affects the brain and its development. The effects of having a mutation or deficiency in this caspase compared to others is detrimental. The initiating role caspase-9 plays in apoptosis is the cause for the severe effects seen in those with an atypical caspase-9. Mice with insufficient caspase-9 have a main phenotype of an affected or abnormal brain. Larger brains due to a decrease in apoptosis, resulting in an increase of extra neurons is an example of a phenotype seen in caspase-9 deficient mice. Those homozygous for no caspase-9 die perinatally as a result of an abnormally developed cerebrum. In humans, expression of caspase-9 varies from tissue to tissue, and the different levels have a physiological role. Low amounts of caspase-9 leads to cancer and neurodegenerative diseases like Alzheimer's disease. Further alterations at single-nucleotide polymorphism (SNP) levels and whole gene levels of caspase-9 can cause germ-line mutations linked to non-Hodgkin's lymphoma. Certain polymorphisms in the promoter of caspase-9 enhances the rate at which caspase-9 is expressed, and this can increase a person's risk of lung cancer. # Clinical Significance The effects of abnormal caspase-9 levels or function impacts the clinical world. The impact caspase-9 has on the brain can lead to future work in inhibition through targeted therapy, specifically with diseases associated with the brain as this enzyme may have take part in the developmental pathways of neuronal disorders. The introduction of caspases may also have medical benefits. In the context of graft versus host disease, caspase-9 can be introduced as an inducible switch. In the presence of a small molecule, it will dimerize and trigger apoptosis, eliminating lymphocytes. # Alternative transcripts Through alternative splicing, four difference caspase-9 variants are produced. ## Caspase-9α (9L) This variant is used as the reference sequence, and it has full cysteine protease activity. ## Caspase-9β (9S) Isoform 2 doesn't include exons 3, 4, 5, and 6; it is missing amino acids 140-289. Caspase-9S doesn't have central catalytic domain, therefore it functions as an inhibitor of caspase-9α by attaching to the apoptosome, suppressing the caspase enzyme cascade and apoptosis. Caspase-9β is referred to as the endogenous dominant-negative isoform. ## Caspase-9γ This variant is missing amino acids 155-416, and for amino acids 152-154, the sequence AYI is changed to TVL. ## Isoform 4 In comparison with the reference sequence, it is missing amino acids 1-83. # Interactions Caspase-9 has been shown to interact with: - APAF1 - BIRC2, - Baculoviral IAP repeat-containing protein 3, - Caspase 8, - NLRP1, and - XIAP.	Caspase-9 Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase,[1] critical to the apoptotic pathway found in many tissues.[2] Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.[3] Caspase-9 belongs to a family of caspases, cysteine-aspartic proteases involved in apoptosis and cytokine signalling.[4] Apoptotic signals cause the release of cytochrome c from mitochondria and activation of apaf-1 (apoptosome), which then cleaves the pro-enzyme of caspase-9 into the active dimer form.[2] Regulation of this enzyme occurs through phosphorylation by an allosteric inhibitor, inhibiting dimerization and inducing a conformational change.[4] Correct caspase-9 function is required for apoptosis, leading to the normal development of the central nervous system.[4] Without correct function, abnormal tissue development can occur leading to abnormal function, diseases and premature death.[4] Certain diseases involving caspase-9 are treated with therapy by targeting this enzyme.[4] Different protein isoforms of caspase-9 are produced due to alternative splicing.[5] # Structure Similar to other caspases, caspase-9 has three domains: N-terminal pro-domain, large subunit, and a small subunit.[4] The N-terminal pro-domain is also called the long pro-domain and this contains the caspase activation domain (CARD) motif.[6] The pro-domain is linked to the catalytic domain by a linker loop.[7] The caspase-9 monomer consists of one large and one small subunit, both comprising the catalytic domain.[8] Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG.[9][7] When dimerized, caspase-9 has two different active site conformations within each dimer.[8] One site closely resembles the catalytic site of other caspases, whereas the second has no 'activation loop', disrupting the catalytic machinery in that particular active site.[8] Surface loops around the active site are short, giving rise to broad substrate specificity as the substrate-binding cleft is more open.[10] Within caspase-9's active site, in order for catalytic activity to occur there has to be specific amino acids in the right position. Amino acid Asp at position P1 is essential, with a preference for amino acid His at position P2.[11] # Localization Within the cell, caspase-9 in humans is found in the mitochondria, cytosol, and nucleus.[12] ## Protein expression Caspase-9 in humans is expressed in fetus and adult tissues.[9][7] Tissue expression of caspase-9 is ubiquitous with the highest expression in the brain and heart, specifically at the developmental stage of an adult in the heart's muscle cells.[13] The liver, pancreas, and skeletal muscle express this enzyme at a moderate level, and all other tissues express caspase-9 at low levels.[13] # Mechanism Active caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating apoptosis.[14] Once activated, caspase-9 goes on to cleave caspase-3, -6, and -7, initiating the caspase cascade as they cleave several other cellular targets.[4] When caspase-9 is inactive, it exists in the cytosol as a zymogen, in its monomer form.[8][15] It is then recruited and activated by the CARDs in apaf-1, recognizing the CARDs in caspase-9.[16] ## Processing Before activation can occur, caspase-9 has to be processed.[17] Initially, caspase-9 is made as an inactive single-chain zymogen.[17] Processing occurs when the apoptosome binds to pro-caspase-9 as apaf-1 assists in the autoproteolytic processing of the zymogen.[17] The processed caspase-9 stays bound to the apoptosome complex, forming a holoenzyme.[18] ## Activation Activation occurs when caspase-9 dimerizes, and there are two different ways for which this can occur: - Caspase-9 is auto-activated when it binds to apaf-1(apoptosome), as apaf-1 oligomerizes the precursor molecules of pro-caspase-9.[12] - Previously activated caspases can cleave caspase-9, causing its dimerization.[19] ## Catalytic activity Caspase-9 has a preferred cleavage sequence of Leu-Gly-His-Asp-(cut)-X.[11] # Regulation Negative regulation of caspase-9 occurs through phosphorylation.[4] This is done by a serine-threonine kinase, Akt, on serine-196 which inhibits the activation and protease activity of caspase-9, suppressing caspase-9 and further activation of apoptosis.[20] Akt acts as an allosteric inhibitor of caspase-9 because the site of phosphorylation of serine-196 is far from the catalytic site.[20] The inhibitor affects the dimerization of caspase-9 and causes a conformational change that affects the substrate-binding cleft of caspase-9.[20] Akt can act on both processed and unprocessed caspase-9 in-vitro, where phosphorylation on processed caspase-9 occurs on the large subunit.[21] # Deficiencies and mutations A deficiency in caspase-9 largely affects the brain and its development.[22] The effects of having a mutation or deficiency in this caspase compared to others is detrimental.[22] The initiating role caspase-9 plays in apoptosis is the cause for the severe effects seen in those with an atypical caspase-9. Mice with insufficient caspase-9 have a main phenotype of an affected or abnormal brain.[4] Larger brains due to a decrease in apoptosis, resulting in an increase of extra neurons is an example of a phenotype seen in caspase-9 deficient mice.[23] Those homozygous for no caspase-9 die perinatally as a result of an abnormally developed cerebrum.[4] In humans, expression of caspase-9 varies from tissue to tissue, and the different levels have a physiological role.[23] Low amounts of caspase-9 leads to cancer and neurodegenerative diseases like Alzheimer's disease.[23] Further alterations at single-nucleotide polymorphism (SNP) levels and whole gene levels of caspase-9 can cause germ-line mutations linked to non-Hodgkin's lymphoma.[24] Certain polymorphisms in the promoter of caspase-9 enhances the rate at which caspase-9 is expressed, and this can increase a person's risk of lung cancer.[25] # Clinical Significance The effects of abnormal caspase-9 levels or function impacts the clinical world. The impact caspase-9 has on the brain can lead to future work in inhibition through targeted therapy, specifically with diseases associated with the brain as this enzyme may have take part in the developmental pathways of neuronal disorders.[4] The introduction of caspases may also have medical benefits.[14] In the context of graft versus host disease, caspase-9 can be introduced as an inducible switch.[26] In the presence of a small molecule, it will dimerize and trigger apoptosis, eliminating lymphocytes.[26] # Alternative transcripts Through alternative splicing, four difference caspase-9 variants are produced. ## Caspase-9α (9L) This variant is used as the reference sequence, and it has full cysteine protease activity.[6][27] ## Caspase-9β (9S) Isoform 2 doesn't include exons 3, 4, 5, and 6; it is missing amino acids 140-289.[6][27] Caspase-9S doesn't have central catalytic domain, therefore it functions as an inhibitor of caspase-9α by attaching to the apoptosome, suppressing the caspase enzyme cascade and apoptosis.[6][28] Caspase-9β is referred to as the endogenous dominant-negative isoform. ## Caspase-9γ This variant is missing amino acids 155-416, and for amino acids 152-154, the sequence AYI is changed to TVL.[27] ## Isoform 4 In comparison with the reference sequence, it is missing amino acids 1-83.[27] # Interactions Caspase-9 has been shown to interact with: - APAF1[29][30][2][31][32] - BIRC2,[33] - Baculoviral IAP repeat-containing protein 3,[33] - Caspase 8,[34][35] - NLRP1,[29][36] and - XIAP.[33][37][38][39]	https://www.wikidoc.org/index.php/CASP9
5f7af030bd9de5454cdfcacab628264a45abc3bb	wikidoc	Clonidine	Clonidine # 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 Clonidine is a central alpha-2 adrenergic agonist that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include contact dermatitis, erythema, pruritus, xerostomia, dizziness, headache, sedation, somnolence, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Hypertension treatment with clonidine can be administered orally (tablets) or by transdermal patches. - Clonidine hydrochloride tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration: - Initial dose: 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. - Maintenance: Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. - Renal Impairment: Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. - The recommended starting dose of clonidine hydrochloride for continuous epidural infusion is 30 mcg/hr. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 mcg/hr is limited. - Familiarization with the continuous epidural infusion device is essential. Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the first few days to assess their response. - The 500 mcg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, U.S.P., to a final concentration of 100 mcg/mL: - Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. - Clonidine hydrochloride mustnotbe used with a preservative. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clonidine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Oral dose: 0.2 mg/day. - Transdermar dose: 0.1 mg/day. - Dosing Information - 0.1 mg/day. - Dosing Information - Oral dose: 0.1 to 0.45 mg/day. - Transdermal patch: 0.1 to 0.2 mg/day. - Dosing information - Initial dose: 0.1 mg PO q8h, titrate every day according to needs: - Second day: 0.4-0.6 mg/day. - Third day: 0.4-0.7 mg/day. - Fourth day: 0.5-0.8 mg/day. - Sixth day: 0.6-1 mg/day. - Do not exceed 1mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Severe Cancer Pain: Epidural Infusion - The safety and effectiveness of clonidine hydrochloride in this limited indication and clinical population have been established in patients old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate and well controlled studies in adults and experience with the use of clonidine in the pediatric age group for other indications. The use of clonidine hydrochloride should be restricted to pediatric patients with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques. The starting dose of clonidine hydrochloride should be selected on per kilogram basis (0.5 mcg per kg per hour) and cautiously adjusted based on the clinical response ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clonidine in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Transdermal patch: 0.05 to 0.1 mg/day. - Dosing Information - Administer clonidine via a trnasdermar patch, the doses should be adjusted according the wight of the patient: - 20 to 40 kg : 0.1 mg/week. - 41 to 60 kg: 1.5 mg/week. - > 60 kg: 2 mg/week. # Contraindications - Clonidine hydrochloride tablets should not be used in patients with known hypersensitivity to clonidine. - Epidural administration is contraindicated in: - The presence of an injection site infection. - In patients on anticoagulant therapy, and in those with a bleeding diathesis. - Administration of clonidine hydrochloride above the C4 dermatome is contraindicated since there are no adequate safety data to support such use. # Warnings ### Oral/Transdermal Administration Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine tablets, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology. An excessive rise in blood pressure following discontinuation of clonidine tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine tablets. Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication. In patients who have developed localized contact sensitization to clonidine, continuation of clonidine or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to clonidine, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There are post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol and temporary cardiac pacing while taking clonidine. In hypertension caused by pheochromocytoma, no therapeutic effect of clonidine tablets can be expected. Administration of clonidine hydrochloride tablets should be continued to within 4 hours of surgery and resumed as soon as possible thereafter. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. ### Epidural Administration Epidural clonidine is not recommended for obstetrical, postpartum, or perioperative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. Because severe hypotension may follow the administration of clonidine, it should be used with caution in all patients. It is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. The benefit of its administration in these patients should be carefully balanced against the potential risks resulting from hypotension. Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. When clonidine is infused into the upper thoracic spinal segments, more pronounced decreases in the blood pressure may be seen. Clonidine decreases sympathetic outflow from the central nervous system resulting in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. However, in the absence of profound hypotension, renal blood flow and glomerular filtration rate remain essentially unchanged. In the pivotal double-blind, randomized study of cancer patients, where 38 subjects were administered epidural clonidine hydrochloride at 30 mcg/hr in addition to epidural morphine, hypotension occurred in 45% of subjects. Most episodes of hypotension occurred within the first four days after beginning epidural clonidine. However, hypotensive episodes occurred throughout the duration of the trial. There was a tendency for these episodes to occur more commonly in women, and in those with higher serum clonidine levels. Patients experiencing hypotension also tended to weigh less than those who did not experience hypotension. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Published reports on the use of epidural clonidine for intraoperative or postoperative analgesia also show a consistent and marked hypotensive response to clonidine. Severe hypotension may occur even if intravenous fluid pretreatment is given. Sudden cessation of clonidine treatment, regardless of the route of administration, has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure. The likelihood of such reactions appears to be greater after administration of higher doses or with concomitant beta-blocker treatment. Special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after abrupt clonidine withdrawal. Patients with a history of hypertension and/or other underlying cardiovascular conditions may be at particular risk of the consequences of abrupt discontinuation of clonidine. In the pivotal double-blind, randomized cancer pain study, four of 38 subjects receiving 720 mcg of clonidine per day experienced rebound hypertension following abrupt withdrawal. One of these patients with rebound hypertension subsequently experienced a cerebrovascular accident. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement can help reduce the risk of inadvertent abrupt withdrawal of epidural clonidine. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients should also be instructed not to discontinue therapy without consulting their physician. When discontinuing therapy with epidural clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of epidural clonidine can be treated by administration of clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of epidural clonidine. Infections related to implantable epidural catheters pose a serious risk. Evaluation of fever in a patient receiving epidural clonidine should include the possibility of a catheter-related infection such as meningitis or epidural abscess. - Cardiac Effects: Epidural clonidine frequently causes decreases in heart rate. Symptomatic bradycardia can be treated with atropine. Rarely, atrioventricular block greater than first degree has been reported. Clonidine does not alter the hemodynamic response to exercise, but may mask the increase in heart rate associated with hypovolemia. - Respiratory Depression and Sedation: Clonidine administration may result in sedation through the activation of alpha-adrenoceptors in the brainstem. High doses of clonidine cause sedation and ventilatory abnormalities that are usually mild. Tolerance to these effects can develop with chronic administration. These effects have been reported with bolus doses that are significantly larger than the infusion rate recommended for treating cancer pain. - Depression: Depression has been seen in a small percentage of patients treated with oral or transdermal clonidine. Depression commonly occurs in cancer patients and may be exacerbated by treatment with clonidine. Patients, especially those with a known history of affective disorders, should be monitored for the signs and symptoms of depression. - Pain of Visceral or Somatic Origin: In the clinical investigations, at doses tested, clonidine hydrochloride was most effective in well-localized, “neuropathic” pain that was characterized as electrical, burning, or shooting in nature, and which was localized to a dermatomal or peripheral nerve distribution. Clonidine hydrochloride may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin. # Adverse Reactions ## Clinical Trials Experience Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established: - Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol. - Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. - Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares. - Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria. - Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting. - Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. - Hematologic: Thrombocytopenia. - Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. - Musculoskeletal: Leg cramps and muscle or joint pain. - Oro-otolaryngeal: Dryness of the nasal mucosa. - Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, postural hypotension, decreased heart rate, rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Hypotension was observed more frequently in women and in lower weight patients, but no dose-related response was established. Implantable epidural catheters are associated with a risk of catheter-related infections, including meningitis and/or epidural abscess. The risk depends on the clinical situation and the type of catheter used, but catheter related infections occur in 5% to 20% of patients, depending on the kind of catheter used, catheter placement technique, quality of catheter care, and length of catheter placement. The inadvertent intrathecal administration of clonidine has not been associated with a significantly increased risk of adverse events, but there are inadequate safety and efficacy data to support the use of intrathecal clonidine. Epidural clonidine was compared to placebo in a two week double-blind study of 85 terminal cancer patients with intractable pain receiving epidural morphine. The following adverse events were reported in two or more patients and may be related to administration of either clonidine hydrochloride or morphine. An open label long-term extension of the above trial was performed. Thirty-two subjects received epidural clonidine and morphine for up to 94 weeks with a median dosing period of 10 weeks. The following adverse events (and percent incidence) were reported: hypotension/postural hypotension (47%); nausea (13%); anxiety/confusion (38%); somnolence (25%); urinary tract infection (22%); constipation, dyspnea, fever, infection (6% each); asthenia, hyperaesthesia, pain, skin ulcer, and vomiting (5% each). Eighteen percent of subjects discontinued this study as a result of catheter-related problems (infections, accidental dislodging, etc.), and one subject developed meningitis, possibly as a result of a catheter-related infection. In this study, rebound hypertension was not assessed, and ECG and laboratory data were not systematically sought. The following adverse reactions have also been reported with the use of any dosage form of clonidine. In many cases patients were receiving concomitant medication and a causal relationship has not been established: - Body as a Whole: Weakness, 10%; fatigue, 4%; headache and withdrawal syndrome, each 1%. Also reported were pallor, a weakly positive Coomb's test, and increased sensitivity to alcohol. - Cardiovascular: Palpitations and tachycardia, and bradycardia, each 0.5%. Syncope, Raynaud's phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree AV block) have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. - Central Nervous System: Nervousness and agitation, 3%; mental depression, 1%; insomnia, 0.5%. Cerebrovascular accidents, other behavioral changes, vivid dreams or nightmares, restlessness, and delirium have been reported rarely. - Dermatological: Rash, 1%; pruritus, 0.7%; hives, angioneurotic edema and urticaria, 0.5%; alopecia, 0.2%. - Gastrointestinal: Anorexia and malaise, each 1%; mild transient abnormalities in liver function tests, 1%; hepatitis, parotitis, ileus and pseudo obstruction, and abdominal pain, rarely. - Genitourinary: Decreased sexual activity and libido, impotence, 3%; nocturia, about 1%; difficulty in micturition, about 0.2%; urinary retention, about 0.1%. - Hematologic: Thrombocytopenia, rarely. - Metabolic: Weight gain, 0.1%; gynecomastia, 1%; transient elevation of glucose or serum phosphatase, rarely. - Musculoskeletal: Muscle or joint pain, about 0.6%; leg cramps, 0.3%. - Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported. - Ophthalmological: Dryness of the eyes, burning of the eyes and blurred vision were rarely reported. ## Postmarketing Experience There is limited information regarding Clonidine Postmarketing Experience in the drug label. # Drug Interactions - Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. - If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. - If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated. - Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers and beta-blockers. - Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil. - Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats. - Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. Causal relationship and relevance for clonidine oral tablets have not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride tablets, USP produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to14 (lowest dose employed in the study was 500 mcg/kg). No adequate, well-controlled studies have been conducted in pregnant women. Clonidine crosses the placental barrier. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clonidine in women who are pregnant. ### Labor and Delivery There are no adequate controlled clinical trials evaluating the safety, efficacy, and dosing of clonidine hydrochloride in obstetrical settings. Because maternal perfusion of the placenta is critically dependent on blood pressure, use of clonidine hydrochloride as an analgesic during labor and delivery is not indicated ### Nursing Mothers As clonidine hydrochloride tablets, USP are excreted in human milk, caution should be exercised when clonidine hydrochloride is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established in adequate and well-controlled trials. ### Geriatic Use There is no FDA guidance on the use of Clonidine in geriatric settings. ### Gender There is no FDA guidance on the use of Clonidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clonidine with respect to specific racial populations. ### Renal Impairment Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. ### Hepatic Impairment There is no FDA guidance on the use of Clonidine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clonidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clonidine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral/Transdermal/Epidural ### Monitoring Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. When clonidine is infused into the upper thoracic spinal segments, more pronounced decreases in the blood pressure may be seen. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement can help reduce the risk of inadvertent abrupt withdrawal of epidural clonidine. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients should also be instructed not to discontinue therapy without consulting their physician. # IV Compatibility There is limited information regarding the compatibility of Clonidine and IV administrations. # Overdosage Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1 hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively. # Pharmacology ## Mechanism of Action Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. ## Structure (clonidine hydrochloride, USP) is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, gelatin, glycerin, lactose, and magnesium stearate. The Catapres 0.1 mg tablet also contains FD&C Blue No.1 and FD&C Red No.3. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. ## Pharmacodynamics The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated. Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. ## Pharmacokinetics The pharmacokinetics of clonidine is dose-proportional in the range of 100 to 600 µg. The absolute bioavailability of clonidine on oral administration is 70% to 80%. Peak plasma clonidine levels are attained in approximately 1 to 3 hours. Following intravenous administration, clonidine displays biphasic disposition with a distribution half-life of about 20 minutes and an elimination half-life ranging from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Clonidine crosses the placental barrier. It has been shown to cross the blood-brain barrier in rats. Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver. Neither food nor the race of the patient influences the pharmacokinetics of clonidine. The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect. ## Nonclinical Toxicology In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days. ## Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Fertility of male or female rats was unaffected by clonidine doses as high as 150 µg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 µg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis). # Clinical Studies In a double-blind, randomized study of cancer patients with severe intractable pain below the C4 dermatome not controlled by morphine, 38 patients were randomized to an epidural infusion of clonidine hydrochloride plus epidural morphine, whereas 47 subjects received epidural placebo plus epidural morphine. Both groups were allowed rescue doses of epidural morphine. Successful analgesia, defined as a decrease in either morphine use or Visual Analog Score (VAS) pain, was significantly more common with epidural clonidine than placebo (45% vs 21%, p=0.016). Only the subgroup of 36 patients with “neuropathic” pain, characterized by the investigator as well-localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution had significant analgesic effects relative to placebo in this study. The most frequent adverse events with clonidine were hypotension (45% vs 11% for placebo, p< 0.001), postural hypotension (32% vs 0%, p< 0.001), dizziness (13% vs 4%, p=0.234), anxiety (11% vs 2%, p=0.168) and dry mouth (13% vs 9%, p=0.505). Both mean blood pressure and heart rate were reduced in the clonidine group. At the conclusion of the two week study period in the clinical trial, all patients were abruptly withdrawn from study drug or placebo. Four patients of the clonidine group suffered rebound hypertension upon withdrawal of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient. # How Supplied Clonidine hydrochloride tablets are supplied as follows: - 0.1 mg: Bottle of 100 (NDC 0597-0006-01) - 0.2 mg: Bottle of 100 (NDC 0597-0007-01) - 0.3 mg: Bottle of 100 (NDC 0597-0011-01) Clonidine transdermal patch: - Principal display panel - 0.1 mg/day - 4 Systems + 4 Adhesive Covers (NDC 0378-0871-99). Clonidine hydrochloride injection is available as: - 100 mcg/mL solution in 10 mL vials, packaged individually (NDC 0517-0730-01) - 500 mcg/mL solution in 10 mL vials, packaged individually (NDC 0517-0731-01) ## Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). - Dispense in tight, light-resistant container. - Store at 20°to 25°C (68°to 77°F); excursions permitted to 15°to 30°C (59°to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be cautioned against interruption of clonidine tablets therapy without their physician's advice. - Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. - Patients who wear contact lenses should be cautioned that treatment with clonidine tablets may cause dryness of eyes. Patients should be cautioned against interruption of Clonidine Transdermal System therapy without their physician’s advice. Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. Patients who wear contact lenses should be cautioned that treatment with Clonidine Transdermal System may cause dryness of eyes. Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash. If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site. If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use. Used Clonidine Transdermal System patches contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CLONIDINE TRANSDERMAL SYSTEM PATCHES OUT OF THE REACH OF CHILDREN. After use, Clonidine Transdermal System should be folded in half with the adhesive sides together and discarded away from children’s reach. Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of Clonidine Transdermal System. Clonidine Transdermal System, USP (Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.) Clonidine Transdermal System is a peach colored, rectangular PATCH with rounded corners, containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the PATCH. The optional ivory ADHESIVE COVER should be applied directly over the PATCH, should the PATCH begin to separate from the skin. The ADHESIVE COVER ensures that the PATCH sticks to the skin. The Clonidine Transdermal System PATCH must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off. How to Apply the Clonidine Transdermal System PATCH 1) Apply the peach colored, rectangular PATCH with rounded corners, once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.). Each box of Clonidine Transdermal System contains two types of pouches: 2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Clonidine Transdermal System PATCH. Do not place the Clonidine Transdermal System PATCH on skin folds or under tight undergarments, since premature loosening may occur. 3) Wash hands with soap and water and thoroughly dry them. 4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue. 5) Select the pouch labeled Clonidine Transdermal System, USP and open it as illustrated in Figure 3. Remove the contents of the pouch and discard the additional pieces of clear protective film above and below the PATCH. 6) Remove the clear plastic protective backing from the peach colored, rectangular PATCH by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Clonidine Transdermal System PATCH. 7) Place the Clonidine Transdermal System PATCH on the prepared skin site (sticky side down) by applying firm pressure over the PATCH to ensure good contact with the skin, especially around the edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands. 8) After one week, remove the old PATCH and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next Clonidine Transdermal System PATCH. What to do if your Clonidine Transdermal System PATCH becomes loose while wearing: How to Apply the ADHESIVE COVER NOTE: The ivory ADHESIVE COVER does not contain any drug and should not be used alone. The COVER should be applied directly over the Clonidine Transdermal System PATCH only if the PATCH begins to separate from the skin, thereby ensuring that it sticks to the skin for 7 full days. 1) Wash hands with soap and water and thoroughly dry them. 2) Using a clean, dry tissue, make sure that the area around the rectangular, peach Clonidine Transdermal System PATCH is clean and dry. Press gently on the Clonidine Transdermal System PATCH to ensure that the edges are in good contact with the skin. 3) Take the ivory ADHESIVE COVER (Figure 6) from the plain white pouch and remove the paper liner backing from the COVER. 4) Carefully center the ivory ADHESIVE COVER over the rectangular, peach Clonidine Transdermal System PATCH and apply firm pressure, especially around the edges in contact with the skin. Instructions for Disposal KEEP OUT OF REACH OF CHILDREN During or even after use, a PATCH contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). # Precautions with Alcohol Clonidine may potentiate the CNS-depressive effects of alcohol # Brand Names - Catapres-TTS-1 - Catapres-TTS-2 - Catapres-TTS-3 - Nexiclon XR # Look-Alike Drug Names - Clonidine - Clonazepam - Clonidine - Clozapine - Clonidine - Klonopin # Drug Shortage Status # Price	Clonidine 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. # Black Box Warning # Overview Clonidine is a central alpha-2 adrenergic agonist that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include contact dermatitis, erythema, pruritus, xerostomia, dizziness, headache, sedation, somnolence, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Hypertension treatment with clonidine can be administered orally (tablets) or by transdermal patches. - Clonidine hydrochloride tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration: - Initial dose: 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. - Maintenance: Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. - Renal Impairment: Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. - The recommended starting dose of clonidine hydrochloride for continuous epidural infusion is 30 mcg/hr. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 mcg/hr is limited. - Familiarization with the continuous epidural infusion device is essential. Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the first few days to assess their response. - The 500 mcg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, U.S.P., to a final concentration of 100 mcg/mL: - Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. - Clonidine hydrochloride mustnotbe used with a preservative. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clonidine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Oral dose: 0.2 mg/day.[1] - Transdermar dose: 0.1 mg/day.[2] - Dosing Information - 0.1 mg/day.[3] - Dosing Information - Oral dose: 0.1 to 0.45 mg/day.[4] - Transdermal patch: 0.1 to 0.2 mg/day.[4] - Dosing information - Initial dose: 0.1 mg PO q8h, titrate every day according to needs:[5] - Second day: 0.4-0.6 mg/day. - Third day: 0.4-0.7 mg/day. - Fourth day: 0.5-0.8 mg/day. - Sixth day: 0.6-1 mg/day. - Do not exceed 1mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Severe Cancer Pain: Epidural Infusion - The safety and effectiveness of clonidine hydrochloride in this limited indication and clinical population have been established in patients old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate and well controlled studies in adults and experience with the use of clonidine in the pediatric age group for other indications. The use of clonidine hydrochloride should be restricted to pediatric patients with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques. The starting dose of clonidine hydrochloride should be selected on per kilogram basis (0.5 mcg per kg per hour) and cautiously adjusted based on the clinical response ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Clonidine in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Transdermal patch: 0.05 to 0.1 mg/day.[6] - Dosing Information - Administer clonidine via a trnasdermar patch, the doses should be adjusted according the wight of the patient:[7] - 20 to 40 kg : 0.1 mg/week. - 41 to 60 kg: 1.5 mg/week. - > 60 kg: 2 mg/week. # Contraindications - Clonidine hydrochloride tablets should not be used in patients with known hypersensitivity to clonidine. - Epidural administration is contraindicated in: - The presence of an injection site infection. - In patients on anticoagulant therapy, and in those with a bleeding diathesis. - Administration of clonidine hydrochloride above the C4 dermatome is contraindicated since there are no adequate safety data to support such use. # Warnings ### Oral/Transdermal Administration Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine tablets, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology. An excessive rise in blood pressure following discontinuation of clonidine tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine tablets. Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication. In patients who have developed localized contact sensitization to clonidine, continuation of clonidine or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to clonidine, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There are post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol and temporary cardiac pacing while taking clonidine. In hypertension caused by pheochromocytoma, no therapeutic effect of clonidine tablets can be expected. Administration of clonidine hydrochloride tablets should be continued to within 4 hours of surgery and resumed as soon as possible thereafter. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. ### Epidural Administration Epidural clonidine is not recommended for obstetrical, postpartum, or perioperative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. Because severe hypotension may follow the administration of clonidine, it should be used with caution in all patients. It is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. The benefit of its administration in these patients should be carefully balanced against the potential risks resulting from hypotension. Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. When clonidine is infused into the upper thoracic spinal segments, more pronounced decreases in the blood pressure may be seen. Clonidine decreases sympathetic outflow from the central nervous system resulting in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. However, in the absence of profound hypotension, renal blood flow and glomerular filtration rate remain essentially unchanged. In the pivotal double-blind, randomized study of cancer patients, where 38 subjects were administered epidural clonidine hydrochloride at 30 mcg/hr in addition to epidural morphine, hypotension occurred in 45% of subjects. Most episodes of hypotension occurred within the first four days after beginning epidural clonidine. However, hypotensive episodes occurred throughout the duration of the trial. There was a tendency for these episodes to occur more commonly in women, and in those with higher serum clonidine levels. Patients experiencing hypotension also tended to weigh less than those who did not experience hypotension. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Published reports on the use of epidural clonidine for intraoperative or postoperative analgesia also show a consistent and marked hypotensive response to clonidine. Severe hypotension may occur even if intravenous fluid pretreatment is given. Sudden cessation of clonidine treatment, regardless of the route of administration, has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure. The likelihood of such reactions appears to be greater after administration of higher doses or with concomitant beta-blocker treatment. Special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after abrupt clonidine withdrawal. Patients with a history of hypertension and/or other underlying cardiovascular conditions may be at particular risk of the consequences of abrupt discontinuation of clonidine. In the pivotal double-blind, randomized cancer pain study, four of 38 subjects receiving 720 mcg of clonidine per day experienced rebound hypertension following abrupt withdrawal. One of these patients with rebound hypertension subsequently experienced a cerebrovascular accident. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement can help reduce the risk of inadvertent abrupt withdrawal of epidural clonidine. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients should also be instructed not to discontinue therapy without consulting their physician. When discontinuing therapy with epidural clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of epidural clonidine can be treated by administration of clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of epidural clonidine. Infections related to implantable epidural catheters pose a serious risk. Evaluation of fever in a patient receiving epidural clonidine should include the possibility of a catheter-related infection such as meningitis or epidural abscess. - Cardiac Effects: Epidural clonidine frequently causes decreases in heart rate. Symptomatic bradycardia can be treated with atropine. Rarely, atrioventricular block greater than first degree has been reported. Clonidine does not alter the hemodynamic response to exercise, but may mask the increase in heart rate associated with hypovolemia. - Respiratory Depression and Sedation: Clonidine administration may result in sedation through the activation of alpha-adrenoceptors in the brainstem. High doses of clonidine cause sedation and ventilatory abnormalities that are usually mild. Tolerance to these effects can develop with chronic administration. These effects have been reported with bolus doses that are significantly larger than the infusion rate recommended for treating cancer pain. - Depression: Depression has been seen in a small percentage of patients treated with oral or transdermal clonidine. Depression commonly occurs in cancer patients and may be exacerbated by treatment with clonidine. Patients, especially those with a known history of affective disorders, should be monitored for the signs and symptoms of depression. - Pain of Visceral or Somatic Origin: In the clinical investigations, at doses tested, clonidine hydrochloride was most effective in well-localized, “neuropathic” pain that was characterized as electrical, burning, or shooting in nature, and which was localized to a dermatomal or peripheral nerve distribution. Clonidine hydrochloride may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin. # Adverse Reactions ## Clinical Trials Experience Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established: - Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol. - Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. - Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares. - Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria. - Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting. - Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. - Hematologic: Thrombocytopenia. - Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. - Musculoskeletal: Leg cramps and muscle or joint pain. - Oro-otolaryngeal: Dryness of the nasal mucosa. - Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, postural hypotension, decreased heart rate, rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Hypotension was observed more frequently in women and in lower weight patients, but no dose-related response was established. Implantable epidural catheters are associated with a risk of catheter-related infections, including meningitis and/or epidural abscess. The risk depends on the clinical situation and the type of catheter used, but catheter related infections occur in 5% to 20% of patients, depending on the kind of catheter used, catheter placement technique, quality of catheter care, and length of catheter placement. The inadvertent intrathecal administration of clonidine has not been associated with a significantly increased risk of adverse events, but there are inadequate safety and efficacy data to support the use of intrathecal clonidine. Epidural clonidine was compared to placebo in a two week double-blind study of 85 terminal cancer patients with intractable pain receiving epidural morphine. The following adverse events were reported in two or more patients and may be related to administration of either clonidine hydrochloride or morphine. An open label long-term extension of the above trial was performed. Thirty-two subjects received epidural clonidine and morphine for up to 94 weeks with a median dosing period of 10 weeks. The following adverse events (and percent incidence) were reported: hypotension/postural hypotension (47%); nausea (13%); anxiety/confusion (38%); somnolence (25%); urinary tract infection (22%); constipation, dyspnea, fever, infection (6% each); asthenia, hyperaesthesia, pain, skin ulcer, and vomiting (5% each). Eighteen percent of subjects discontinued this study as a result of catheter-related problems (infections, accidental dislodging, etc.), and one subject developed meningitis, possibly as a result of a catheter-related infection. In this study, rebound hypertension was not assessed, and ECG and laboratory data were not systematically sought. The following adverse reactions have also been reported with the use of any dosage form of clonidine. In many cases patients were receiving concomitant medication and a causal relationship has not been established: - Body as a Whole: Weakness, 10%; fatigue, 4%; headache and withdrawal syndrome, each 1%. Also reported were pallor, a weakly positive Coomb's test, and increased sensitivity to alcohol. - Cardiovascular: Palpitations and tachycardia, and bradycardia, each 0.5%. Syncope, Raynaud's phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree AV block) have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. - Central Nervous System: Nervousness and agitation, 3%; mental depression, 1%; insomnia, 0.5%. Cerebrovascular accidents, other behavioral changes, vivid dreams or nightmares, restlessness, and delirium have been reported rarely. - Dermatological: Rash, 1%; pruritus, 0.7%; hives, angioneurotic edema and urticaria, 0.5%; alopecia, 0.2%. - Gastrointestinal: Anorexia and malaise, each 1%; mild transient abnormalities in liver function tests, 1%; hepatitis, parotitis, ileus and pseudo obstruction, and abdominal pain, rarely. - Genitourinary: Decreased sexual activity and libido, impotence, 3%; nocturia, about 1%; difficulty in micturition, about 0.2%; urinary retention, about 0.1%. - Hematologic: Thrombocytopenia, rarely. - Metabolic: Weight gain, 0.1%; gynecomastia, 1%; transient elevation of glucose or serum phosphatase, rarely. - Musculoskeletal: Muscle or joint pain, about 0.6%; leg cramps, 0.3%. - Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported. - Ophthalmological: Dryness of the eyes, burning of the eyes and blurred vision were rarely reported. ## Postmarketing Experience There is limited information regarding Clonidine Postmarketing Experience in the drug label. # Drug Interactions - Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. - If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. - If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated. - Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers and beta-blockers. - Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil. - Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats. - Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. Causal relationship and relevance for clonidine oral tablets have not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride tablets, USP produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to14 (lowest dose employed in the study was 500 mcg/kg). No adequate, well-controlled studies have been conducted in pregnant women. Clonidine crosses the placental barrier. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clonidine in women who are pregnant. ### Labor and Delivery There are no adequate controlled clinical trials evaluating the safety, efficacy, and dosing of clonidine hydrochloride in obstetrical settings. Because maternal perfusion of the placenta is critically dependent on blood pressure, use of clonidine hydrochloride as an analgesic during labor and delivery is not indicated ### Nursing Mothers As clonidine hydrochloride tablets, USP are excreted in human milk, caution should be exercised when clonidine hydrochloride is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established in adequate and well-controlled trials. ### Geriatic Use There is no FDA guidance on the use of Clonidine in geriatric settings. ### Gender There is no FDA guidance on the use of Clonidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Clonidine with respect to specific racial populations. ### Renal Impairment Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis. ### Hepatic Impairment There is no FDA guidance on the use of Clonidine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Clonidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Clonidine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral/Transdermal/Epidural ### Monitoring Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. When clonidine is infused into the upper thoracic spinal segments, more pronounced decreases in the blood pressure may be seen. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement can help reduce the risk of inadvertent abrupt withdrawal of epidural clonidine. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients should also be instructed not to discontinue therapy without consulting their physician. # IV Compatibility There is limited information regarding the compatibility of Clonidine and IV administrations. # Overdosage Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1 hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively. # Pharmacology ## Mechanism of Action Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. ## Structure (clonidine hydrochloride, USP) is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, gelatin, glycerin, lactose, and magnesium stearate. The Catapres 0.1 mg tablet also contains FD&C Blue No.1 and FD&C Red No.3. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. ## Pharmacodynamics The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated. Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. ## Pharmacokinetics The pharmacokinetics of clonidine is dose-proportional in the range of 100 to 600 µg. The absolute bioavailability of clonidine on oral administration is 70% to 80%. Peak plasma clonidine levels are attained in approximately 1 to 3 hours. Following intravenous administration, clonidine displays biphasic disposition with a distribution half-life of about 20 minutes and an elimination half-life ranging from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Clonidine crosses the placental barrier. It has been shown to cross the blood-brain barrier in rats. Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver. Neither food nor the race of the patient influences the pharmacokinetics of clonidine. The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect. ## Nonclinical Toxicology In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days. ## Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Fertility of male or female rats was unaffected by clonidine doses as high as 150 µg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 µg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis). # Clinical Studies In a double-blind, randomized study of cancer patients with severe intractable pain below the C4 dermatome not controlled by morphine, 38 patients were randomized to an epidural infusion of clonidine hydrochloride plus epidural morphine, whereas 47 subjects received epidural placebo plus epidural morphine. Both groups were allowed rescue doses of epidural morphine. Successful analgesia, defined as a decrease in either morphine use or Visual Analog Score (VAS) pain, was significantly more common with epidural clonidine than placebo (45% vs 21%, p=0.016). Only the subgroup of 36 patients with “neuropathic” pain, characterized by the investigator as well-localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution had significant analgesic effects relative to placebo in this study. The most frequent adverse events with clonidine were hypotension (45% vs 11% for placebo, p< 0.001), postural hypotension (32% vs 0%, p< 0.001), dizziness (13% vs 4%, p=0.234), anxiety (11% vs 2%, p=0.168) and dry mouth (13% vs 9%, p=0.505). Both mean blood pressure and heart rate were reduced in the clonidine group. At the conclusion of the two week study period in the clinical trial, all patients were abruptly withdrawn from study drug or placebo. Four patients of the clonidine group suffered rebound hypertension upon withdrawal of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient. # How Supplied Clonidine hydrochloride tablets are supplied as follows: - 0.1 mg: Bottle of 100 (NDC 0597-0006-01) - 0.2 mg: Bottle of 100 (NDC 0597-0007-01) - 0.3 mg: Bottle of 100 (NDC 0597-0011-01) Clonidine transdermal patch: - Principal display panel - 0.1 mg/day - 4 Systems + 4 Adhesive Covers (NDC 0378-0871-99). Clonidine hydrochloride injection is available as: - 100 mcg/mL solution in 10 mL vials, packaged individually (NDC 0517-0730-01) - 500 mcg/mL solution in 10 mL vials, packaged individually (NDC 0517-0731-01) ## Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). - Dispense in tight, light-resistant container. - Store at 20°to 25°C (68°to 77°F); excursions permitted to 15°to 30°C (59°to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be cautioned against interruption of clonidine tablets therapy without their physician's advice. - Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. - Patients who wear contact lenses should be cautioned that treatment with clonidine tablets may cause dryness of eyes. Patients should be cautioned against interruption of Clonidine Transdermal System therapy without their physician’s advice. Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery. Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. Patients who wear contact lenses should be cautioned that treatment with Clonidine Transdermal System may cause dryness of eyes. Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash. If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site. If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use. Used Clonidine Transdermal System patches contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CLONIDINE TRANSDERMAL SYSTEM PATCHES OUT OF THE REACH OF CHILDREN. After use, Clonidine Transdermal System should be folded in half with the adhesive sides together and discarded away from children’s reach. Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of Clonidine Transdermal System. Clonidine Transdermal System, USP (Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.) Clonidine Transdermal System is a peach colored, rectangular PATCH with rounded corners, containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the PATCH. The optional ivory ADHESIVE COVER should be applied directly over the PATCH, should the PATCH begin to separate from the skin. The ADHESIVE COVER ensures that the PATCH sticks to the skin. The Clonidine Transdermal System PATCH must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off. How to Apply the Clonidine Transdermal System PATCH 1) Apply the peach colored, rectangular PATCH with rounded corners, once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.). Each box of Clonidine Transdermal System contains two types of pouches: 2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Clonidine Transdermal System PATCH. Do not place the Clonidine Transdermal System PATCH on skin folds or under tight undergarments, since premature loosening may occur. 3) Wash hands with soap and water and thoroughly dry them. 4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue. 5) Select the pouch labeled Clonidine Transdermal System, USP and open it as illustrated in Figure 3. Remove the contents of the pouch and discard the additional pieces of clear protective film above and below the PATCH. 6) Remove the clear plastic protective backing from the peach colored, rectangular PATCH by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Clonidine Transdermal System PATCH. 7) Place the Clonidine Transdermal System PATCH on the prepared skin site (sticky side down) by applying firm pressure over the PATCH to ensure good contact with the skin, especially around the edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands. 8) After one week, remove the old PATCH and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next Clonidine Transdermal System PATCH. What to do if your Clonidine Transdermal System PATCH becomes loose while wearing: How to Apply the ADHESIVE COVER NOTE: The ivory ADHESIVE COVER does not contain any drug and should not be used alone. The COVER should be applied directly over the Clonidine Transdermal System PATCH only if the PATCH begins to separate from the skin, thereby ensuring that it sticks to the skin for 7 full days. 1) Wash hands with soap and water and thoroughly dry them. 2) Using a clean, dry tissue, make sure that the area around the rectangular, peach Clonidine Transdermal System PATCH is clean and dry. Press gently on the Clonidine Transdermal System PATCH to ensure that the edges are in good contact with the skin. 3) Take the ivory ADHESIVE COVER (Figure 6) from the plain white pouch and remove the paper liner backing from the COVER. 4) Carefully center the ivory ADHESIVE COVER over the rectangular, peach Clonidine Transdermal System PATCH and apply firm pressure, especially around the edges in contact with the skin. Instructions for Disposal KEEP OUT OF REACH OF CHILDREN During or even after use, a PATCH contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). # Precautions with Alcohol Clonidine may potentiate the CNS-depressive effects of alcohol # Brand Names - Catapres-TTS-1 - Catapres-TTS-2 - Catapres-TTS-3 - Nexiclon XR # Look-Alike Drug Names - Clonidine - Clonazepam - Clonidine - Clozapine - Clonidine - Klonopin # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/CATAPRES_adverse_reactions
e0fc753a2433145c674e1ce09a56aaaeb4e3fee0	wikidoc	Cyclin A2	Cyclin A2 Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells. # Function Cyclin A2 belongs to the cyclin family, whose members regulate cell cycle progression by interacting with CDK kinases. Cyclin A2 is unique in that it can activate two different CDK kinases; it binds CDK2 during S phase, and CDK1 during the transition from G2 to M phase. Cyclin A2 is synthesized at the onset of S phase and localizes to the nucleus, where the cyclin A2-CDK2 complex is implicated in the initiation and progression of DNA synthesis. Phosphorylation of CDC6 and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle. Cyclin A2 is involved in the G2/M transition but it cannot independently form a maturation promoting factor (MPF). Recent studies have shown that the cyclin A2-CDK1 complex triggers cyclin B1-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope. # Regulation The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle. Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2. Cyclin A2 transcription is mostly regulated by the transcription factor E2F and begins in G1, after the R point. Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated retinoblastoma protein (pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription. The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription. E2F promotes cyclin A2 transcription by de-repressing the promoter. # Interactions Cyclin A2 has been shown to interact with: - CDC6, - E2F1, - FEN1, - ITGB3BP, - RBL1, and - SKP2. # Clinical significance Cyclin A2 (Ccna2) is a key protein involved in the direction of mammalian cardiac myocytes to grow and divide, and has been shown to induce cardiac repair following myocardial infarction. Normally, Ccna2 is silenced postnatally in mammalian cardiac myocytes. Because of this gene silencing, adult heart muscle cells cannot divide readily to repair and regenerate after a heart attack. Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction. Preclinical trials involving injections of adenovirus which contained the Ccna2 gene into infarcted porcine (pig) hearts has shown to be protective of MI in pig hearts. Ccna2 mediated cardiac repair showed both a decrease in fibrosis in the peri-infarct tissue and a greater number of cardiomyocytes at the sites of injection. Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function. # Cancer Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others. While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis, it is indicative of prognostic values such as predictions of survival or relapse. Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase and anaphase. It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins or tumor suppressors like p53.	Cyclin A2 Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene.[1] It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.[2] # Function Cyclin A2 belongs to the cyclin family, whose members regulate cell cycle progression by interacting with CDK kinases. Cyclin A2 is unique in that it can activate two different CDK kinases; it binds CDK2 during S phase, and CDK1 during the transition from G2 to M phase.[3] Cyclin A2 is synthesized at the onset of S phase and localizes to the nucleus, where the cyclin A2-CDK2 complex is implicated in the initiation and progression of DNA synthesis. Phosphorylation of CDC6 and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle.[2] Cyclin A2 is involved in the G2/M transition but it cannot independently form a maturation promoting factor (MPF).[4] Recent studies have shown that the cyclin A2-CDK1 complex triggers cyclin B1-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope.[5] # Regulation The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle.[6] Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2.[6][2] Cyclin A2 transcription is mostly regulated by the transcription factor E2F and begins in G1, after the R point.[6][2] Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated retinoblastoma protein (pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription.[7][8] The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription.[6] E2F promotes cyclin A2 transcription by de-repressing the promoter.[6][7] # Interactions Cyclin A2 has been shown to interact with: - CDC6,[9][10] - E2F1,[8] - FEN1,[11] - ITGB3BP,[12] - RBL1,[13][14] and - SKP2.[15][16] # Clinical significance Cyclin A2 (Ccna2) is a key protein involved in the direction of mammalian cardiac myocytes to grow and divide, and has been shown to induce cardiac repair following myocardial infarction.[17] Normally, Ccna2 is silenced postnatally in mammalian cardiac myocytes. Because of this gene silencing, adult heart muscle cells cannot divide readily to repair and regenerate after a heart attack.[17] Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction.[17] Preclinical trials involving injections of adenovirus which contained the Ccna2 gene into infarcted porcine (pig) hearts has shown to be protective of MI in pig hearts.[17] Ccna2 mediated cardiac repair showed both a decrease in fibrosis in the peri-infarct tissue and a greater number of cardiomyocytes at the sites of injection.[17] Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function.[17][18][19] # Cancer Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others.[2][20][21][22][23] While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis, it is indicative of prognostic values such as predictions of survival or relapse.[2] Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase and anaphase.[24] It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins or tumor suppressors like p53.[25]	https://www.wikidoc.org/index.php/CCNA2
8726c9c5baf6b891d78907bcac932f9abfdce0f4	wikidoc	Cyclin B1	Cyclin B1 G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene. # Function Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites. Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well-regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated, it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis, such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly. Once activated, cyclin B1-Cdk1 promotes several of the events of early mitosis. The active complex phosphorylates and activates 13S condensin, which helps to condense chromosomes. Another important function of the cyclin B1-Cdk1 complex is to break down the nuclear envelope. The nuclear envelope is a membranous structure containing large protein complexes supported by a network of nuclear lamins. Phosphorylation of the lamins by cyclin B1-Cdk1 causes them to dissociate, compromising the structural integrity of the nuclear envelope so that it breaks down. The destruction of the nuclear envelope is important because it allows the mitotic spindle to access the chromosomes. # Regulation Like all cyclins, levels of cyclin B1 oscillate over the course of the cell cycle. Just prior to mitosis, a large amount of cyclin B1 is present in the cell, but it is inactive due to phosphorylation of Cdk1 by the Wee1 kinase. The complex is activated by dephosphorylation by the phosphatase Cdc25. Cdc25 is always present in the cell but must be activated by phosphorylation. A possible trigger for activation is phosphorylation by cyclin A-Cdk, which functions before cyclin B1-Cdk in the cell cycle. Active Cdk1 is also capable of phosphorylating and activating Cdc25 and thus promote its own activation, resulting in a positive feedback loop. Once cyclin B1-Cdk1 is activated, it remains stably active for the rest of mitosis. Another mechanism by which cyclin B1-Cdk1 activity is regulated is through subcellular localization. Before mitosis almost all cyclin B1 in the cell is located in the cytoplasm, but in late prophase it relocates to the nucleus. This is regulated by the phosphorylation of cyclin B1, in contrast to phosphorylation of Cdk1 regulating the activity of the complex. Phosphorylation of cyclin B1 causes it to be imported to the nucleus, and phosphorylation also prevents export from the nucleus by blocking the nuclear export signal. Cyclin B1 is phosphorylated by Polo kinase and Cdk1 , again setting up a positive feedback loop that commits cyclin B1-Cdk1 to its fate. At the end of mitosis, cyclin B1 is targeted for degradation by the APC through its APC localization sequence, permitting the cell to exit mitosis. # Interactions Cyclin B1 has been shown to interact with Cdk1, GADD45A and RALBP1. # Cancer One of the hallmarks of cancer is the lack of regulation in the cell cycle. The role of cyclin B1 is to transition the cell from G2 to M phase but becomes unregulated in cancer cells where overexpression of cyclin B1 can lead to uncontrolled cell growth by binding to its partner Cdks. Binding of Cdks can lead to phosphorylation of other substrates at inappropriate time and unregulated proliferation. This is a consequence of p53, tumor suppressor protein, being inactivated. Wild-type p53 have been shown to suppress cyclin B1 expression. Previous work has shown that high cyclin B1 expression levels are found in variety of cancers such as breast, cervical, gastric, colorectal, head and neck squamous cell, non-small-cell lung cancer, colon, prostate, oral and esophageal. High expression levels are usually seen before the tumor cells become immortalized and aneuploid which can contribute to the chromosomal instability and the aggressive nature of certain cancers. These high levels of cyclin B1 can also be associated to the extent of tumor invasion and aggressiveness therefore concentration of cyclin B1 can be used to determine the prognosis of cancer patients. For example, an increase in expression of cyclin B1/cdc2 is significantly higher in breast tumor tissue and shown to increase lymph node metastasis in breast cancer. Cyclin B1 can reside in the nucleus or the cytoplasm which can have an effect on the malignant potential of cyclin B1 when overexpressed in each location. Nuclear-dominant expression of cyclin B1 leads to poorer prognosis due to its weak activity compared to cytoplasmic cyclin B1. This trend has been observed in esophageal cancer, head and neck squamous cell cancer and breast cancer. ## Down regulation and tumor suppression While the exact mechanism that explains how cyclin B1 becomes overexpressed is not very well understood, previous work has shown that down regulation of cyclin B1 can lead to tumor regression. A possible treatment option for tumor suppression is to deliver gene or protein to target the degradation of cyclin B1. Previous work done has shown that cyclin B1 is essential for tumor cell survival and proliferation and that a decrease in expression levels only leads to tumor-specific and not normal cell death. Reduction of cyclin B1 can stop cells in the G2 phase of the cell cycle and triggers cell death by preventing the chromosomes from condensing and aligning. The specific downregulation of cyclin B1, however, did not influence other molecules that facilitated the transition from the G2 to M phase such as Cdk1, Cdc25c, Plk1 and cyclin A. Therefore the delivery of a therapeutic gene to correct these mutations is a viable treatment option for tumor suppression. ## Tumor antigen In early stages of cancer when the cyclin B1 concentration is high, it is recognized by the immune system, leading to the production of antibodies and T cells. It would then be possible to take advantage of this to monitor the immune response for early cancer detection. An ELISA (Enzyme-linked immunosorbent assay) can be performed to the measure the antibodies recognizing cyclin B1. ## Breast cancer Cyclin B1 expression levels can be used as a tool to determine prognosis of patients with breast cancers. The intracellular concentration can have important implications for cancer prognosis. High levels of nuclear cyclin B1 is associated with high tumor grade, larger tumor size and higher metastasis probability, therefore a high level of cyclin B1 is a predictor of poor prognosis. ## Lung cancer Studies in non-small cell lung cancer demonstrated that high levels of cyclin B1 are associated with poorer prognosis. The study also found that this correlation between expression levels was only found in patients with squamous cell carcinoma. This finding indicates the possibility of using cyclin B1 expression as a prognostic marker for patients with early stage non-small cell lung cancer.	Cyclin B1 G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.[1] # Function Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.[2] Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well-regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated, it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis, such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly. Once activated, cyclin B1-Cdk1 promotes several of the events of early mitosis. The active complex phosphorylates and activates 13S condensin,[3] which helps to condense chromosomes. Another important function of the cyclin B1-Cdk1 complex is to break down the nuclear envelope. The nuclear envelope is a membranous structure containing large protein complexes supported by a network of nuclear lamins. Phosphorylation of the lamins by cyclin B1-Cdk1 causes them to dissociate,[4] compromising the structural integrity of the nuclear envelope so that it breaks down. The destruction of the nuclear envelope is important because it allows the mitotic spindle to access the chromosomes. # Regulation Like all cyclins, levels of cyclin B1 oscillate over the course of the cell cycle. Just prior to mitosis, a large amount of cyclin B1 is present in the cell, but it is inactive due to phosphorylation of Cdk1 by the Wee1 kinase. The complex is activated by dephosphorylation by the phosphatase Cdc25.[5] Cdc25 is always present in the cell but must be activated by phosphorylation. A possible trigger for activation is phosphorylation by cyclin A-Cdk, which functions before cyclin B1-Cdk in the cell cycle. Active Cdk1 is also capable of phosphorylating and activating Cdc25 and thus promote its own activation, resulting in a positive feedback loop. Once cyclin B1-Cdk1 is activated, it remains stably active for the rest of mitosis. Another mechanism by which cyclin B1-Cdk1 activity is regulated is through subcellular localization. Before mitosis almost all cyclin B1 in the cell is located in the cytoplasm, but in late prophase it relocates to the nucleus. This is regulated by the phosphorylation of cyclin B1, in contrast to phosphorylation of Cdk1 regulating the activity of the complex. Phosphorylation of cyclin B1 causes it to be imported to the nucleus,[6] and phosphorylation also prevents export from the nucleus by blocking the nuclear export signal.[7] Cyclin B1 is phosphorylated by Polo kinase and Cdk1 , again setting up a positive feedback loop that commits cyclin B1-Cdk1 to its fate. At the end of mitosis, cyclin B1 is targeted for degradation by the APC through its APC localization sequence, permitting the cell to exit mitosis. # Interactions Cyclin B1 has been shown to interact with Cdk1,[8][9] [10][11] GADD45A[12][13] and RALBP1.[14] # Cancer One of the hallmarks of cancer is the lack of regulation in the cell cycle. The role of cyclin B1 is to transition the cell from G2 to M phase but becomes unregulated in cancer cells where overexpression of cyclin B1 can lead to uncontrolled cell growth by binding to its partner Cdks. Binding of Cdks can lead to phosphorylation of other substrates at inappropriate time and unregulated proliferation.[15] This is a consequence of p53, tumor suppressor protein, being inactivated. Wild-type p53 have been shown to suppress cyclin B1 expression.[16][17] Previous work has shown that high cyclin B1 expression levels are found in variety of cancers such as breast, cervical, gastric, colorectal, head and neck squamous cell, non-small-cell lung cancer, colon, prostate, oral and esophageal.[15][18][19][20][21] High expression levels are usually seen before the tumor cells become immortalized and aneuploid which can contribute to the chromosomal instability and the aggressive nature of certain cancers.[22] These high levels of cyclin B1 can also be associated to the extent of tumor invasion and aggressiveness therefore concentration of cyclin B1 can be used to determine the prognosis of cancer patients.[18][23] For example, an increase in expression of cyclin B1/cdc2 is significantly higher in breast tumor tissue and shown to increase lymph node metastasis in breast cancer.[18][24] Cyclin B1 can reside in the nucleus or the cytoplasm which can have an effect on the malignant potential of cyclin B1 when overexpressed in each location. Nuclear-dominant expression of cyclin B1 leads to poorer prognosis due to its weak activity compared to cytoplasmic cyclin B1.[22] This trend has been observed in esophageal cancer, head and neck squamous cell cancer and breast cancer.[15][25] ## Down regulation and tumor suppression While the exact mechanism that explains how cyclin B1 becomes overexpressed is not very well understood, previous work has shown that down regulation of cyclin B1 can lead to tumor regression. A possible treatment option for tumor suppression is to deliver gene or protein to target the degradation of cyclin B1. Previous work done has shown that cyclin B1 is essential for tumor cell survival and proliferation and that a decrease in expression levels only leads to tumor-specific and not normal cell death.[26] Reduction of cyclin B1 can stop cells in the G2 phase of the cell cycle and triggers cell death by preventing the chromosomes from condensing and aligning. The specific downregulation of cyclin B1, however, did not influence other molecules that facilitated the transition from the G2 to M phase such as Cdk1, Cdc25c, Plk1 and cyclin A. Therefore the delivery of a therapeutic gene to correct these mutations is a viable treatment option for tumor suppression.[15] ## Tumor antigen In early stages of cancer when the cyclin B1 concentration is high, it is recognized by the immune system, leading to the production of antibodies and T cells. It would then be possible to take advantage of this to monitor the immune response for early cancer detection.[27] An ELISA (Enzyme-linked immunosorbent assay) can be performed to the measure the antibodies recognizing cyclin B1. ## Breast cancer Cyclin B1 expression levels can be used as a tool to determine prognosis of patients with breast cancers. The intracellular concentration can have important implications for cancer prognosis. High levels of nuclear cyclin B1 is associated with high tumor grade, larger tumor size and higher metastasis probability, therefore a high level of cyclin B1 is a predictor of poor prognosis.[22] ## Lung cancer Studies in non-small cell lung cancer demonstrated that high levels of cyclin B1 are associated with poorer prognosis. The study also found that this correlation between expression levels was only found in patients with squamous cell carcinoma. This finding indicates the possibility of using cyclin B1 expression as a prognostic marker for patients with early stage non-small cell lung cancer.[28]	https://www.wikidoc.org/index.php/CCNB1
c1cf69b764cfa22c4638cfe535d0ab80ea356a43	wikidoc	Cyclin B2	Cyclin B2 G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene. # Function Cyclin B2 is a member of the cyclin family, specifically the B-type cyclins. The B-type cyclins, B1 and B2, associate with p34cdc2 and are essential components of the cell cycle regulatory machinery. B1 and B2 differ in their subcellular localization. Cyclin B1 co-localizes with microtubules, whereas cyclin B2 is primarily associated with the Golgi region. Cyclin B2 also binds to transforming growth factor beta RII and thus cyclin B2/cdc2 may play a key role in transforming growth factor beta-mediated cell cycle control. # Interactions Cyclin B2 has been shown to interact with TGF beta receptor 2.	Cyclin B2 G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene. # Function Cyclin B2 is a member of the cyclin family, specifically the B-type cyclins. The B-type cyclins, B1 and B2, associate with p34cdc2 and are essential components of the cell cycle regulatory machinery. B1 and B2 differ in their subcellular localization. Cyclin B1 co-localizes with microtubules, whereas cyclin B2 is primarily associated with the Golgi region. Cyclin B2 also binds to transforming growth factor beta RII and thus cyclin B2/cdc2 may play a key role in transforming growth factor beta-mediated cell cycle control.[1] # Interactions Cyclin B2 has been shown to interact with TGF beta receptor 2.[2]	https://www.wikidoc.org/index.php/CCNB2
99b2a6c1abb47a3ca9d3b04f32cccb219d07b3eb	wikidoc	Cyclin D1	Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the CCND1 gene. # Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs long, and translates into 295 amino acids. Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid). # Protein structure Cyclin D1 is composed of the following protein domains and motifs: - retinoblastoma protein (pRb) binding motif; - cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding; - LxxLL binding motif for co-activator recruitment; - PEST sequence that may mark the protein for degradation; - threonine residue (threonine 286) that controls nuclear export and protein stability. # Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs (Cyclin-dependent kinase). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis. Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma. Cyclin D1 has been found to be overexpressed in breast carcinoma. Its potential use as a biomarker was suggested. ## Normal function Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration, angiogenesis and to induce the Warburg effect. Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle. During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase. Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase. ## CDK dependent functions The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb). Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase. Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis. Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase. Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators. ## CDK independent functions Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ and AR ) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes in the early to mid-G1 phase. # Synthesis and degradation Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors primarily through Ras mediated pathways, and hormones. These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus. Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase. Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation. # Clinical significance ## Deregulation in cancer Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production. Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis. An abundance of cyclin D1 can be caused by various types of deregulation, including: - amplification of the CCND1 gene / overexpression of cyclin D1; - chromosomal translocation of the CCND1 gene; - disruption of nuclear export and proteolysis of cyclin D1 - induction of transcription by oncogenic Ras, Src, ErbB2 and STATs; Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis. Amplification of the CCND1 gene is present in: - non-small cell lung cancers (30-46%) - head and neck squamous cell carcinomas (30-50%) - pancreatic carcinomas (25%) - bladder cancer (15%) - pituitary adenomas (49-54%) - breast carcinoma (13%) Cyclin D1 overexpression is strongly correlated to ER+ breast cancer and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer. Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers. Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas. ## Therapeutic target in cancer Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs: # Interactions Cyclin D1 has been shown to interact with: - NR3C4, - BRCA1, - CCNDBP1, - CDK4, - CDK6, - ESR1 - HDAC3, - HDACs - NEUROD1, - NCOA1, - NRF1, - p300, - PACSIN2, - PCNA, - PPARG, - RAD51, - RB1, - TAF1, and - NR1A2.	Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.[1][2] # Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs long, and translates into 295 amino acids.[3] Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).[4][5] # Protein structure Cyclin D1 is composed of the following protein domains and motifs:[6][7] - retinoblastoma protein (pRb) binding motif; - cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding; - LxxLL binding motif for co-activator recruitment; - PEST sequence that may mark the protein for degradation; - threonine residue (threonine 286) that controls nuclear export and protein stability. # Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs (Cyclin-dependent kinase). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis.[8] Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma. Cyclin D1 has been found to be overexpressed in breast carcinoma. Its potential use as a biomarker was suggested.[9] ## Normal function Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma[10] and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration,[11] angiogenesis[12] and to induce the Warburg effect.[13] Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.[14] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.[14] Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase. ## CDK dependent functions The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).[15] Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase. Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis. Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase.[16] Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.[6] ## CDK independent functions Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α,[17] thyroid hormone receptor, PPARγ [18][19] and AR[20] ) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes [21][22][20][23] in the early to mid-G1 phase. # Synthesis and degradation Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors [24] primarily through Ras mediated pathways,[25][26][27] and hormones.[21] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.[28] Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase. Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation.[29] # Clinical significance ## Deregulation in cancer Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression [16] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.[30] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.[30] An abundance of cyclin D1 can be caused by various types of deregulation, including: - amplification of the CCND1 gene / overexpression of cyclin D1; - chromosomal translocation of the CCND1 gene; - disruption of nuclear export [31] and proteolysis of cyclin D1[32] - induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;[33][34][35][36] Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[37][38] Amplification of the CCND1 gene is present in: - non-small cell lung cancers (30-46%) [39][40] - head and neck squamous cell carcinomas (30-50%) [41][42][43] - pancreatic carcinomas (25%) [44] - bladder cancer (15%) [45] - pituitary adenomas (49-54%) [46][47] - breast carcinoma (13%) [48][49][50] Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[50] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[29][51][52] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.[7] Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter[53] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.[54][55] ## Therapeutic target in cancer Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs: # Interactions Cyclin D1 has been shown to interact with: - NR3C4,[20][66][67] - BRCA1,[68][69] - CCNDBP1,[70] - CDK4,[71][72][73][74][75][76] - CDK6,[71][73] - ESR1[68][69][77][17] - HDAC3,[66][78] - HDACs[23] - NEUROD1,[79] - NCOA1,[80] - NRF1,[81] - p300,[82] - PACSIN2,[83] - PCNA,[84][85] - PPARG,[86] - RAD51,[87] - RB1,[88][89] - TAF1,[88][90] and - NR1A2.[78]	https://www.wikidoc.org/index.php/CCND1
cd4d90aacd90a451d2989c700a5143306f0d12eb	wikidoc	Cyclin D2	Cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene. # Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of cyclin-dependent kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors. # Clinical significance Mutations in CCND2 are associated to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome .	Cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.[1] # Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of cyclin-dependent kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors.[2] # Clinical significance Mutations in CCND2 are associated to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome .[3]	https://www.wikidoc.org/index.php/CCND2
f8f9aab5302122c65a14dce9804bb1ae10c32edf	wikidoc	Stimulant	Stimulant # Overview Stimulants are drugs that temporarily increase alertness and awareness. They usually have increased side-effects with increased effectiveness, and the more powerful variants are therefore often prescription medicines or illegal drugs. # Function Stimulants increase the activity of either the sympathetic nervous system, the central nervous system (CNS) or both. Some stimulants produce a sense of euphoria, in particular the stimulants which exert influence on the CNS. Stimulants are used therapeutically to increase or maintain alertness, to counteract fatigue in situations where sleep is not practical (e.g. while operating vehicles), to counteract abnormal states that diminish alertness consciousness, (such as in narcolepsy), to promote weight loss (phentermine) as well as to enhance the ability to concentrate in people diagnosed with attentional disruptions (especially ADHD). Occasionally, they are also used to treat depression. Stimulants are sometimes used to boost endurance and productivity as well as to suppress appetite. The euphoria produced by some stimulants leads to their recreational use, although this is illegal in the majority of jurisdictions. Caffeine, found in beverages such as[coffee and soft drinks, as well as nicotine, which is found in tobacco, are among some of the world's most commonly used stimulants. Examples of other well known stimulants include ephedrine, amphetamines, cocaine, methylphenidate, MDMA, and modafinil. Stimulants are commonly referred in slang as "uppers". Stimulants with significant abuse potential are very carefully controlled substances in America and most other jurisdictions. Some may be legally available only by prescription (e.g. methamphetamine, brand name Desoxyn, mixed amphetamine salts, brand name Adderall, dexamphetamine, brand name Dexedrine) or not at all (e.g. methcathinone). # Phenethylamines Phenethylamine is an alkaloid and monoamine and believed to be a neuromodulator or neurotransmitter. Furthermore it is the basic chemical structure behind most stimulants, especially sympathomimetic amines. Common phenethylamines include: - catecholamines: dopamine, epinephrine, and norepinephrine - plant alkaloids: ephedrine, pseudoephedrine, cathinone, cathine - amphetamines and substituted amphetamines: amphetamine, methamphetamine, MDA, MDMA, MDMC, DOM, DOB, DOI - methylphenidate - bronchodilators: albuterol, clenbuterol - psychedelics: 2C (psychedelics), mescaline Amphetamines Amphetamines (prescribed as either racemic amphetamine or dextroamphetamine) increase the heart and respiration rates, increase blood pressure and in some users, dilate the pupils of the eyes and decrease appetite. Like NDRIs, amphetamine increases the levels of norepinephrine and dopamine in the brain via reuptake inhibition; however, the more important mechanism by which amphetamines cause stimulation is through the direct release of these catecholamines from storage vesicles in cells. Amphetamines are known to cause elevated mood and euphoria as well as rebound depression and anxiety. Other possible effects include blurred vision, insomnia, and dizziness. Amphetamines are sometimes prescribed therapeutically by physicians and their availability makes them prime candidates for misuse . Used properly, amphetamines increase alertness, concentration and physical endurance. They are often prescribed to counter the effects of narcolepsy, a disorder marked by episodes of uncontrollable sleep, and to help patients with learning disabilities such as ADD and ADHD. Dextrorotary methamphetamine is occasionally used in the treatment of AD(H)D that does not respond sufficiently to traditional amphetamines. On occasion, major depression is treated with amphetamines as well. Amphetamines can be used as an add-on to antidepressant therapy as well, with some success in certain populations. Methylenedioxymethamphetamine Methylenedioxymethamphetamine (MDMA) is a drug that comes either in tablet or capsule form (known as ecstasy, zoom, scrap), as a powder or crystal. Stimulant effects of MDMA include increased blood pressure and heart rate, loss of appetite, rapid sweating, and a dry mouth and throat. Ecstasy pills often contain amounts of other drugs which may include any of a wide range of substances such as MDA, MDEA, MBDB, PCP, DXM, Ketamine, Caffeine, Amphetamine, Methamphetamine, Ephedrine, Pseudoephedrine, Aspirin, Paracetamol, and, in a small number of cases, PMA , Cocaine , Fentanyl , mCPP, BZP+TFMPP, DOB , and 2C-B . In some cases the substance sold as ecstasy may not contain MDMA at all. MDMA was historically used in a therapeutic setting by a small number of psychiatrists for marriage counseling, before it was outlawed by the DEA because of its widespread recreational use. As of 2001, it is being considered by the FDA in the treatment of Post-traumatic stress disorder. It is also being evaluated for possible usages in palliative care . # Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs) These compounds inhibit the uptake of the monoamines dopamine and norepinephrine into storage vesicles, effectively increasing their amounts in the brain and causing a stimulating effect. Many of these compounds are effective ADHD medications and antidepressants. The most popular and well-known dopamine and norepinephrine reuptake inhibitor antidepressant is bupropion (Wellbutrin). Other examples of NDRIs include MDPV, ciclazindol, pyrovalerone, mazindol, pipradrol, and amfonelic acid. Although these medicines have similar methods of action to stimulants, they are less popular for abuse (thus not scheduled) and have an extended release mechanism or a very long half life. Many NDRIs are also phenethylamines. # Cocaine Cocaine is made from the leaves of the coca shrub, which grows in the mountain regions of South American countries such as Bolivia, Colombia, and Peru. In Europe and North America, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, particularly in ophthalmology. Most cocaine use is recreational and its abuse potential is high, and so its sale and possession are strictly controlled in most jurisdictions. # Caffeine Caffeine is a drug that is found naturally in coffee, tea, and to a small extent cocoa. It is also found in many soft drinks particularly energy drin]s. Caffeine stimulates the body, increasing heart rate and blood pressure, and alertness, making some people feel better and able to concentrate. Caffeine is also a diuretic. The vast majority (over 80%) of people in the United States consume caffeine on a daily basis. As a result, few jurisdictions restrict its sale and use. Caffeine is also sold in some countries as an isolated drug (as opposed to its natural occurrence in many foods). It serves as a mild stimulant to ward off sleepiness and sees wide use among people who must remain alert in their work (e.g., truck drivers). Some medications contain caffeine as one of their minor active ingredients, often for the purpose of enhancing the effect of the main ingredient or reducing one of its side effects. # Nicotine Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper. Nicotine alkaloids are also found in the leaves of the coca plant. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots, and accumulates in the leaves. It is a potent nerve poison and is included in many insecticides. The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with its risks to health. In very low concentrations, nicotine acts as a stimulant, and it is one of the main factors responsible for the dependence-forming properties of tobacco smoking. Although pure nicotine is noncarcinogenic, its presence may inhibit the body's ability to cull aberrant cells . # Ampakines Recently, there have been improvements in the area of stimulant pharmacology, producing a class of chemicals known as Ampakines, or eugeroics, (good arousal). These stimulants tend to increase alertness without the peripheral (body) effects or addiction/tolerance/abuse potential of the traditional stimulants. They have minimal effect on sleep structure, and do not cause rebound hypersomnolence or "come down" effects. Currently, there are two stimulants in this class being used: modafinil and adrafinil, marketed as Provigil and Olmifon, respectively. In Russia, Carphedon is sold as a general stimulant under the brand name Phenotropil.	Stimulant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Stimulants are drugs that temporarily increase alertness and awareness. They usually have increased side-effects with increased effectiveness, and the more powerful variants are therefore often prescription medicines or illegal drugs. # Function Stimulants increase the activity of either the sympathetic nervous system, the central nervous system (CNS) or both. Some stimulants produce a sense of euphoria, in particular the stimulants which exert influence on the CNS. Stimulants are used therapeutically to increase or maintain alertness, to counteract fatigue in situations where sleep is not practical (e.g. while operating vehicles), to counteract abnormal states that diminish alertness consciousness, (such as in narcolepsy), to promote weight loss (phentermine) as well as to enhance the ability to concentrate in people diagnosed with attentional disruptions (especially ADHD). Occasionally, they are also used to treat depression. Stimulants are sometimes used to boost endurance and productivity as well as to suppress appetite. The euphoria produced by some stimulants leads to their recreational use, although this is illegal in the majority of jurisdictions. Caffeine, found in beverages such as[coffee and soft drinks, as well as nicotine, which is found in tobacco, are among some of the world's most commonly used stimulants. Examples of other well known stimulants include ephedrine, amphetamines, cocaine, methylphenidate, MDMA, and modafinil. Stimulants are commonly referred in slang as "uppers". Stimulants with significant abuse potential are very carefully controlled substances in America and most other jurisdictions. Some may be legally available only by prescription (e.g. methamphetamine, brand name Desoxyn, mixed amphetamine salts, brand name Adderall, dexamphetamine, brand name Dexedrine) or not at all (e.g. methcathinone). # Phenethylamines Phenethylamine is an alkaloid and monoamine and believed to be a neuromodulator or neurotransmitter. Furthermore it is the basic chemical structure behind most stimulants, especially sympathomimetic amines. Common phenethylamines include: - catecholamines: dopamine, epinephrine, and norepinephrine - plant alkaloids: ephedrine, pseudoephedrine, cathinone, cathine - amphetamines and substituted amphetamines: amphetamine, methamphetamine, MDA, MDMA, MDMC, DOM, DOB, DOI - methylphenidate - bronchodilators: albuterol, clenbuterol - psychedelics: 2C (psychedelics), mescaline Amphetamines Amphetamines (prescribed as either racemic amphetamine or dextroamphetamine) increase the heart and respiration rates, increase blood pressure and in some users, dilate the pupils of the eyes and decrease appetite. Like NDRIs, amphetamine increases the levels of norepinephrine and dopamine in the brain via reuptake inhibition; however, the more important mechanism by which amphetamines cause stimulation is through the direct release of these catecholamines from storage vesicles in cells. Amphetamines are known to cause elevated mood and euphoria as well as rebound depression and anxiety. Other possible effects include blurred vision, insomnia, and dizziness. Amphetamines are sometimes prescribed therapeutically by physicians and their availability makes them prime candidates for misuse [2]. Used properly, amphetamines increase alertness, concentration and physical endurance. They are often prescribed to counter the effects of narcolepsy, a disorder marked by episodes of uncontrollable sleep, and to help patients with learning disabilities such as ADD and ADHD. Dextrorotary methamphetamine is occasionally used in the treatment of AD(H)D that does not respond sufficiently to traditional amphetamines. On occasion, major depression is treated with amphetamines as well. Amphetamines can be used as an add-on to antidepressant therapy as well, with some success in certain populations. Methylenedioxymethamphetamine Methylenedioxymethamphetamine (MDMA) is a drug that comes either in tablet or capsule form (known as ecstasy, zoom, scrap), as a powder or crystal. Stimulant effects of MDMA include increased blood pressure and heart rate, loss of appetite, rapid sweating, and a dry mouth and throat. Ecstasy pills often contain amounts of other drugs which may include any of a wide range of substances such as MDA, MDEA, MBDB, PCP, DXM, Ketamine, Caffeine, Amphetamine, Methamphetamine, Ephedrine, Pseudoephedrine, Aspirin, Paracetamol, and, in a small number of cases, PMA [3], Cocaine [4], Fentanyl [5], mCPP, BZP+TFMPP, DOB [6], and 2C-B [7]. In some cases the substance sold as ecstasy may not contain MDMA at all. MDMA was historically used in a therapeutic setting by a small number of psychiatrists for marriage counseling, before it was outlawed by the DEA because of its widespread recreational use. As of 2001, it is being considered by the FDA in the treatment of Post-traumatic stress disorder. It is also being evaluated for possible usages in palliative care [8]. # Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs) These compounds inhibit the uptake of the monoamines dopamine and norepinephrine into storage vesicles, effectively increasing their amounts in the brain and causing a stimulating effect. Many of these compounds are effective ADHD medications and antidepressants. The most popular and well-known dopamine and norepinephrine reuptake inhibitor antidepressant is bupropion (Wellbutrin). Other examples of NDRIs include MDPV, ciclazindol, pyrovalerone, mazindol, pipradrol, and amfonelic acid. Although these medicines have similar methods of action to stimulants, they are less popular for abuse (thus not scheduled) and have an extended release mechanism or a very long half life. Many NDRIs are also phenethylamines. # Cocaine Cocaine is made from the leaves of the coca shrub, which grows in the mountain regions of South American countries such as Bolivia, Colombia, and Peru. In Europe and North America, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, particularly in ophthalmology. Most cocaine use is recreational and its abuse potential is high, and so its sale and possession are strictly controlled in most jurisdictions. # Caffeine Caffeine is a drug that is found naturally in coffee, tea, and to a small extent cocoa. It is also found in many soft drinks particularly energy drin]s. Caffeine stimulates the body, increasing heart rate and blood pressure, and alertness, making some people feel better and able to concentrate. Caffeine is also a diuretic. The vast majority (over 80%) of people in the United States consume caffeine on a daily basis. As a result, few jurisdictions restrict its sale and use. Caffeine is also sold in some countries as an isolated drug (as opposed to its natural occurrence in many foods). It serves as a mild stimulant to ward off sleepiness and sees wide use among people who must remain alert in their work (e.g., truck drivers). Some medications contain caffeine as one of their minor active ingredients, often for the purpose of enhancing the effect of the main ingredient or reducing one of its side effects. # Nicotine Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper. Nicotine alkaloids are also found in the leaves of the coca plant. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots, and accumulates in the leaves. It is a potent nerve poison and is included in many insecticides. The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with its risks to health. In very low concentrations, nicotine acts as a stimulant, and it is one of the main factors responsible for the dependence-forming properties of tobacco smoking. Although pure nicotine is noncarcinogenic, its presence may inhibit the body's ability to cull aberrant cells [9]. # Ampakines Recently, there have been improvements in the area of stimulant pharmacology, producing a class of chemicals known as Ampakines, or eugeroics, (good arousal). These stimulants tend to increase alertness without the peripheral (body) effects or addiction/tolerance/abuse potential of the traditional stimulants. They have minimal effect on sleep structure, and do not cause rebound hypersomnolence or "come down" effects. Currently, there are two stimulants in this class being used: modafinil and adrafinil, marketed as Provigil and Olmifon, respectively. In Russia, Carphedon is sold as a general stimulant under the brand name Phenotropil.	https://www.wikidoc.org/index.php/CNS_stimulant
87d9c07f0b877fa5cf24715ec4428df41cd715bb	wikidoc	CNTO 1275	CNTO 1275 CNTO 1275 is the experimental name for a human immunosuppressive drug developed by the biotechnology company Centocor. It is a laboratory-manufactured, monoclonal antibody directed against interleukins IL-12 and IL-23 and presently undergoing clinical trials to determine its safety and effectiveness against the diseases Multiple Sclerosis, Psoriasis, and Psoriatic Arthritis. Once released for public use, administration and dosage of the drug will most likely by doctor's prescription and direction only. # Development As of January 2007, there were 5 NIH-listed research studies involving CNTO 1275 on a multinational basis, including 3 Phase II and 2 Phase III trials. Three studies are focused on patients with psoriasis, one on psoriatic arthritis, and one on Multiple Sclerosis. CNTO 1275 is not yet approved by the U.S. Food and Drug Administration. # Delivery Note: Because the drug is not yet released for public use, the official drug's prescribing information and disclosure (required by federal law) is not available. Patients enrolled in clinical trials of CNTO 1275 are scheduled to receive the drug by subcutaneous injections at doses of either 45 or 90 mg. The dosage and frequency varies by study and application (type of disease targeted). Generally the initial dosing interval is once per week followed by a step-down to once per month or even once every three months. # Mode of action Similar to the immunosuppressive function of Etanercept(Enbrel), CNTO 1275 is designed to interfere with the triggering of the body's inflamatory response through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin IL-12 and IL-23 which help activiate certain T-cells.	CNTO 1275 CNTO 1275 is the experimental name for a human immunosuppressive drug developed by the biotechnology company Centocor. It is a laboratory-manufactured, monoclonal antibody directed against interleukins IL-12 and IL-23 and presently undergoing clinical trials to determine its safety and effectiveness against the diseases Multiple Sclerosis, Psoriasis, and Psoriatic Arthritis. Once released for public use, administration and dosage of the drug will most likely by doctor's prescription and direction only. # Development As of January 2007, there were 5 NIH-listed research studies involving CNTO 1275 on a multinational basis, including 3 Phase II and 2 Phase III trials. Three studies are focused on patients with psoriasis, one on psoriatic arthritis, and one on Multiple Sclerosis. CNTO 1275 is not yet approved by the U.S. Food and Drug Administration. # Delivery Note: Because the drug is not yet released for public use, the official drug's prescribing information and disclosure (required by federal law) is not available. Patients enrolled in clinical trials of CNTO 1275 are scheduled to receive the drug by subcutaneous injections at doses of either 45 or 90 mg. The dosage and frequency varies by study and application (type of disease targeted). Generally the initial dosing interval is once per week followed by a step-down to once per month or even once every three months. # Mode of action Similar to the immunosuppressive function of Etanercept(Enbrel), CNTO 1275 is designed to interfere with the triggering of the body's inflamatory response through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin IL-12 and IL-23 which help activiate certain T-cells. # External links - Centocor official site - CNTO 1275 research studies registered with U.S. National Institutes of Health: Phase II Study on Multiple Sclerosis (NCT00207727) Phase II Study on Psoriasis (NCT00320216) Phase III Study on Psoriasis (NCT00267969) Phase III Study on Psoriasis (NCT00307437) Phase II Study on Psoriatic Arthritis (NCT00267956) - Phase II Study on Multiple Sclerosis (NCT00207727) - Phase II Study on Psoriasis (NCT00320216) - Phase III Study on Psoriasis (NCT00267969) - Phase III Study on Psoriasis (NCT00307437) - Phase II Study on Psoriatic Arthritis (NCT00267956) - Sylvester, Bruce (2006-03-06). "CNTO 1275 Shows Efficacy for Psoriasis: Presented at AAD". Doctor's Guide Publishing. Retrieved 2007-01-25..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Template:Immunosuppressants Template:WikiDoc Sources	https://www.wikidoc.org/index.php/CNTO_1275
9d291f73d6e330a8dd98864e42d468ff21901a22	wikidoc	COUP-TFII	COUP-TFII COUP-TFII (COUP transcription factor 2), also known as NR2F2 (nuclear receptor subfamily 2, group F, member 2) is a protein that in humans is encoded by the NR2F2 gene. The COUP acronym stands for chicken ovalbumin upstream promoter. # Function COUP-TFII plays a critical role in controlling the development of a number of tissues and organs including heart, blood vessels, muscles and limbs. The glucocorticoid receptor (GR) stimulates COUP-TFII-induced transactivation while COUP-TFII represses the GR transcriptional activity. COUP-TFII interacts with GATA2 to inhibit adipocyte differentiation. # Interactions COUP-TFII has been shown to interact with: - HDAC1 - Lck - V-erbA-related gene. - Nucleolin	COUP-TFII COUP-TFII (COUP transcription factor 2), also known as NR2F2 (nuclear receptor subfamily 2, group F, member 2) is a protein that in humans is encoded by the NR2F2 gene.[1][2] The COUP acronym stands for chicken ovalbumin upstream promoter. # Function COUP-TFII plays a critical role in controlling the development of a number of tissues and organs including heart, blood vessels, muscles and limbs.[3][4] The glucocorticoid receptor (GR) stimulates COUP-TFII-induced transactivation while COUP-TFII represses the GR transcriptional activity.[5][6] COUP-TFII interacts with GATA2 to inhibit adipocyte differentiation.[7] # Interactions COUP-TFII has been shown to interact with: - HDAC1[8] - Lck[9] - V-erbA-related gene.[10] - Nucleolin[11]	https://www.wikidoc.org/index.php/COUP-TFII
ba609c8b79e2bf8a069405a9985a0d3113f5d678	wikidoc	CRE boxes	CRE boxes CREB (cAMP response element-binding protein) is a cellular transcription factor that binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cyclic adenosine monophosphate (cAMP)-responsive transcription factor regulating the somatostatin gene. Genes whose transcription is regulated by CREB include: c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (such as somatostatin, enkephalin, VGF, corticotropin-releasing hormone), and genes involved in the mammalian circadian clock (PER1, PER2). CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory. CREB downregulation is implicated in the pathology of Alzheimer's disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer's disease. # Consensus sequence "Each species' promoter contains a cAMP/response element (CRE)1 consensus sequence () upstream of a TATA box. Two other members of this family of proteins, chromogranin B and secretogranin II (also known as chromogranin C), contain similar CRE and TATA homologies in their proximal gene promoters (8, 9)." "Within the cAMP-responsive element of the somatostatin gene, we observed an 8-base palindrome, 5'-TGACGTCA-3', which is highly conserved in many other genes whose expression is regulated by cAMP." # cAMP response element The cAMP response element (CRE) is the response element for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. CRE sites are typically found upstream of genes, within the promoter or enhancer regions. There are approximately 750,000 palindromic and half-site CREs in the human genome. However, the majority of these sites remain unbound due to cytosine methylation. # Samplings of the A1BG promoters For the Basic programs (starting with SuccessablesCRE.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), including extension of nts from 958 to 4445, the programs are, are looking for, and found: - negative strand in the negative direction (from ZSCAN22 to A1BG) is SuccessablesCRE--.bas, looking for 3'-TGACGTCA-5', 1, 3'-TGACGTCA-5', 4317, - negative strand in the positive direction (from ZNF497 to A1BG) is SuccessablesCRE-+.bas, looking for 3'-TGACGTCA-5', 0, - positive strand in the negative direction is SuccessablesCRE+-.bas, looking for 3'-TGACGTCA-5', 0, - positive strand in the positive direction is SuccessablesCRE++.bas, looking for 3'-TGACGTCA-5', 0, - complement, negative strand, negative direction is SuccessablesCREc--.bas, looking for 3'-ACTGCAGT-5', 0, - complement, negative strand, positive direction is SuccessablesCREc-+.bas, looking for 3'-ACTGCAGT-5', 0, - complement, positive strand, negative direction is SuccessablesCREc+-.bas, looking for 3'-ACTGCAGT-5', 1, 3'-ACTGCAGT-5', 4317, - complement, positive strand, positive direction is SuccessablesCREc++.bas, looking for 3'-ACTGCAGT-5', 0, - inverse complement, negative strand, negative direction is SuccessablesCREci--.bas, looking for 3'-TGACGTCA-5', 1, 3'-TGACGTCA-5', 4317, - inverse complement, negative strand, positive direction is SuccessablesCREci-+.bas, looking for 3'-TGACGTCA-5', 0, - inverse complement, positive strand, negative direction is SuccessablesCREci+-.bas, looking for 3'-TGACGTCA-5', 0, - inverse complement, positive strand, positive direction is SuccessablesCREci++.bas, looking for 3'-TGACGTCA-5', 0, - inverse, negative strand, negative direction, is SuccessablesCREi--.bas, looking for 3'-ACTGCAGT-5', 0, - inverse, negative strand, positive direction, is SuccessablesCREi-+.bas, looking for 3'-ACTGCAGT-5', 0, - inverse, positive strand, negative direction, is SuccessablesCREi+-.bas, looking for 3'-ACTGCAGT-5', 1, 3'-ACTGCAGT-5', 4317, - inverse, positive strand, positive direction, is SuccessablesCREi++.bas, looking for 3'-ACTGCAGT-5', 0. # Transcribed CRE boxes GeneID: 627 BDNF brain derived neurotrophic factor. Also known as ANON2; BULN2. "This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders." GeneID: 1113 CHGA chromogranin A. Also known as CGA. "The protein encoded by this gene is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. It is found in secretory vesicles of neurons and endocrine cells. This gene product is a precursor to three biologically active peptides; vasostatin, pancreastatin, and parastatin. These peptides act as autocrine or paracrine negative modulators of the neuroendocrine system. Two other peptides, catestatin and chromofungin, have antimicrobial activity and antifungal activity, respectively. Two transcript variants encoding different isoforms have been found for this gene." Secretory "stimulation of pheochromocytoma cells also activates the biosynthesis of the major secreted protein (chromogranin A), that the activation is transcriptional, and that a small proximal domain, including the CRE box, is, at least in part, both necessary and sufficient to account for the positive response to nicotine." "A CRE box containing somatostatin promoter (-71 bp to +55 bp)/luciferase reporter plasmid was obtained from Marc Montminy, Salk Institute, La Jolla, CA. Its CRE box (TGACGTCA) was at -41 to -48 bp." "Since the proximal positive response region contains a CRE homology ((-71 bp)-TGACGTAA-(-64 bp)), we tested the effect of a CRE box point-gap mutation (TGA-GTAA) in a transfected 77-bp chromogranin A promoter/luciferase reporter construct . The nicotinic induction ratio (nicotine stimulation/mock stimulation) fell from 2.58-fold in the wild-type promoter down to 1.64-fold (i.e. a 60% fall, p < 0.05) in the promoter with the CRE box point-gap mutation." "We then tested whether a CRE box alone could transfer nicotinic responsiveness to a heterologous (TK) promoter (in pTK-LUC). The chromogranin A CRE (TGACGTAA) insert conferred 3.97-fold nicotinic induction , while a consensus CRE (TGACGTCA) was induced 4.94-fold by nicotine; each of these nicotinic responses was significantly (p < 0.05) greater than that of the original TK promoter vector . The nicotinic induction was blunted (down to 1.31-fold) by point-gap mutation of the CRE box (TGA-GTAA). Even a CRE box (TGACGTCA) in the transfected promoter of a gene (somatostatin) not ordinarily expressed in chromaffin cells responded 2.03-fold (p < 0.05) to nicotine (from 134 ± 10.1 to 272 ± 19.6 luciferase light units/mg protein; n = 4 transfected wells/condition)." "In electrophoretic gel mobility shift assays, we tested the effect of PC12 nicotine exposure (at a dose (10-3 M) and time (16 h) which stimulated the transfected promoter on nuclear protein binding to four promoter regions: three that responded positively to nicotine during transfection (-432 to -312, -147 to -77, and -71 to -64 bp (the CRE box)), and one that seemed to respond negatively (-181 to -147 bp). None of these regions showed any significant change in band retardation pattern after nicotine ." "Because CREB-bound CRE boxes are only transcriptionally transactivated when CREB itself has been activated by phosphorylation at serine 133 (33), we undertook antibody supershift assays , using not only an antibody directed against CREB (epitope: the CREB kinase-inducible domain), but also an antibody which specifically recognized CREB only in its activated, phosphorylated form (pS133-CREB). Cell exposure to nicotine did not alter the anti-CREB supershift by PC12 nuclear proteins, but did result in a qualitatively new anti-pS133-CREB supershift band. Competition experiments with a 100-fold molar excess of unlabeled CRE indicated that both the anti-CREB and the anti-pS133-CREB supershifts represented CRE-binding complexes." "The CRE box is at promoter position (-71 bp)TGACGTAA(-64 bp)." "Each species' promoter contains a cAMP/response element (CRE)1 consensus sequence () upstream of a TATA box. Two other members of this family of proteins, chromogranin B and secretogranin II (also known as chromogranin C), contain similar CRE and TATA homologies in their proximal gene promoters (8, 9)." "1. Abbreviations used: CMV, cytomegalovirus; CRE, cAMP responsive element; CREB, CRE-binding protein; CREM, CRE modulator protein; DBH, dopamine ,/-hydroxylase; LUC, luciferase; TK, thymidine kinase." "Within the cAMP-responsive element of the somatostatin gene, we observed an 8-base palindrome, 5'-TGACGTCA-3', which is highly conserved in many other genes whose expression is regulated by cAMP." GeneID: 1114 CHGB chromogranin B. Also known as SCG1. "This gene encodes a tyrosine-sulfated secretory protein abundant in peptidergic endocrine cells and neurons. This protein may serve as a precursor for regulatory peptides." The "isolated mouse chromogranin B promoter the proximal chromogranin B promoter (from −216 to −91 bp); contains an E box (at CACCTG), four G/C-rich regions (atCCCCGC, CCGCCCGC,GGCGCCGCC, and CGGGGC), and a cAMP response element (CRE; at TGACGTCA). A 60-bp core promoter region, defined by an internal deletion from −134 to −74 bp upstream of the cap site and spanning the CRE and three G/C-rich regions, directed tissue-specific expression of the gene. The CRE motif directed cell type-specific expression of the chromogranin B gene in neurons, whereas three of the G/C-rich regions played a crucial role in neuroendocrine cells. Both the endogenous chromogranin B gene and the transfected chromogranin B promoter were induced by preganglionic secretory stimuli (pituitary adenylyl cyclase-activating polypeptide, vasoactive intestinal peptide, or a nicotinic cholinergic agonist), establishing stimulus-transcription coupling for this promoter. The adenylyl cyclase activator forskolin, nerve growth factor, and retinoic acid also activated the chromogranin B gene. Secretagogue-inducible expression of chromogranin B also mapped onto the proximal promoter; inducible expression was entirely lost upon internal deletion of the 60-bp core (from −134 to −74 bp). CRE and G/C-rich domains are crucial determinants of both cell type-specific and secretagogue-inducible expression of the chromogranin B gene." "Sequence analysis of 2908 bp of the 5′-flanking region of the mouse chromogranin B gene revealed several consensus matches for cis-acting transcriptional control elements reported as base pairs upstream of the cap site (+1): 1) the TATA box at TTCATAA; 2) a cAMP response element (CRE) (24) at TGACGTCA; 3) eight G/C-rich elements of 6 consecutive bp or more (potential binding sites for such factors as Sp1, Ap2, or Egr1) at −8/−2 bp, −45/−39 bp, −62/−53 bp, −83/−64 bp, −115/−110 bp, −125/−117 bp, −134/−127 bp, and− 196/−191 bp GGGGCGCCCC (25); several of these G/C-rich sites overlap partial matches for Ap2 motifs (e.g. GSSWGSCC; IUPAC nomenclature) (25)]; and 4) an E-box (CANNTG; IUPAC nomenclature) at CACCTG (25)." "Mouse chromogranin B promoter sequence. Nucleotides are numbered from the transcription initiation site (+1) of the gene. Note the positions of the TATA box at TTCATAA, the CRE at TGACGTCA, and eight G/C-rich elements of 6 or more consecutive bp (potential binding sites for such factors as Sp1, Ap2, or Egr1) at CCGCGCC, CCCCGCC, CGCCCCCGGG,GGGGCGCCCCCGCCCGCCGC, CGGGGC, GGCGCCGCC, CCGCCCGC, and CCCCGC. One of these G/C-rich sites is a perfect (9/9 bp) consensus match for an Egr1 recognition site: CGCCCCCGC. One of these G/C-rich sites overlaps a perfect (10/10 bp) consensus match (GGGRNNYYCC; IUPAC nomenclature) for a nuclear factor-κB site: GGGGCGCCCC. Several of these G/C-rich sites overlap partial matches for Ap2 motifs (e.g. GSSWGSCC; IUPAC nomenclature). There is an E box (CANNTG; IUPAC nomenclature) at CACCTG." GeneID: 1392 CRH corticotropin releasing hormone. Also known as CRF; CRH1. "This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition." GeneID: 1843 DUSP1 dual specificity phosphatase 1. Also known as HVH1; MKP1; CL100; MKP-1; PTPN10. "The protein encoded by this gene is a phosphatase with dual specificity for tyrosine and threonine. The encoded protein can dephosphorylate MAP kinase MAPK1/ERK2, which results in its involvement in several cellular processes. This protein appears to play an important role in the human cellular response to environmental stress as well as in the negative regulation of cellular proliferation. Finally, the encoded protein can make some solid tumors resistant to both chemotherapy and radiotherapy, making it a target for cancer therapy." Although "macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between -380 and -180bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS- or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box." The "same region, which contains a CREB/AP-1 box, is required for M-CSF- or LPS-dependent stimulation, although this stimulation is induced at different times after stimulation. CREB and c-Jun are responsible for MKP-1 induction. The induction of c-Jun is correlated with the kinetics of MKP-1 induction by M-CSF or LPS." "MKP-1 expression induced by M-CSF or LPS is regulated by a CREB/AP-1 box." The "CRE/AP-1 box (TGACGTCT), which has been reported to be involved in the regulation of several genes , was critical." "When we mutated either the CRE or the AP-1 box, M-CSF- or LPS- dependent inducibility was lost . Surprisingly, although the kinetics of inductions differed, the same region controlled M-CSF- and LPS-stimulated MKP-1 expression." "The DNA fragment spanned the promoter region from -193 to -169 bp containing the CRE/AP-1 box." "AP-1 is not a single protein but a series of dimeric basic region-leucine zipper proteins that belong to the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1 and Fra2), and ATF (ATF2, LRF1/ATF3, B-ATF, JDP1, JDP2) subfamilies, which recognize either 12-otetradecanoylphorbol-13-acetate response elements (5'-TGAG/CTCA-3') or cAMP response elements (CRE, 5'-TGACGTCA-3') ." GeneID: 2353 FOS Fos proto-oncogene, AP-1 transcription factor subunit. Also known as p55; AP-1; C-FOS. "The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death." GeneID: 5179 PENK proenkephalin. Also known as PE; PENK-A. "This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the pentapeptide opioids Met-enkephalin and Leu-enkephalin, which are stored in synaptic vesicles, then released into the synapse where they bind to mu- and delta-opioid receptors to modulate the perception of pain. Other non-opioid cleavage products may function in distinct biological activities." Two forms of enkephalin have been found, one containing leucine, and the other containing methionine, both are products of the proenkephalin gene. The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene. During a stress response, several Met-enkephalin analogs had increased activity in the hippocampus, while Leu-enkephalin analogs as well as somatostatins were downregulated during stress; hence, stressors impact neuropeptides, and their action is localized to a specific brain region. GeneID: 5187 PER1 period circadian regulator 1. Also known as PER; hPER; RIGUI. "This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described." GeneID: 6750 SST somatostatin. Also known as SMST. "The hormone somatostatin has active 14 aa and 28 aa forms that are produced by alternate cleavage of the single preproprotein encoded by this gene. Somatostatin is expressed throughout the body and inhibits the release of numerous secondary hormones by binding to high-affinity G-protein-coupled somatostatin receptors. This hormone is an important regulator of the endocrine system through its interactions with pituitary growth hormone, thyroid stimulating hormone, and most hormones of the gastrointestinal tract. Somatostatin also affects rates of neurotransmission in the central nervous system and proliferation of both normal and tumorigenic cells." GeneID: 7054 TH tyrosine hydroxylase. Also known as TYH; DYT14; DYT5b. "The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene." GeneID: 7425 VGF VGF nerve growth factor inducible. Also known as SCG7; SgVII. "This gene is specifically expressed in a subpopulation of neuroendocrine cells, and is upregulated by nerve growth factor. The structural organization of this gene is similar to that of the rat gene, and both the translated and the untranslated regions show a high degree of sequence similarity to the rat gene. The encoded secretory protein also shares similarities with the secretogranin/chromogranin family, however, its exact function is not known." GeneID: 8864 PER2 period circadian regulator 2. Also known as FASPS; FASPS1. "This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers and have been linked to sleep disorders."	CRE boxes Editor-In-Chief: Henry A. Hoff CREB (cAMP response element-binding protein)[1] is a cellular transcription factor that binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes.[2] CREB was first described in 1987 as a cyclic adenosine monophosphate (cAMP)-responsive transcription factor regulating the somatostatin gene.[3] Genes whose transcription is regulated by CREB include: c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (such as somatostatin, enkephalin, VGF, corticotropin-releasing hormone),[2] and genes involved in the mammalian circadian clock (PER1, PER2).[4] CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory.[5] CREB downregulation is implicated in the pathology of Alzheimer's disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer's disease.[6] # Consensus sequence "Each species' promoter contains a cAMP/response element (CRE)1 consensus sequence ([7]) upstream of a TATA box. Two other members of this family of proteins, chromogranin B and secretogranin II (also known as chromogranin C), contain similar CRE and TATA homologies in their proximal gene promoters (8, 9)."[8] "Within the cAMP-responsive element of the somatostatin gene, we observed an 8-base palindrome, 5'-TGACGTCA-3', which is highly conserved in many other genes whose expression is regulated by cAMP."[7] # cAMP response element The cAMP response element (CRE) is the response element for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. CRE sites are typically found upstream of genes, within the promoter or enhancer regions.[9] There are approximately 750,000 palindromic and half-site CREs in the human genome. However, the majority of these sites remain unbound due to cytosine methylation.[10] # Samplings of the A1BG promoters For the Basic programs (starting with SuccessablesCRE.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), including extension of nts from 958 to 4445, the programs are, are looking for, and found: - negative strand in the negative direction (from ZSCAN22 to A1BG) is SuccessablesCRE--.bas, looking for 3'-TGACGTCA-5', 1, 3'-TGACGTCA-5', 4317, - negative strand in the positive direction (from ZNF497 to A1BG) is SuccessablesCRE-+.bas, looking for 3'-TGACGTCA-5', 0, - positive strand in the negative direction is SuccessablesCRE+-.bas, looking for 3'-TGACGTCA-5', 0, - positive strand in the positive direction is SuccessablesCRE++.bas, looking for 3'-TGACGTCA-5', 0, - complement, negative strand, negative direction is SuccessablesCREc--.bas, looking for 3'-ACTGCAGT-5', 0, - complement, negative strand, positive direction is SuccessablesCREc-+.bas, looking for 3'-ACTGCAGT-5', 0, - complement, positive strand, negative direction is SuccessablesCREc+-.bas, looking for 3'-ACTGCAGT-5', 1, 3'-ACTGCAGT-5', 4317, - complement, positive strand, positive direction is SuccessablesCREc++.bas, looking for 3'-ACTGCAGT-5', 0, - inverse complement, negative strand, negative direction is SuccessablesCREci--.bas, looking for 3'-TGACGTCA-5', 1, 3'-TGACGTCA-5', 4317, - inverse complement, negative strand, positive direction is SuccessablesCREci-+.bas, looking for 3'-TGACGTCA-5', 0, - inverse complement, positive strand, negative direction is SuccessablesCREci+-.bas, looking for 3'-TGACGTCA-5', 0, - inverse complement, positive strand, positive direction is SuccessablesCREci++.bas, looking for 3'-TGACGTCA-5', 0, - inverse, negative strand, negative direction, is SuccessablesCREi--.bas, looking for 3'-ACTGCAGT-5', 0, - inverse, negative strand, positive direction, is SuccessablesCREi-+.bas, looking for 3'-ACTGCAGT-5', 0, - inverse, positive strand, negative direction, is SuccessablesCREi+-.bas, looking for 3'-ACTGCAGT-5', 1, 3'-ACTGCAGT-5', 4317, - inverse, positive strand, positive direction, is SuccessablesCREi++.bas, looking for 3'-ACTGCAGT-5', 0. # Transcribed CRE boxes GeneID: 627 BDNF brain derived neurotrophic factor. Also known as ANON2; BULN2. "This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders."[11] GeneID: 1113 CHGA chromogranin A. Also known as CGA. "The protein encoded by this gene is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. It is found in secretory vesicles of neurons and endocrine cells. This gene product is a precursor to three biologically active peptides; vasostatin, pancreastatin, and parastatin. These peptides act as autocrine or paracrine negative modulators of the neuroendocrine system. Two other peptides, catestatin and chromofungin, have antimicrobial activity and antifungal activity, respectively. Two transcript variants encoding different isoforms have been found for this gene."[12] Secretory "stimulation of pheochromocytoma cells also activates the biosynthesis of the major secreted protein (chromogranin A), that the activation is transcriptional, and that a small proximal domain, including the CRE box, is, at least in part, both necessary and sufficient to account for the positive response to nicotine."[13] "A CRE box containing somatostatin promoter (-71 bp to +55 bp)/luciferase reporter plasmid was obtained from Marc Montminy, Salk Institute, La Jolla, CA. Its CRE box (TGACGTCA) was at -41 to -48 bp."[13] "Since the proximal positive response region [...] contains a CRE homology ((-71 bp)-TGACGTAA-(-64 bp)), we tested the effect of a CRE box point-gap mutation (TGA-GTAA) in a transfected 77-bp chromogranin A promoter/luciferase reporter construct [...]. The nicotinic induction ratio (nicotine stimulation/mock stimulation) fell from 2.58-fold in the wild-type promoter down to 1.64-fold (i.e. a 60% fall, p < 0.05) in the promoter with the CRE box point-gap mutation."[13] "We then tested whether a CRE box alone could transfer nicotinic responsiveness to a heterologous (TK) promoter (in pTK-LUC). The chromogranin A CRE (TGACGTAA) insert conferred 3.97-fold nicotinic induction [...], while a consensus CRE (TGACGTCA) was induced 4.94-fold by nicotine; each of these nicotinic responses was significantly (p < 0.05) greater than that of the original TK promoter vector [...]. The nicotinic induction was blunted (down to 1.31-fold) by point-gap mutation of the CRE box (TGA-GTAA). Even a CRE box (TGACGTCA) in the transfected promoter of a gene (somatostatin) not ordinarily expressed in chromaffin cells responded 2.03-fold (p < 0.05) to nicotine (from 134 ± 10.1 to 272 ± 19.6 luciferase light units/mg protein; n = 4 transfected wells/condition)."[13] "In electrophoretic gel mobility shift assays, we tested the effect of PC12 nicotine exposure (at a dose (10-3 M) and time (16 h) which stimulated the transfected promoter [...] on nuclear protein binding to four promoter regions: three that responded positively to nicotine during transfection (-432 to -312, -147 to -77, and -71 to -64 bp (the CRE box)), and one that seemed to respond negatively (-181 to -147 bp). None of these regions showed any significant change in band retardation pattern after nicotine [...]."[13] "Because CREB-bound CRE boxes are only transcriptionally transactivated when CREB itself has been activated by phosphorylation at serine 133 (33), we undertook antibody supershift assays [...], using not only an antibody directed against CREB (epitope: the CREB kinase-inducible domain), but also an antibody which specifically recognized CREB only in its activated, phosphorylated form (pS133-CREB). Cell exposure to nicotine did not alter the anti-CREB supershift by PC12 nuclear proteins, but did result in a qualitatively new anti-pS133-CREB supershift band. Competition experiments with a 100-fold molar excess of unlabeled CRE [...] indicated that both the anti-CREB and the anti-pS133-CREB supershifts represented CRE-binding complexes."[13] "The CRE box is at promoter position (-71 bp)TGACGTAA(-64 bp)."[13] "Each species' promoter contains a cAMP/response element (CRE)1 consensus sequence ([7]) upstream of a TATA box. Two other members of this family of proteins, chromogranin B and secretogranin II (also known as chromogranin C), contain similar CRE and TATA homologies in their proximal gene promoters (8, 9)."[8] "1. Abbreviations used: CMV, cytomegalovirus; CRE, cAMP responsive element; CREB, CRE-binding protein; CREM, CRE modulator protein; DBH, dopamine ,/-hydroxylase; LUC, luciferase; TK, thymidine kinase."[8] "Within the cAMP-responsive element of the somatostatin gene, we observed an 8-base palindrome, 5'-TGACGTCA-3', which is highly conserved in many other genes whose expression is regulated by cAMP."[7] GeneID: 1114 CHGB chromogranin B. Also known as SCG1. "This gene encodes a tyrosine-sulfated secretory protein abundant in peptidergic endocrine cells and neurons. This protein may serve as a precursor for regulatory peptides."[14] The "isolated mouse chromogranin B promoter [specifically] the proximal chromogranin B promoter (from −216 to −91 bp); [...] contains an E box (at [−206 bp]CACCTG[−201 bp]), four G/C-rich regions (at[− 196 bp]CCCCGC[−191 bp], [−134 bp]CCGCCCGC[−127 bp],[− 125 bp]GGCGCCGCC[−117 bp], and [−115 bp]CGGGGC[−110 bp]), and a cAMP response element (CRE; at [−102 bp]TGACGTCA[−95 bp]). A 60-bp core promoter region, defined by an internal deletion from −134 to −74 bp upstream of the cap site and spanning the CRE and three G/C-rich regions, directed tissue-specific expression of the gene. The CRE motif directed cell type-specific expression of the chromogranin B gene in neurons, whereas three of the G/C-rich regions played a crucial role in neuroendocrine cells. Both the endogenous chromogranin B gene and the transfected chromogranin B promoter were induced by preganglionic secretory stimuli (pituitary adenylyl cyclase-activating polypeptide, vasoactive intestinal peptide, or a nicotinic cholinergic agonist), establishing stimulus-transcription coupling for this promoter. The adenylyl cyclase activator forskolin, nerve growth factor, and retinoic acid also activated the chromogranin B gene. Secretagogue-inducible expression of chromogranin B also mapped onto the proximal promoter; inducible expression was entirely lost upon internal deletion of the 60-bp core (from −134 to −74 bp). [...] CRE and G/C-rich domains are crucial determinants of both cell type-specific and secretagogue-inducible expression of the chromogranin B gene."[15] "Sequence analysis of 2908 bp of the 5′-flanking region of the mouse chromogranin B gene revealed several consensus matches for cis-acting transcriptional control elements [...] reported as base pairs upstream of the cap site (+1): 1) the TATA box at [−33 bp]TTCATAA[−27 bp]; 2) a cAMP response element (CRE) (24) at [−102 bp]TGACGTCA[−95 bp]; 3) eight G/C-rich elements of 6 consecutive bp or more (potential binding sites for such factors as Sp1, Ap2, or Egr1) at −8/−2 bp, −45/−39 bp, −62/−53 bp, −83/−64 bp, −115/−110 bp, −125/−117 bp, −134/−127 bp, and− 196/−191 bp [one of these G/C-rich sites contains a perfect (9/9 bp) consensus match for an Egr1 recognition site: −79/−71 bp (25); another G/C-rich site overlaps a perfect (10/10 bp) consensus match (GGGRNNYYCC; IUPAC nomenclature) for a nuclear factor-κB site: [−83 bp]GGGGCGCCCC[−74 bp] (25); several of these G/C-rich sites overlap partial matches for Ap2 motifs (e.g. GSSWGSCC; IUPAC nomenclature) (25)]; and 4) an E-box (CANNTG; IUPAC nomenclature) at [−206 bp]CACCTG[−201 bp] (25)."[15] "Mouse chromogranin B promoter sequence. Nucleotides are numbered from the transcription initiation site (+1) of the gene. Note the positions of the TATA box at [−33 bp]TTCATAA[−27 bp], the CRE at [−102 bp]TGACGTCA[−95 bp], and eight G/C-rich elements of 6 or more consecutive bp (potential binding sites for such factors as Sp1, Ap2, or Egr1) at [−8 bp]CCGCGCC[−2 bp], [−45 bp]CCCCGCC[−39 bp], [−62 bp]CGCCCCCGGG[−53 bp],[−83 bp]GGGGCGCCCCCGCCCGCCGC[−64 bp], [−115bp]CGGGGC[−110 bp], [−125 bp]GGCGCCGCC[−117 bp], [−134]CCGCCCGC[−127 bp], and [−196 bp]CCCCGC[−191 bp]. One of these G/C-rich sites is a perfect (9/9 bp) consensus match for an Egr1 recognition site: [−79 bp]CGCCCCCGC[−71 bp]. One of these G/C-rich sites overlaps a perfect (10/10 bp) consensus match (GGGRNNYYCC; IUPAC nomenclature) for a nuclear factor-κB site: [−83 bp]GGGGCGCCCC[−74 bp]. Several of these G/C-rich sites overlap partial matches for Ap2 motifs (e.g. GSSWGSCC; IUPAC nomenclature). There is an E box (CANNTG; IUPAC nomenclature) at [−206 bp]CACCTG[−201 bp]."[15] GeneID: 1392 CRH corticotropin releasing hormone. Also known as CRF; CRH1. "This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition."[16] GeneID: 1843 DUSP1 dual specificity phosphatase 1. Also known as HVH1; MKP1; CL100; MKP-1; PTPN10. "The protein encoded by this gene is a phosphatase with dual specificity for tyrosine and threonine. The encoded protein can dephosphorylate MAP kinase MAPK1/ERK2, which results in its involvement in several cellular processes. This protein appears to play an important role in the human cellular response to environmental stress as well as in the negative regulation of cellular proliferation. Finally, the encoded protein can make some solid tumors resistant to both chemotherapy and radiotherapy, making it a target for cancer therapy."[17] Although "macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between -380 and -180bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS- or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box."[18] The "same region, which contains a CREB/AP-1 box, is required for M-CSF- or LPS-dependent stimulation, although this stimulation is induced at different times after stimulation. [...] CREB and c-Jun are responsible for MKP-1 induction. The induction of c-Jun is correlated with the kinetics of MKP-1 induction by M-CSF or LPS."[18] "MKP-1 expression induced by M-CSF or LPS is regulated by a CREB/AP-1 box."[18] The "CRE/AP-1 box (TGACGTCT), which has been reported to be involved in the regulation of several genes [43], was critical."[18] "When we mutated either the CRE or the AP-1 box, M-CSF- or LPS- dependent inducibility was lost [...]. Surprisingly, although the kinetics of inductions differed, the same region controlled M-CSF- and LPS-stimulated MKP-1 expression."[18] "The DNA fragment spanned the promoter region from -193 to -169 bp containing the CRE/AP-1 box."[18] "AP-1 is not a single protein but a series of dimeric basic region-leucine zipper proteins that belong to the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1 and Fra2), and ATF (ATF2, LRF1/ATF3, B-ATF, JDP1, JDP2) subfamilies, which recognize either 12-otetradecanoylphorbol-13-acetate response elements (5'-TGAG/CTCA-3') or cAMP response elements (CRE, 5'-TGACGTCA-3') [44]."[18] GeneID: 2353 FOS Fos proto-oncogene, AP-1 transcription factor subunit. Also known as p55; AP-1; C-FOS. "The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death."[19] GeneID: 5179 PENK proenkephalin. Also known as PE; PENK-A. "This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the pentapeptide opioids Met-enkephalin and Leu-enkephalin, which are stored in synaptic vesicles, then released into the synapse where they bind to mu- and delta-opioid receptors to modulate the perception of pain. Other non-opioid cleavage products may function in distinct biological activities."[20] Two forms of enkephalin have been found, one containing leucine, and the other containing methionine, both are products of the proenkephalin gene.[21] The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene.[22] During a stress response, several Met-enkephalin analogs had increased activity in the hippocampus, while Leu-enkephalin analogs as well as somatostatins were downregulated during stress; hence, stressors impact neuropeptides, and their action is localized to a specific brain region.[23] GeneID: 5187 PER1 period circadian regulator 1. Also known as PER; hPER; RIGUI. "This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described."[24] GeneID: 6750 SST somatostatin. Also known as SMST. "The hormone somatostatin has active 14 aa and 28 aa forms that are produced by alternate cleavage of the single preproprotein encoded by this gene. Somatostatin is expressed throughout the body and inhibits the release of numerous secondary hormones by binding to high-affinity G-protein-coupled somatostatin receptors. This hormone is an important regulator of the endocrine system through its interactions with pituitary growth hormone, thyroid stimulating hormone, and most hormones of the gastrointestinal tract. Somatostatin also affects rates of neurotransmission in the central nervous system and proliferation of both normal and tumorigenic cells."[25] GeneID: 7054 TH tyrosine hydroxylase. Also known as TYH; DYT14; DYT5b. "The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene."[26] GeneID: 7425 VGF VGF nerve growth factor inducible. Also known as SCG7; SgVII. "This gene is specifically expressed in a subpopulation of neuroendocrine cells, and is upregulated by nerve growth factor. The structural organization of this gene is similar to that of the rat gene, and both the translated and the untranslated regions show a high degree of sequence similarity to the rat gene. The encoded secretory protein also shares similarities with the secretogranin/chromogranin family, however, its exact function is not known."[27] GeneID: 8864 PER2 period circadian regulator 2. Also known as FASPS; FASPS1. "This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers and have been linked to sleep disorders."[28]	https://www.wikidoc.org/index.php/CRE_boxes
fca9a47768716e48fba9c6c6bb375dd6e3b159bc	wikidoc	CYP2C9*13	CYP2C913 Cytochrome P450 2C9 (CYP2C9), a member of the CYP2C enzyme subfamily, ranks amongst the most important drug metabolizing enzymes in humans. Human CYP2C9 has been shown to exhibit genetic polymorphism. In addition to the wild-type protein CYP2C91, at least 30 single nucleotide polymorphisms (SNPs) have been reported within the coding region of the CYP2C9 gene producing the variant allozymes. CYP2C913 is one of them. It involves a T-to-C transversion at nucleotide position 269 causing a mutation at codon 90, which results in a Leu->Pro substitution. Frequency analysis in 147 unrelated Chinese males indicated approximately 2% of the Chinese population carry the allele. CYP2C913 was found in Japanese and Korean, too. CYP2C913 allele was correlated with reduced plasma clearance of drugs that are substrates for CYP2C9. CYP2C913 was found by Si Dayong, Zhou Hui*, Zhang Yifan and Zhong Dafang- in 2004.	CYP2C913 Cytochrome P450 2C9 (CYP2C9), a member of the CYP2C enzyme subfamily, ranks amongst the most important drug metabolizing enzymes in humans. Human CYP2C9 has been shown to exhibit genetic polymorphism. In addition to the wild-type protein CYP2C91, at least 30 single nucleotide polymorphisms (SNPs) have been reported within the coding region of the CYP2C9 gene producing the variant allozymes. CYP2C913 is one of them. It involves a T-to-C transversion at nucleotide position 269 causing a mutation at codon 90, which results in a Leu->Pro substitution. Frequency analysis in 147 unrelated Chinese males indicated approximately 2% of the Chinese population carry the allele.[1][2] CYP2C913 was found in Japanese and Korean[3][4], too. CYP2C913 allele was correlated with reduced plasma clearance of drugs that are substrates for CYP2C9.[5][6][7] CYP2C913 was found by Si Dayong[6], Zhou Hui[7], Zhang Yifan and Zhong Dafang[8] in 2004.	https://www.wikidoc.org/index.php/CYP2C9*13
e3a1f1c325d4cdb5ab39d83797abd42cfa1ca773	wikidoc	Caecilian	Caecilian The caecilians (Template:Pron-en) are an order (Gymnophiona or Apoda) of amphibians that superficially resemble earthworms or snakes. They mostly live hidden in the ground, which makes them the least explored order of amphibians, and widely unknown. # Anatomy Caecilians completely lack limbs, making the smaller species resemble worms, while the larger species with lengths up to 1.5 m resemble snakes. The tail is short and the cloaca is near the end of the body. Their skin is smooth and usually dark-matte, but some species have colorful skins. Inside the skin are calcite scales, which suggests that they may be related to the fossil Stegocephalia. However the scales are now believed to be a secondary development, and not directly inherited from Stegocephalia. Owing to their underground life the eyes are small and covered by skin for protection, which has led to the misconception that they are blind. This is not strictly true, although their sight is limited to simple dark-light perception. All caecilians share two tentacles at their head, which are probably used for a second olfactory capability in addition to the normal sense of smell based in the nose. Except for one lungless species — Atretochoana eiselti, only known from two specimens collected in South America — all caecilians have lungs, but also use the skin or the mouth for oxygen absorption. Often the left lung is much smaller than the right one, an adaptation to body shape that is also found in snakes. # Distribution Caecilians are found in most of the tropical regions of South-East Asia, Africa, the Seychelles islands and South America, except the dry areas and high mountains. In South America their distribution extends well into the temperate zone in the north of Argentina. They can be seen as far south as Buenos Aires, when they are carried by the flood waters of the Parana river coming from farther north. No studies have been made in central Africa, but it is likely that caecilians are found in the tropical rainforests there. The northernmost distribution is of the species Ichthyophis sikkimensis of Northern India. In Africa caecilians are found from Guinea Bissau (Geotrypetes) to Northern Zambia (Scolecomorphus). In South-East Asia the Wallace-Line is not crossed and they are not found in Australia or the islands in between. Ichthyophis is also found in South China and North-Vietnam. # Reproduction Caecilians are the only order of amphibians which only use internal insemination. The male caecilians have a penis-like organ, the phallodeum, which is inserted into the cloaca of the female for 2 to 3 hours. About 25% of the species are oviparous (egg-laying); the eggs are guarded by the female. For some species the young caecilians are already metamorphosed when they hatch; others hatch as larvae. The larvae are not fully aquatic, but spend the daytime in the soil near the water. 75% of the species are viviparous, meaning that they give birth to already developed offspring. The fetus is fed inside the female with special cells of the oviduct, which are eaten by the fetus with special scraping teeth. The egg laying species Boulengerula taitanus feeds its young by developing a special outer layer of skin, high in fat and other nutrients, which the young peel off with similar teeth. This allows them to grow by up to ten times their own weight in a week. The skin is consumed every three days, the time it takes for a new layer to grow, and the young have only been observed to eat it at night. It was previously thought that the juveniles subsisted on a liquid secretion from their mother, but the BBC documentary 'Life In Cold Blood' filmed the bizarre feeding ritual for the first time to reveal the surprising truth. Some larvae, such as those of Typhlonectes, are born with enormous external gills which are shed almost immediately. Ichthyophis is oviparous and is also known to show maternal care. # Diet The diet of caecilians is not known well, though it seems it mostly consists of insects and invertebrates found in the habitat of the respective species. The stomach contents of 14 specimens of Afrocaecilia taitana consisted of mostly undefinable organic material and plantal remains. Where identifiable remains were most abundant, they were found to be termite heads. While it was suggested that the undefinable organic material shows that the caecilians eat detritus, others believe these are in fact the remains of earthworms. Caecilians in captivity can be easily fed with earthworms, and worms are also common in the habitat of many caecilian species. # Origin of the name The name caecilian derives from the Latin word caecus = blind, referring to the small or sometimes non-existing eyes. The name dates back to the taxonomic name of the first species described by Carolus Linnaeus, which he gave the name Caecilia tentaculata. The taxonomic name of the order derives from the Greek words γυμνος (gymnos, naked) and οφις (ophis, snake), as the caecilians were originally thought to be related to snakes. # Taxonomy Taxonomically the caecilians are divided into 6 families. The species numbers are approximate and many of these species are identified on the basis of only one specimen. It is likely that not all species have been described yet, and that some of the species described below as different may be combined into one species in future reclassifications. - Beaked Caecilians (Rhinatrematidae) - 2 genera, 9 species - Fish Caecilians (Ichthyophiidae) - 2 genera, 39 species - Indian Caecilians (Uraeotyphlidae) - 1 genus, 5 species - Tropical Caecilians (Scolecomorphidae) - 2 genera, 6 species - Aquatic Caecilians (Typhlonectidae) - 5 genera, 13 species - Common Caecilians (Caeciliidae) - 26 genera, 99 species # Recent discoveries A Swiss researcher, Daniel Hofer, has recently found that certain caecilians produce potent skin poisons from specialized poison glands. The poison prevents predation and the poison of the bright yellow caecilian of São Tomé Island (Schistometopum thomense) in West Africa kills other animals kept in the same tank within a few days. The chemical contents of caecilian poison have not been well studied. Werner Himstedt has shown that the skin glands of Ichthyophis protect the eggs from germs and fungi. It has also been shown that these poisons are very different from those from other amphibians such as the Poison dart frog. British nature expert David Attenborough found that the young can increase their weight up to ten times in one week, post birth. When on filming the nest the young had teeth. It was then discovered that the young did not just diet on secretion/ milk but that the mother was able to reproduce fatty skin every three days for the young to feast on. This was documented on his BBC programme Life in Cold Blood and is the only currently known instance of dermatotrophy, or deriving necessary nutrients from the consumption of skin.	Caecilian The caecilians (Template:Pron-en) are an order (Gymnophiona or Apoda) of amphibians that superficially resemble earthworms or snakes. They mostly live hidden in the ground, which makes them the least explored order of amphibians, and widely unknown. # Anatomy Caecilians completely lack limbs, making the smaller species resemble worms, while the larger species with lengths up to 1.5 m resemble snakes. The tail is short and the cloaca is near the end of the body. Their skin is smooth and usually dark-matte, but some species have colorful skins. Inside the skin are calcite scales, which suggests that they may be related to the fossil Stegocephalia. However the scales are now believed to be a secondary development, and not directly inherited from Stegocephalia. Owing to their underground life the eyes are small and covered by skin for protection, which has led to the misconception that they are blind. This is not strictly true, although their sight is limited to simple dark-light perception. All caecilians share two tentacles at their head, which are probably used for a second olfactory capability in addition to the normal sense of smell based in the nose. Except for one lungless species — Atretochoana eiselti, only known from two specimens collected in South America — all caecilians have lungs, but also use the skin or the mouth for oxygen absorption. Often the left lung is much smaller than the right one, an adaptation to body shape that is also found in snakes. # Distribution Caecilians are found in most of the tropical regions of South-East Asia, Africa, the Seychelles islands and South America, except the dry areas and high mountains. In South America their distribution extends well into the temperate zone in the north of Argentina. They can be seen as far south as Buenos Aires, when they are carried by the flood waters of the Parana river coming from farther north. No studies have been made in central Africa, but it is likely that caecilians are found in the tropical rainforests there. The northernmost distribution is of the species Ichthyophis sikkimensis of Northern India. In Africa caecilians are found from Guinea Bissau (Geotrypetes) to Northern Zambia (Scolecomorphus). In South-East Asia the Wallace-Line is not crossed and they are not found in Australia or the islands in between. Ichthyophis is also found in South China and North-Vietnam. # Reproduction Caecilians are the only order of amphibians which only use internal insemination. The male caecilians have a penis-like organ, the phallodeum, which is inserted into the cloaca of the female for 2 to 3 hours. About 25% of the species are oviparous (egg-laying); the eggs are guarded by the female. For some species the young caecilians are already metamorphosed when they hatch; others hatch as larvae. The larvae are not fully aquatic, but spend the daytime in the soil near the water. 75% of the species are viviparous, meaning that they give birth to already developed offspring. The fetus is fed inside the female with special cells of the oviduct, which are eaten by the fetus with special scraping teeth. The egg laying species Boulengerula taitanus feeds its young by developing a special outer layer of skin, high in fat and other nutrients, which the young peel off with similar teeth. This allows them to grow by up to ten times their own weight in a week. The skin is consumed every three days, the time it takes for a new layer to grow, and the young have only been observed to eat it at night. It was previously thought that the juveniles subsisted on a liquid secretion from their mother, but the BBC documentary 'Life In Cold Blood' filmed the bizarre feeding ritual for the first time to reveal the surprising truth.[1] [2][3] Some larvae, such as those of Typhlonectes, are born with enormous external gills which are shed almost immediately. Ichthyophis is oviparous and is also known to show maternal care. # Diet The diet of caecilians is not known well, though it seems it mostly consists of insects and invertebrates found in the habitat of the respective species. The stomach contents of 14 specimens of Afrocaecilia taitana consisted of mostly undefinable organic material and plantal remains. Where identifiable remains were most abundant, they were found to be termite heads. [4] While it was suggested that the undefinable organic material shows that the caecilians eat detritus, others believe these are in fact the remains of earthworms. Caecilians in captivity can be easily fed with earthworms, and worms are also common in the habitat of many caecilian species. # Origin of the name The name caecilian derives from the Latin word caecus = blind, referring to the small or sometimes non-existing eyes. The name dates back to the taxonomic name of the first species described by Carolus Linnaeus, which he gave the name Caecilia tentaculata. The taxonomic name of the order derives from the Greek words γυμνος (gymnos, naked) and οφις (ophis, snake), as the caecilians were originally thought to be related to snakes. # Taxonomy Taxonomically the caecilians are divided into 6 families. The species numbers are approximate and many of these species are identified on the basis of only one specimen. It is likely that not all species have been described yet, and that some of the species described below as different may be combined into one species in future reclassifications. - Beaked Caecilians (Rhinatrematidae) - 2 genera, 9 species - Fish Caecilians (Ichthyophiidae) - 2 genera, 39 species - Indian Caecilians (Uraeotyphlidae) - 1 genus, 5 species - Tropical Caecilians (Scolecomorphidae) - 2 genera, 6 species - Aquatic Caecilians (Typhlonectidae) - 5 genera, 13 species - Common Caecilians (Caeciliidae) - 26 genera, 99 species # Recent discoveries A Swiss researcher, Daniel Hofer, has recently found that certain caecilians produce potent skin poisons from specialized poison glands. The poison prevents predation and the poison of the bright yellow caecilian of São Tomé Island (Schistometopum thomense) in West Africa kills other animals kept in the same tank within a few days. The chemical contents of caecilian poison have not been well studied. Werner Himstedt has shown that the skin glands of Ichthyophis protect the eggs from germs and fungi. It has also been shown that these poisons are very different from those from other amphibians such as the Poison dart frog. British nature expert David Attenborough found that the young can increase their weight up to ten times in one week, post birth. When on filming the nest the young had teeth. It was then discovered that the young did not just diet on secretion/ milk but that the mother was able to reproduce fatty skin every three days for the young to feast on. This was documented on his BBC programme Life in Cold Blood and is the only currently known instance of dermatotrophy, or deriving necessary nutrients from the consumption of skin.	https://www.wikidoc.org/index.php/Caecilian
26005adaa0dedfd4f3c233dad00c846feb3dbf3f	wikidoc	Verapamil	Verapamil # 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 Verapamil is a calcium channel blocker that is FDA approved for the treatment of essential hypertension (tablet and capsule), rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, and temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation (injection). Common adverse reactions include edema, hypotension, constipation, dizziness, headache, pharyngitis, sinusitis, and influenza-like symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Essential Hypertension - Dosing information (tablet) - The dose of verapamil HCl extended-release should be individualized by titration and the drug should be administered with food. - Initiate dosage: 180 mg in the morning. - Lower initial dosage: 120 mg PO qd may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). - Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. - The antihypertensive effects of verapamil HCl extended-release are evident within the first week of therapy. - If adequate response is not obtained with 180 mg of verapamil HCl extended-release, the dose may be titrated upward in the following manner: - 240 mg each morning, - 180 mg each morning plus 180 mg each evening; or 240 mg each morning plus 120 mg each evening, - 240 mg every twelve hours. - When switching from immediate release verapamil to extended-release verapamil, the total daily dose in milligrams may remain the same. - Dosing information (capsule) - Administer Verapamil Hydrochloride Extended-release Capsules (PM) once daily at bedtime. - Usual dosage: 200 mg PO qd at bedtime - In rare instances, initial doses of 100 mg PO qd may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. - Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verapamil Hydrochloride Extended-release Capsules (PM) are evident within the first week of therapy. - If an adequate response is not obtained with 200 mg of Verapamil Hydrochloride Extended-release Capsules (PM), the dose may be titrated upward in the following manner: - a) 300 mg each evening - b) 400 mg each evening (2 × 200 mg) - When Verapamil Hydrochloride Extended-release Capsules (PM) is administered at bedtime, office evaluation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose of Verapamil Hydrochloride Extended-release Capsules (PM), would be just prior to bedtime. - THE CONTENTS OF THE Verapamil Hydrochloride Extended-release Capsules (PM) CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verapamil Hydrochloride Extended-release Capsules (PM) ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE. - Sprinkling the Capsule Contents on Food - Verapamil Hydrochloride Extended-release Capsules (PM) capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and it should be soft enough to be swallowed without chewing. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verapamil Hydrochloride Extended-release Capsules (PM) capsule is not recommended. ### paroxysmal supraventricular tachycardias - Indication (injection only) - Rapid conversion to sinus rhythm of Paroxysmal supraventricular tachycardia, including those associated with accessory bypass tracts (Wolff-Parkinson-White and Lown-Ganong- Levine syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride administration. ### atrial flutter or atrial fibrillation - Indication (injection only) - Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White (W-P-W) and Lown-Ganong-Levine (L-G-L) syndromes). - In controlled studies in the United States, about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil hydrochloride. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a faster ventricular rate respond with a decrease in ventricular rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after verapamil hydrochloride and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. Slowing of the ventricular rate in patients with atrial fibrillation/flutter lasts 30 to 60 minutes after a single injection. - Because a small fraction (<1%) of patients treated with verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation, and an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole − , the initial use of verapamil hydrochloride injection should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including D.C.-cardioversion capability . As familiarity with the patient’s response is gained, use in an office setting may be acceptable. - Cardioversion has been used safely and effectively after verapamil hydrochloride injection. - Dosing information (injection) - Initial dosage: 5 to 10 mg (0.075 to 0.15 mg/kg body weight) given as an intravenous bolus over at least 2 minutes. - Repeat dosage: 10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - Older patients − The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Myocardial Infarction - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Not applicable - Dosing Information - Not applicable ### Non–Guideline-Supported Use ### Arteriosclerotic vascular disease - Dosing Information - 120 mg PO tid - 240 mg PO bid ### Amaurosis fugax - Dosing information - 120 mg/day , ### Cluster headache - Dosing information - 120 to 1200 mg/day - 120 mg bid - 120 mg/day - 120 mg tid ### Muscle Cramp - Dosing information - 120 mg PO at bedtime - 60 mg tid - 80 mg tid - 240 mg/day ### Electroconvulsive therapy - Dosing information - 0.1 mg/kg ### Hypertrophic cardiomyopathy - Dosing information - 320-480 mg/day - 240-360 mg/day ### Keloid scar - Dosing information - Intralesional injection 0.5 to 2 mL ### Kidney disease - Dosing information - 180 mg/day ### Prophylaxis of Migraine - Dosing information - 80 mg qid ### Peyronie's disease - Dosing information - 5 mg ### Pulmonary hypertension - Dosing information - 17.5 mg over 25 minutes - 5 mg IV ### Spasm of cerebral arteries - Dosing information - 20 mg # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing information - Initial dose: - 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) should be administered as an intravenous bolus over at least 2 minutes under continuous ECG monitoring. - 1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) should be administered as an intravenous bolus over at least 2 minutes. Do not exceed 5 mg. - Repeat dose: - 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) 30 minutes after the first dose if the initial response is not adequate (under continuous ECG monitoring). An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - 1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a single dose. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. - For stability reasons this product is not recommended for dilution with Sodium Lactate Injection, USP in polyvinyl chloride bags. Verapamil is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions. Admixing verapamil hydrochloride injection with albumin, amphotericin B, hydralazine hydrochloride and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride injection will precipitate in any solution with a pH above 6.0. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Verapamil in pediatric patients. ### Non–Guideline-Supported Use ### Cluster Headache - Dosing information - 4.3 to 5.5 mg/kg/day ### Hypertrophic cardiomyopathy - Dosing information - 3-6 mg/kg/day - 4 mg/kg/day # Contraindications ## Contradiction to Verapamil tablet and capsule, injection 1-Severe left ventricular dysfunction (see WARNINGS) 2-Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock 3-Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4-degree AV block or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 5-Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndrome) 6-Patients with known hypersensitivity to verapamil hydrochloride ## Contradiction to Verapamil injection only 7.Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy). 8.Ventricular tachycardia: Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. # Warnings ## Heart failure - Verapamil has a negative inotropic effect, which in most patients is compensated by its afterloadreduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure orpulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. ## Hypotension - Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension. ## Elevated liver enzymes - Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even with continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. ## Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine) - Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). - Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral Verapamil. ## Atrioventricular block - The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-degree AV blockor third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending on the clinical situation. ## Patients with hypertrophic cardiomyopathy (IHSS) - In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Verapamil Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Verapamil Postmarketing Experience in the drug label. # Drug Interactions ### Cytochrome inducers/inhibitors - In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil. ### HMG-CoA reductase inhibitors - The use of statins that are CYP3A4substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. - Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. ### Aspirin - In a few reported cases, co-administration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone. ### Grapefruit juice - Grapefruit juice may increase plasma levels of verapamil. ### Alcohol - Verapamil may increase blood alcohol concentrations and prolong its effects. ### Beta-blockers - Controlled studies in small numbers of patients suggest that the concomitant use of Verapamil and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility. - In one study involving 15 patients treated with high doses of propranolol (median dose: 480 mg/day; range: 160 to 1,280 mg/day) for severe angina, with preserved left ventricular function (ejection fraction greater than 35%), the hemodynamic effects of additional therapy with verapamil HCl were assessed using invasive methods. The addition of verapamil to high-dose beta-blockers induced modest negative inotropic and chronotropic effects that were not severe enough to limit short-term (48 hours) combination therapy in this study. These modest cardiodepressant effects persisted for greater than 6 but less than 30 hours after abrupt withdrawal of beta-blockers and were closely related to plasma levels of propranolol. The primary verapamil/beta-blocker interaction in this study appeared to be hemodynamic rather than electrophysiologic. - In other studies, verapamil did not generally induce significant negative inotropic, chronotropic, or dromotropic effects in patients with preserved left ventricular function receiving low or moderate doses of propranolol (less than or equal to 320 mg/day); in some patients, however, combined therapy did produce such effects. Therefore, if combined therapy is used, close surveillance of clinical status should be carried out. Combined therapy should usually be avoided in patients with atrioventricular conduction abnormalities and those with depressed left ventricular function. - Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. - A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. ### Digitalis - Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of Verapamil use, the patient should be reassessed to avoid under-digitalization. ### Antihypertensive agents - Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. ### Antiarrhythmic agents Disopyramide - Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide - A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine - In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. - The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. ### Other agents Nitrates - Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Cimetidine - The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium - Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. Carbamazepine - Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin - Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital - Phenobarbital therapy may increase verapamil clearance. Cyclosporine - Verapamil therapy may increase serum levels of cyclosporine. Theophylline - Verapamil may inhibit the clearance and increase the plasma levels of theophylline. Inhalation anesthetics - Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular blocking agents - Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Telithromycin - Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine - Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Verapamil in women who are pregnant. ### Labor and Delivery - It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. ### Nursing Mothers - Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Verapamil in geriatric settings. ### Gender There is no FDA guidance on the use of Verapamil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Verapamil with respect to specific racial populations. ### Renal Impairment - About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. ### Hepatic Impairment - Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects should be carried out. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Verapamil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Verapamil in patients who are immunocompromised. ### Use in patients with attenuated (decreased) neuromuscular transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. # Administration and Monitoring ### Administration - Oral, intravenous ### Monitoring FDA Package Insert for Verapamil contains no information regarding drug monitoring. # IV Compatibility FDA Package Insert for Verapamil contains no information regarding IV compatibility. # Overdosage - Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Verapamil SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. - Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. # Pharmacology ## Mechanism of Action ### Angina - The precise mechanism of action of Verapamil as an antianginal agent remains to be fully determined, but includes the following two mechanisms: Relaxation and prevention of coronary artery spasm: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of Verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate–pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Reduction of oxygen utilization: Verapamil regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil in chronic stable effort angina. ### Arrhythmia - Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation. - Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, Verapamil may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects. Verapamil decreases the frequency of episodes of paroxysmal supraventricular tachycardia. - Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but in depressed atrial fibers it decreases amplitude, velocity of depolarization, and conduction velocity. Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. - Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. ### Essential hypertension - Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise, Verapamil does not alter systolic cardiac function in patients with normal ventricular function. - Verapamil does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of Verapamil. ## Structure - Verapamil hydrochloride is a calcium antagonist or slow-channel inhibitor. Verapamil Hydrochloride Injection, USP is a sterile, nonpyrogenic solution containing verapamil hydrochloride 2.5 mg/mL and sodium chloride 8.5 mg/mL in water for injection. The solution contains no bacteriostat or antimicrobial agent and is intended for single-dose intravenous administration. May contain hydrochloric acid for pH adjustment; pH is 4.9 (4.0 to 6.5). The chemical name of Verapamil Hydrochloride, USP is benzeneacetonitrile, α- propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride. Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odorless and has a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether. It has the following structural formula: - Verapamil hydrochloride is not chemically related to other antiarrhythmic drugs. ## Pharmacodynamics - Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with Verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of Verapamil is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (eg, pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur. ## Pharmacokinetics - More than 90% of the orally administered dose of Verapamil is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil HCl every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/ml, with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. In early dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single-dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In healthy men, orally administered Verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. - Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours; the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. ## Nonclinical Toxicology ## Carcinogenesis, mutagenesis, impairment of fertility - An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day). - Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation. - Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. ## Animal pharmacology and/or animal toxicology - In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater, and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not in the rat. Development of cataracts due to verapamil has not been reported in man. # Clinical Studies FDA Package Insert for Verapamil contains no information regarding clinical studies. # How Supplied ## Verapamil tablet - Verapamil Hydrochloride Extended-Release Tablets, USP 120 mg are supplied as ivory, round, unscored, film-coated tablets debossed with “120” on one side - on the other side, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets. - Verapamil Hydrochloride Extended-Release Tablets USP, 180 mg are supplied as light orange, capsule-shaped, scored, film-coated tablets debossed with “7301” on one side, - on the other side, packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100 tablets. - Verapamil Hydrochloride Extended-Release Tablets USP, 240 mg are supplied as ivory, capsule-shaped, scored, film-coated tablets debossed with “7300” on one side, - on the other side, packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100 tablets. ## Verapamil capsule - Verapamil Hydrochloride Extended-release Capsules (PM); pellet filled capsules are supplied in three dosage strengths: ## Verapamil injection - Verapamil Hydrochloride Injection, USP 2.5 mg/mL is supplied in single-dose containers as follows: ## Storage ## Verapamil tablet - Store between 20˚ to 25˚ C (68˚ to 77˚ F) . ## Verapamil capsule - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. - Dispense in tight, light-resistant container as defined in USP. ## Verapamil injection - Store at 20 to 25°C (68 to 77°F). - Protect from light by retaining in package until ready to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Verapamil Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Verapamil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Verapamil - Verapamil SR - Covera-HS - Isoptin SR - Verelan - Verelan PM # Look-Alike Drug Names FDA Package Insert for Verapamil contains no information regarding look-alike names. # Drug Shortage Status # Price	Verapamil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Verapamil is a calcium channel blocker that is FDA approved for the treatment of essential hypertension (tablet and capsule), rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, and temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation (injection). Common adverse reactions include edema, hypotension, constipation, dizziness, headache, pharyngitis, sinusitis, and influenza-like symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Essential Hypertension - Dosing information (tablet) - The dose of verapamil HCl extended-release should be individualized by titration and the drug should be administered with food. - Initiate dosage: 180 mg in the morning. - Lower initial dosage: 120 mg PO qd may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). - Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. - The antihypertensive effects of verapamil HCl extended-release are evident within the first week of therapy. - If adequate response is not obtained with 180 mg of verapamil HCl extended-release, the dose may be titrated upward in the following manner: - 240 mg each morning, - 180 mg each morning plus 180 mg each evening; or 240 mg each morning plus 120 mg each evening, - 240 mg every twelve hours. - When switching from immediate release verapamil to extended-release verapamil, the total daily dose in milligrams may remain the same. - Dosing information (capsule) - Administer Verapamil Hydrochloride Extended-release Capsules (PM) once daily at bedtime. - Usual dosage: 200 mg PO qd at bedtime - In rare instances, initial doses of 100 mg PO qd may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. - Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verapamil Hydrochloride Extended-release Capsules (PM) are evident within the first week of therapy. - If an adequate response is not obtained with 200 mg of Verapamil Hydrochloride Extended-release Capsules (PM), the dose may be titrated upward in the following manner: - a) 300 mg each evening - b) 400 mg each evening (2 × 200 mg) - When Verapamil Hydrochloride Extended-release Capsules (PM) is administered at bedtime, office evaluation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose of Verapamil Hydrochloride Extended-release Capsules (PM), would be just prior to bedtime. - THE CONTENTS OF THE Verapamil Hydrochloride Extended-release Capsules (PM) CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verapamil Hydrochloride Extended-release Capsules (PM) ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE. - Sprinkling the Capsule Contents on Food - Verapamil Hydrochloride Extended-release Capsules (PM) capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and it should be soft enough to be swallowed without chewing. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verapamil Hydrochloride Extended-release Capsules (PM) capsule is not recommended. ### paroxysmal supraventricular tachycardias - Indication (injection only) - Rapid conversion to sinus rhythm of Paroxysmal supraventricular tachycardia, including those associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong- Levine [L-G-L] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride administration. ### atrial flutter or atrial fibrillation - Indication (injection only) - Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White (W-P-W) and Lown-Ganong-Levine (L-G-L) syndromes). - In controlled studies in the United States, about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil hydrochloride. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a faster ventricular rate respond with a decrease in ventricular rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after verapamil hydrochloride and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. Slowing of the ventricular rate in patients with atrial fibrillation/flutter lasts 30 to 60 minutes after a single injection. - Because a small fraction (<1%) of patients treated with verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation, and an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole − , the initial use of verapamil hydrochloride injection should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including D.C.-cardioversion capability . As familiarity with the patient’s response is gained, use in an office setting may be acceptable. - Cardioversion has been used safely and effectively after verapamil hydrochloride injection. - Dosing information (injection) - Initial dosage: 5 to 10 mg (0.075 to 0.15 mg/kg body weight) given as an intravenous bolus over at least 2 minutes. - Repeat dosage: 10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - Older patients − The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Myocardial Infarction - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Not applicable - Dosing Information - Not applicable ### Non–Guideline-Supported Use ### Arteriosclerotic vascular disease - Dosing Information - 120 mg PO tid [1] - 240 mg PO bid [2] ### Amaurosis fugax - Dosing information - 120 mg/day [3], [4] ### Cluster headache - Dosing information - 120 to 1200 mg/day [5] - 120 mg bid [6] - 120 mg/day [7] - 120 mg tid [8] ### Muscle Cramp - Dosing information - 120 mg PO at bedtime [9] - 60 mg tid [10] - 80 mg tid [10] - 240 mg/day [11] ### Electroconvulsive therapy - Dosing information - 0.1 mg/kg[12] ### Hypertrophic cardiomyopathy - Dosing information - 320-480 mg/day[13] - 240-360 mg/day[14] ### Keloid scar - Dosing information - Intralesional injection 0.5 to 2 mL [15] ### Kidney disease - Dosing information - 180 mg/day [16] ### Prophylaxis of Migraine - Dosing information - 80 mg qid [17] ### Peyronie's disease - Dosing information - 5 mg [18] ### Pulmonary hypertension - Dosing information - 17.5 mg over 25 minutes [19] - 5 mg IV [20] ### Spasm of cerebral arteries - Dosing information - 20 mg [21] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing information - Initial dose: - 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) should be administered as an intravenous bolus over at least 2 minutes under continuous ECG monitoring. - 1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) should be administered as an intravenous bolus over at least 2 minutes. Do not exceed 5 mg. - Repeat dose: - 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) 30 minutes after the first dose if the initial response is not adequate (under continuous ECG monitoring). An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - 1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a single dose. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. - Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. - For stability reasons this product is not recommended for dilution with Sodium Lactate Injection, USP in polyvinyl chloride bags. Verapamil is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions. Admixing verapamil hydrochloride injection with albumin, amphotericin B, hydralazine hydrochloride and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride injection will precipitate in any solution with a pH above 6.0. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Verapamil in pediatric patients. ### Non–Guideline-Supported Use ### Cluster Headache - Dosing information - 4.3 to 5.5 mg/kg/day [22] ### Hypertrophic cardiomyopathy - Dosing information - 3-6 mg/kg/day [23] - 4 mg/kg/day [24] # Contraindications ## Contradiction to Verapamil tablet and capsule, injection 1-Severe left ventricular dysfunction (see WARNINGS) 2-Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock 3-Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4-degree AV block or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 5-Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndrome) 6-Patients with known hypersensitivity to verapamil hydrochloride ## Contradiction to Verapamil injection only 7.Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy). 8.Ventricular tachycardia: Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. # Warnings ## Heart failure - Verapamil has a negative inotropic effect, which in most patients is compensated by its afterloadreduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure orpulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. ## Hypotension - Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension. ## Elevated liver enzymes - Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even with continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. ## Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine) - Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). - Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral Verapamil. ## Atrioventricular block - The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-degree AV blockor third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending on the clinical situation. ## Patients with hypertrophic cardiomyopathy (IHSS) - In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Verapamil Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Verapamil Postmarketing Experience in the drug label. # Drug Interactions ### Cytochrome inducers/inhibitors - In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil. ### HMG-CoA reductase inhibitors - The use of statins that are CYP3A4substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. - Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. ### Aspirin - In a few reported cases, co-administration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone. ### Grapefruit juice - Grapefruit juice may increase plasma levels of verapamil. ### Alcohol - Verapamil may increase blood alcohol concentrations and prolong its effects. ### Beta-blockers - Controlled studies in small numbers of patients suggest that the concomitant use of Verapamil and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility. - In one study involving 15 patients treated with high doses of propranolol (median dose: 480 mg/day; range: 160 to 1,280 mg/day) for severe angina, with preserved left ventricular function (ejection fraction greater than 35%), the hemodynamic effects of additional therapy with verapamil HCl were assessed using invasive methods. The addition of verapamil to high-dose beta-blockers induced modest negative inotropic and chronotropic effects that were not severe enough to limit short-term (48 hours) combination therapy in this study. These modest cardiodepressant effects persisted for greater than 6 but less than 30 hours after abrupt withdrawal of beta-blockers and were closely related to plasma levels of propranolol. The primary verapamil/beta-blocker interaction in this study appeared to be hemodynamic rather than electrophysiologic. - In other studies, verapamil did not generally induce significant negative inotropic, chronotropic, or dromotropic effects in patients with preserved left ventricular function receiving low or moderate doses of propranolol (less than or equal to 320 mg/day); in some patients, however, combined therapy did produce such effects. Therefore, if combined therapy is used, close surveillance of clinical status should be carried out. Combined therapy should usually be avoided in patients with atrioventricular conduction abnormalities and those with depressed left ventricular function. - Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. - A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. ### Digitalis - Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of Verapamil use, the patient should be reassessed to avoid under-digitalization. ### Antihypertensive agents - Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. ### Antiarrhythmic agents Disopyramide - Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide - A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine - In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. - The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. ### Other agents Nitrates - Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Cimetidine - The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium - Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. Carbamazepine - Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin - Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital - Phenobarbital therapy may increase verapamil clearance. Cyclosporine - Verapamil therapy may increase serum levels of cyclosporine. Theophylline - Verapamil may inhibit the clearance and increase the plasma levels of theophylline. Inhalation anesthetics - Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular blocking agents - Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Telithromycin - Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine - Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Verapamil in women who are pregnant. ### Labor and Delivery - It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. ### Nursing Mothers - Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Verapamil in geriatric settings. ### Gender There is no FDA guidance on the use of Verapamil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Verapamil with respect to specific racial populations. ### Renal Impairment - About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. ### Hepatic Impairment - Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects should be carried out. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Verapamil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Verapamil in patients who are immunocompromised. ### Use in patients with attenuated (decreased) neuromuscular transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. # Administration and Monitoring ### Administration - Oral, intravenous ### Monitoring FDA Package Insert for Verapamil contains no information regarding drug monitoring. # IV Compatibility FDA Package Insert for Verapamil contains no information regarding IV compatibility. # Overdosage - Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Verapamil SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. - Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. # Pharmacology ## Mechanism of Action ### Angina - The precise mechanism of action of Verapamil as an antianginal agent remains to be fully determined, but includes the following two mechanisms: Relaxation and prevention of coronary artery spasm: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of Verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate–pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Reduction of oxygen utilization: Verapamil regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil in chronic stable effort angina. ### Arrhythmia - Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation. - Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, Verapamil may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects. Verapamil decreases the frequency of episodes of paroxysmal supraventricular tachycardia. - Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but in depressed atrial fibers it decreases amplitude, velocity of depolarization, and conduction velocity. Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. - Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. ### Essential hypertension - Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise, Verapamil does not alter systolic cardiac function in patients with normal ventricular function. - Verapamil does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of Verapamil. ## Structure - Verapamil hydrochloride is a calcium antagonist or slow-channel inhibitor. Verapamil Hydrochloride Injection, USP is a sterile, nonpyrogenic solution containing verapamil hydrochloride 2.5 mg/mL and sodium chloride 8.5 mg/mL in water for injection. The solution contains no bacteriostat or antimicrobial agent and is intended for single-dose intravenous administration. May contain hydrochloric acid for pH adjustment; pH is 4.9 (4.0 to 6.5). The chemical name of Verapamil Hydrochloride, USP is benzeneacetonitrile, α-[3-[{2-(3,4-dimethoxyphenyl)ethyl} methylamino] propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride. Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odorless and has a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether. It has the following structural formula: - Verapamil hydrochloride is not chemically related to other antiarrhythmic drugs. ## Pharmacodynamics - Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with Verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of Verapamil is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (eg, pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur. ## Pharmacokinetics - More than 90% of the orally administered dose of Verapamil is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil HCl every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/ml, with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. In early dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single-dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In healthy men, orally administered Verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. - Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours; the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. ## Nonclinical Toxicology ## Carcinogenesis, mutagenesis, impairment of fertility - An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day). - Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation. - Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. ## Animal pharmacology and/or animal toxicology - In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater, and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not in the rat. Development of cataracts due to verapamil has not been reported in man. # Clinical Studies FDA Package Insert for Verapamil contains no information regarding clinical studies. # How Supplied ## Verapamil tablet - Verapamil Hydrochloride Extended-Release Tablets, USP 120 mg are supplied as ivory, round, unscored, film-coated tablets debossed with “120” on one side - on the other side, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets. - Verapamil Hydrochloride Extended-Release Tablets USP, 180 mg are supplied as light orange, capsule-shaped, scored, film-coated tablets debossed with “7301” on one side, - on the other side, packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100 tablets. - Verapamil Hydrochloride Extended-Release Tablets USP, 240 mg are supplied as ivory, capsule-shaped, scored, film-coated tablets debossed with “7300” on one side, - on the other side, packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100 tablets. ## Verapamil capsule - Verapamil Hydrochloride Extended-release Capsules (PM); pellet filled capsules are supplied in three dosage strengths: ## Verapamil injection - Verapamil Hydrochloride Injection, USP 2.5 mg/mL is supplied in single-dose containers as follows: ## Storage ## Verapamil tablet - Store between 20˚ to 25˚ C (68˚ to 77˚ F) [See USP Controlled Room Temperature]. ## Verapamil capsule - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. - Dispense in tight, light-resistant container as defined in USP. ## Verapamil injection - Store at 20 to 25°C (68 to 77°F). - Protect from light by retaining in package until ready to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Verapamil Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Verapamil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Verapamil - Verapamil SR - Covera-HS - Isoptin SR - Verelan - Verelan PM # Look-Alike Drug Names FDA Package Insert for Verapamil contains no information regarding look-alike names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Calan
64f6e77fcad2dda7a7be946745986b2416ccb5d6	wikidoc	Calbindin	Calbindin Calbindin refers to several calcium-binding proteins. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classified in different sub-families as they differ in the number of Ca2+ binding EF-hand sites. # Calbindin-D28k Calbindin-D28k was first shown to be present in the intestine in birds and then found in the mammalian kidney. It is also expressed in a number of neuronal and endocrine cells, particularly in the cerebellum. It is encoded in humans by the CALB1 gene. Calbindin-D28k contains 4 active calcium-binding domains, and 2 modified domains that have lost their calcium-binding capacity. Calbindin-D28k acts as a calcium buffer and calcium sensor and can hold four Ca2+ in the EF-hands of loops EF1, EF3, EF4 and EF5. The structure of rat calbindin was originally solved by nuclear magnetic resonance and was one of the largest proteins then to be determined by this technique. The sequence of calbindin is 263 residues in length and has only one chain. The sequence consists mostly of alpha helices but beta sheets are not absent. According to the NMR PDB it is 44% helical with 14 helices containing 117 residues, and 4% beta sheet with 9 strands containing 13 residues. In 2018 the X-ray crystal structure of human calbindin was published (PDB entry 2g9b). There were differences observed between the nuclear magnetic resonance and crystal structure despite 98% sequence identity between the Rat and human isoforms. Small angle X-ray scattering indicates that the crystal structure better predicts the properties of calbindin in solution compared with the structure determined by nuclear magnetic resonance. Calbindin-D28k is a vitamin D responsive gene in many tissues, in particular the chick intestine, where it has a clear function in mediating calcium absorption. In the brain, its synthesis is independent of vitamin-D. There is no homology between calbindin-D28k and calbindin-D9k, apart from their calcium binding domains (EF-hands): calbindin-D9k has two EF-hands, and calbindin-D28k has six. # Calretinin Calretinin is a 29kDa protein with 58% homology to calbindin-D28k and principally found in nervous tissues. It is encoded in humans by the CALB2 gene. # Calbindin-D9k Calbindin-D9k is present in mammalian intestinal epithelial cells (enterocytes). Calbindin-D9k can also be found in the kidney and uterus in some mammalian species. It in encoded in humans by the S100G gene which has also been termed CALB3. Calbindin-D9k is a member of the S100 family of calcium-binding proteins. It has two EF-hands sequences which bind Ca2+ with high affinity. Calbindin-D9k mediates the transport of calcium across the enterocytes from the apical side, where entry is regulated by the calcium channel TRPV6, to the basolateral side, where calcium pumps such as PMCA1 utilize intracellular adenosine triphosphate to pump calcium into the blood. The transport of calcium across the enterocyte cytoplasm appears to be rate-limiting for calcium absorption in the intestine; the presence of calbindin increases the amount of calcium crossing the cell without raising the free concentration. Calbindin-D9k may also stimulate the basolateral calcium-pumping ATPases. Expression of calbindin-D9k, like that of calbindin-D28k, is stimulated by the active vitamin D metabolite, calcitriol although the precise mechanisms are still controversial. In mice in which the receptor for vitamin D is not expressed, calbindin-D9k is reduced, but not absent.	Calbindin Calbindin refers to several calcium-binding proteins. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classified in different sub-families as they differ in the number of Ca2+ binding EF-hand sites. # Calbindin-D28k Calbindin-D28k was first shown to be present in the intestine in birds and then found in the mammalian kidney. It is also expressed in a number of neuronal and endocrine cells, particularly in the cerebellum. It is encoded in humans by the CALB1 gene. Calbindin-D28k contains 4 active calcium-binding domains, and 2 modified domains that have lost their calcium-binding capacity. Calbindin-D28k acts as a calcium buffer and calcium sensor and can hold four Ca2+ in the EF-hands of loops EF1, EF3, EF4 and EF5. The structure of rat calbindin was originally solved by nuclear magnetic resonance and was one of the largest proteins then to be determined by this technique.[1] The sequence of calbindin is 263 residues in length and has only one chain. The sequence consists mostly of alpha helices but beta sheets are not absent. According to the NMR PDB it is 44% helical with 14 helices containing 117 residues, and 4% beta sheet with 9 strands containing 13 residues. In 2018 the X-ray crystal structure of human calbindin was published (PDB entry 2g9b)[2]. There were differences observed between the nuclear magnetic resonance and crystal structure despite 98% sequence identity between the Rat and human isoforms. Small angle X-ray scattering indicates that the crystal structure better predicts the properties of calbindin in solution compared with the structure determined by nuclear magnetic resonance. Calbindin-D28k is a vitamin D responsive gene in many tissues, in particular the chick intestine, where it has a clear function in mediating calcium absorption.[3] In the brain, its synthesis is independent of vitamin-D. There is no homology between calbindin-D28k and calbindin-D9k, apart from their calcium binding domains (EF-hands): calbindin-D9k has two EF-hands, and calbindin-D28k has six. # Calretinin Calretinin is a 29kDa protein with 58% homology to calbindin-D28k and principally found in nervous tissues.[4] It is encoded in humans by the CALB2 gene. # Calbindin-D9k Calbindin-D9k is present in mammalian intestinal epithelial cells (enterocytes). Calbindin-D9k can also be found in the kidney and uterus in some mammalian species. It in encoded in humans by the S100G gene which has also been termed CALB3. Calbindin-D9k is a member of the S100 family of calcium-binding proteins. It has two EF-hands sequences which bind Ca2+ with high affinity. Calbindin-D9k mediates the transport of calcium across the enterocytes from the apical side, where entry is regulated by the calcium channel TRPV6, to the basolateral side, where calcium pumps such as PMCA1 utilize intracellular adenosine triphosphate to pump calcium into the blood.[5] The transport of calcium across the enterocyte cytoplasm appears to be rate-limiting for calcium absorption in the intestine; the presence of calbindin increases the amount of calcium crossing the cell without raising the free concentration.[6] Calbindin-D9k may also stimulate the basolateral calcium-pumping ATPases. Expression of calbindin-D9k, like that of calbindin-D28k, is stimulated by the active vitamin D metabolite, calcitriol although the precise mechanisms are still controversial.[7] In mice in which the receptor for vitamin D is not expressed, calbindin-D9k is reduced, but not absent.	https://www.wikidoc.org/index.php/Calbindin
edb7e1e8441f4885c60a27b0f2d75556b2542fdb	wikidoc	Calcaneus	Calcaneus # Overview The calcaneus is the largest bone of the human foot. The skeleton of the human foot is made up of three groups of bones: the tarsus, the metatarsus and the phalanges. The tarsal bones consist of the calcaneus, talus, cuboid, navicular, and the first, second, and third cuneiforms. The calcaneus forms part of the tarsi and constitutes the heel of the human foot or the point of an animal's hock . It is also known as the heel bone. # Human It articulates with two other tarsal bones, the talus above and the cuboid toward the midfoot. In addition to receiving the weight of the body with each step, the calcaneus is the anchor for the plantar fascia, which supports the arch of the foot. ## Calcaneal tuberosity The posterior-most portion of the calcaneus is the calcaneal tuberosity, a large, non-articulating process that is the insertion point for the calcaneal tendon (or Achilles tendon). In addition, this process is the origin for some of the muscles and tendons of the foot. # Horse The calcaneus has two articulations, being part of the Proximal intertarsal joint and the Talocalcaneal joint. As in humans it is the insertion of the gastrocnemius and superficial digital flexor tendons. The point of the calcaneus is covered by the calcanean bursa.	Calcaneus Template:Infobox Bone # Overview The calcaneus is the largest bone of the human foot. The skeleton of the human foot is made up of three groups of bones: the tarsus, the metatarsus and the phalanges. The tarsal bones consist of the calcaneus, talus, cuboid, navicular, and the first, second, and third cuneiforms. The calcaneus forms part of the tarsi and constitutes the heel of the human foot or the point of an animal's hock . It is also known as the heel bone. # Human It articulates with two other tarsal bones, the talus above and the cuboid toward the midfoot. In addition to receiving the weight of the body with each step, the calcaneus is the anchor for the plantar fascia, which supports the arch of the foot. ## Calcaneal tuberosity The posterior-most portion of the calcaneus is the calcaneal tuberosity, a large, non-articulating process that is the insertion point for the calcaneal tendon (or Achilles tendon). In addition, this process is the origin for some of the muscles and tendons of the foot. # Horse The calcaneus has two articulations, being part of the Proximal intertarsal joint and the Talocalcaneal joint. As in humans it is the insertion of the gastrocnemius and superficial digital flexor tendons. The point of the calcaneus is covered by the calcanean bursa.	https://www.wikidoc.org/index.php/Calcaneal_tuberosity
7637ce6f959df2de67e354d23f3c55a276517b5b	wikidoc	Vitamin D	Vitamin D # Overview Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Vitamin D plays an important role in the maintenance of organ systems. - Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys. - It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton. - It inhibits parathyroid hormone secretion from the parathyroid gland. - Vitamin D affects the immune system by promoting immunosuppression, phagocytosis, and anti-tumor activity. Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. Vitamin D deficiency may also be linked to many forms of cancer. # Forms Several forms of vitamin D have been described. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. - Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1 - Vitamin D2: ergocalciferol or calciferol (made from ergosterol) - Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the skin). - Vitamin D4: 22-dihydroergocalciferol - Vitamin D5: sitocalciferol (made from 7-dehydrositosterol) Chemically, the various forms of vitamin D are secosteroids; i.e. broken-open steroids. The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–290 nm. These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated. In most mammals, including humans, D3 is more effective than D2 at increasing the levels of vitamin D hormone in circulation; D3 is at least 3-fold, and likely closer to 10-fold, more potent than D2. However, in some species, such as rats, vitamin D2 is more effective than D3. Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. Some forms of activated vitamin D like calcitriol, that are commonly used in the chronic kidney disease population, can cause increase absorption of calcium and phosphorus in the gut leading to high serum levels. Some companies modified the structures of the side-chain decreasing the gut effect and maintaining the effect in the parathyroid gland. These group of compounds includes paricalcitol and the one named after Hector DeLuca, hectorol. # Biochemistry Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a hormone 1,25-D which does, through a tightly regulated synthesis mechanism. ## Production in the skin The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum. The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is reduced. Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths between 270–290 nm and thus the production of vitamin D3 will only occur at those wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum. A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 mg/cm² of skin) are available in the stratum spinosum and stratum basale of human skin to meet the body's vitamin D requirements, and melanin content does not alter the amount of vitamin D that can be produced. Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. ### Synthesis mechanism (form 3) ## Mechanism of action Once vitamin D is produced in the skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs. The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The Vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content. The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. # Nutrition Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains. A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D remains a point for debate among medical scientists. The U.S. Dietary Reference Intake for Adequate Intake (AI) of vitamin D for infants, children and men and women aged 19–50 is 5 micrograms/day (200 IU/day). Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women aged 51–70 and to 15 micrograms/day (600 IU/day) past the age of 70. ## In food Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet. In some countries, foods such as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency. In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50. Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D. Natural sources of vitamin D include: - Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU - Fatty fish species, such as: Catfish, 3 oz provides 425 IU Salmon, cooked, 3.5 oz provides 360 IU Mackerel, cooked, 3.5 oz, 345 IU Sardines, canned in oil, drained, 1.75 oz, 250 IU Tuna, canned in oil, 3 oz, 200 IU Eel, cooked, 3.5 oz, 200 IU - Catfish, 3 oz provides 425 IU - Salmon, cooked, 3.5 oz provides 360 IU - Mackerel, cooked, 3.5 oz, 345 IU - Sardines, canned in oil, drained, 1.75 oz, 250 IU - Tuna, canned in oil, 3 oz, 200 IU - Eel, cooked, 3.5 oz, 200 IU - Mushrooms provide over 2700 IU per serving (approx. 3 oz or 1/2 cup) of vitamin D2, if exposed to just 5 minutes of UV light after being harvested; this is one of a few natural sources of vitamin D for vegans. - One whole egg, 20 IU - Yeast # Deficiency There is no consensus on the serum 25-hydroxyvitamin D levels, "25(OH)D", considered "normal". 12 ng per milliliter (50 nmol per liter) ihas been proposed. However, "a common misconception is that the RDA functions as a “cut point” and that nearly the entire population must have a serum 25(OH)D level above 20 ng per milliliter to achieve good bone health. The reality is that the majority (about 97.5%) of the population has a requirement of 20 ng per milliliter or less. Moreover, by definition of an average requirement, approximately half the population has a requirement of 16 ng per milliliter (the EAR) or less. " (italics added) Previous opinions suggested a value equal or less than 20 ng per milliliter (50 nmol per liter) is in the deficient range., , , The definition can be based on the point at which the parathyroid hormone (PTH) levels off as the cutoff point, which may be at 12 ng per milliliter (30 nmol per liter) or is close to 30 ng per milliliter (75 nmol per liter). The Institute of Medicine states (page 13): - Levels over 20 ng/ml: "Practically all persons are sufficient" - Levels 12-20 ng/ml: "Some, but not all, persons are potentially at risk for inadequacy." - Levels below 12 ng/ml: "persons are at risk of deficiency." # Causes of vitamin D deficiency Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. ## Diseases caused by deficiency The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920. In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D. The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid, 7-dehydrocholesterol, the precursor of vitamin D. Vitamin D deficiency is known to cause several bone diseases including: - Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. - Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterised by proximal muscle weakness and bone fragility. - Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases. Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder and several autoimmune diseases (see role in immunomodulation). ## Vitamin D dosage for deficiencies There are 2 major forms of vitamin D available, Vitamin D2 and D3. We prefer Vitamin D3 supplements as it is naturally available form and very effective. 25OHD is measured in blood if you suspect vitamin D deficiency and based on the value supplements are given. Normal value of 25OHD is 30-80 ng/ml. If 25OHD is less than 20 ng/ml-50,000 IU Vitamin D3 per week for 6-8 weeks, followed by 800 to 100 IU/ day daily thereafter. If 25OHD is 20 to 30 ng/ml-800-1000 IU vitamin D3 per day for 3 months, after 25OHD reached normal values continue with 800 IU it D per day. In adults with normal 25OHD more than 30 ng/ml- 800 IU of Vitamin D3 daily is recommended. For children and infants with 25OHD less than 20 ng/ml-vitamin D3 1000-500 IU per day for 3 months. During pregnancy vitamin D3 400IU/day is recommended. ## Groups at greater risk of deficiency Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 decreases. In addition the ability of the kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L. The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards. Health Canada recommends 400IU/day (10μg/d). While infant formula is generally fortified with vitamin D, breast milk does not contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes. Liquid "drops" of vitamin D, as a single nutrient or combined with other vitamins, are available in water based or oil-based preparations ("Baby Drops" in North America, or "Vigantol oil" in Europe). However, babies may be safely exposed to sunlight for short periods; as little as 10 minutes a day without a hat can suffice, depending on location and season. The vitamin D found in supplements and infant formula is less easily absorbed than that produced by the body naturally and carries a risk of overdose that is not present with natural exposure to sunlight. Obese individuals may have lower levels of the circulating form of vitamin D, probably because of reduced bioavailability, and are at higher risk of deficiency. To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly renal dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism. Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin. Recent studies showed that, following the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient. Ironically, there are indications that vitamin D deficiency may lead to skin cancer. To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use. The reduced pigmentation of light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency. However, at higher latitudes (above 30°) during the winter months, the decreased angle of the sun's rays, reduced daylight hours, protective clothing during cold weather, and fewer hours of outside activity, diminish absorption of sunlight and the production of vitamin D. Because melanin acts like a sun-block, prolonging the time required to generate vitamin D, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required. Individuals clad in full body coverings during all their outdoor activity, most notably women wearing burquas in daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk mostly for female residents of conservative Muslim nations in the Middle East, but also for strict adherents in other parts of the world. # Overdose Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a long half-life (about 20 to 29 days). However, the synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity usually occurs only if excessive doses (prescription or megavitamin) are taken. Although normal food and pill vitamin D concentration levels are too low to be toxic in adults, because of the high vitamin A content in codliver oil it is possible to reach poisonous levels of vitamin A, if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most cases of vitamin D overdose have occurred due to manufacturing and industrial accidents. Exposure to sunlight for extended periods of time does not cause Vitamin D toxicity. This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded. Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day. The exact long-term safe dose of vitamin D is not entirely known, but dosages up to 60 micrograms (2,400 IU) /day in healthy adults are believed to be safe., and all known cases of vitamin D toxicity with hypercalcemia involve intake of or over 1,000 micrograms (40,000 IU)/day. The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2,000 IU/day). In adults, sustained intake of 2500 μg/day (100,000 IU) can produce toxicity within a few months. For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death. Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 25 to 40 ng/mL (60 to 100 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. The symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Gastrointestinal symptoms of vitamin D toxicity can develop including anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop. In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity. Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL. Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible. # Medical uses The United States Preventive Services Task Force in 2013 concluded "the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins for the prevention of cardiovascular disease or cancer". ## Role in depression prevention The VITAL-DEP analysis of the VITAL randomized controlled trial found no benefit from vitamin D to prevent depression ## Role in diabetes prevention in patients with prediabetes A systematic review of randomized controlled trials, including the D2d trial, suggests benefit. In the D2d trial, the results were negative; however, the patients mean baseline vitamin D level (28 nl/ml) was above the Academy of Medicine's definition of at risk of inadequacy (levels 12-20 ng/ml). The large VITAL randomized controlled, that has previously reported on other outcomes from vitamin D supplementation, has registered an analysis of diabetes prevention. ## Role in fall prevention Vitamin D did not prevent falls in a randomized controlled trial. In this trial of 4 doses of vitamin D (200 , 1000, 2000, or 4000 IU of vitamin D3 per day), patients were 70 years and older with vitamin D levels of 25 to 72.5 nmol/L with a mean total 25-(OH)D level of 55.3 nmol/L. The final final vitamin D level achieved was 67.1, 80.3, 87.3, and 119.2 nmol/L for doses of 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. Earlier, in 2012, the USPSTF had recommendated vitamin D supplementation for fall prevention in adults over 65 years old. Subsequently, in 2018, the USPSTF did not make this recommendation. ## Role in fracture prevention ### All patients The large VITAL-D randomized controlled trial used vitamin D3 (2000 IU per day) and found no reduction in fractures. - No benefit among the 8,374 patients with baseline vitamin D level below 30 ng/mL (75 nmol/L). - No subgroup among patients with both low baseline levels and high follow-up levels as done by the Bischoff-Ferrari pooled analysis In prior systematic reviews: - The Cochrane Collaboration concluded that "vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture.". - Vitamin D given in an individual patient analysis of randomized controlled trials of women with mean age of 76 and mean vitamin D level of about 47 nmol/L, affect on fracture rate was a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval , 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99) In a subgroup analysis the benefit was statistically significant for women whose intake was > 800 IU per day. There was a strong, but insignificant trend toward benefit among the 106 patients with baseline vitamin D less than 30 ng/mL (75 nmol/L) and who had the highest actual intake of vitamin D. Much of this benefit may have been due to the trial by Chapuy which studied 3270 women (1765 or 54% completed the 18 months of follow-up) in structured living arrangements with baseline levels of 16 ng/mL and a mean post-treatment level of 42 ng/mL - There was a strong, but insignificant trend toward benefit among the 106 patients with baseline vitamin D less than 30 ng/mL (75 nmol/L) and who had the highest actual intake of vitamin D. Much of this benefit may have been due to the trial by Chapuy which studied 3270 women (1765 or 54% completed the 18 months of follow-up) in structured living arrangements with baseline levels of 16 ng/mL and a mean post-treatment level of 42 ng/mL In patients starting long-term corticosteroid therapy, a randomized control trial found that vitamin D can reduce loss of bone densitiy. ### Patients with osteopososis Vitamin D, when combined with calcium, prevents fractures among patients with osteoporosis according to a systematic review by the Cochrane Collaboration. ## Role in immunomodulation The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects. Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns. VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression. VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi. Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets. These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection. However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosis and other diseases involving vitamin D hypersensitivity. A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D. In 2022; the VITAL randomized controlled trial reported a reduction autoimmune disease in among subjects randomized to vitamin D. ## Role in cancer prevention and recovery The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. Although the anti-cancer activity of vitamin D is not fully understood, it is thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related to its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer. In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%. Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer.. A recent study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers. In June 2007, The Canadian Cancer Society began recommending that all adult Canadians consider taking 1000 IU of vitamin D during the fall and winter months (when typically the country's northern latitude prevents sufficient sun-stimulated production of vitamin D). This kind of recommendation is a first for cancer agencies. Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight. ### Randomized controlled trials A randomized controlled trial found no benefit. Previously, in 2017, a randomized controlled trial reported no reduction in cancer among postmenopausal women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL from supplementation with vitamin D3.. Earlier, a trial found benefit amond 1,200 women receiving vitamin D supplementation (1,100 international units (IU) / day). This resulted in a 60% reduction in cancer incidence over four-years, rising to a 77% reduction if cancers diagnosed in the first year (and therefore more likely to have originated prior to the intervention) were excluded. ## Role in cardiovascular diseases ### History One of the very first indications of the association between cardiovascular diseases and vitamin D was in the most severe form of the vitamin deficiency, Rickets, in which patients had cardiomyopathy. Evidence of an intracellular vitamin D receptor in rat cardiomyocytes was described in the early 1980's and in human heart tissue in the mid 1990s. Xiang W. et al. provided further evidence of the relationship between vitamin D and cardiovascular diseases in his VDR knockout mouse model, in which the mice had severe cardiac hypertrophy. VDR knockout mice also under-express tissue inhibitors of metalloproteinases (TIMP-1 & TIMP-3) in comparison to the wild-type, which may contribute to increased oxidation of the extracellular matrix proteins and perivascular tissues. Interestingly, spontaneous hypertensive rats (SHR) were found to be more vitamin D deficient as measures of blood pressure increased. Contrary to data in the vitamin D receptor knockout mice model, the wild-type had higher blood pressures compared to the knockout. ### In vitro and animal studies In vitro data showed that 1,25-hydroxyvitamin D has a regulatory effect on myoblast proliferation as well as some rapid genomic effect, suggesting some action independent of transcription. To further explore possible non-genomic effects, Tishkoff et al. explored the location of the VDR intracellularly and found signaling in the T-tubules, close to the sarcoendoplasmic reticulum Ca++- ATPase (SERCA). They also reported accelerated rates of myocyte contraction and relaxation in VDR knockout mice cells as compared to the wild-type. Dahl salt-sensitive rats (DSS) are an interesting animal model to study direct cardiac vitamin D effects on the heart since the DSS rats become vitamin D deficient, hypertensive and develop increased heart mass if fed with high-salt diet. Bodyak et al. showed decreased heart size and improved contraction by m-mode echocardiography in rats treated with paricalcitol versus rats treated with placebo. Atrial natriuretic factor (ANP) was lower in the treated group, findings which are similar to those previously described in cardiomyocyte cell cultures. There were differences shown in the gene expression profiles between DSS treated with paricalcitol versus vehicle. ### Observational studies Multiple epidemiologic studies have shown improved in cardiovascular morbidity and mortality in several populations. One of the earliest associations was shown by Teng et al. in the New England Journal of Medicine in 2003, where they showed a benefit in survival independent of calcium, phosphorus and PTH for patients treated with activated vitamin D. There was controversy regarding the activated vitamin D effects in mortality, because of higher risk of hypercalcemia, hyperposphatemia and their effect in the cardiovascular system. Patients treated with Paricalcitol, an activated vitamin D analogue with less effect on calcium and phosphorus, had improved survival compared to those treated with calcitriol. In further studies in the chronic kidney disease population, the vitamin D level was shown to be predictive of 90-day all-cause and cardiovascular mortality and the administration of activated form of vitamin D was shown to improve survival. Recently, in the New England Journal of Medicine Dr. Lee et al. described how the sicker patients in multiple intesive care units have lower levels of vitamin D. There is discrepancy in the prevalence and in the response to treatment of cardiovascular diseases among different races and ethnicities. In the third National Health and Nutrition Examination Survey (NHANES) black people, who have higher cardiovascular risk compared to whites, had lower levels of 25-hydroxyvitamin D. Moreover, multiple risk factors such as obesity, hypertension and diabetes mellitus were associated with lower 25-hydroxyvitamin D levels. In other studies 25-hydroxyvitamin D levels were inversely correlated with the prevalence of metabolic syndrome, type 2 diabetes mellitus and hypertension. In a cohort study with more than five thousand participants that were followed for twenty years the cumulative incidence of heart failure in black woman was 1.1% and in black men 0.9% compared to 0.8% and 0% in white women and men respectively. Interestingly, paradoxically to other scenarios, the african-american population has a survival advantage compared to whites in hemodialysis. Wolf et al. showed that they are more likely to be treated with activated vitamin D. Therefore, if you compare african-american versus whites in the non-treated population their survival advantage is lost. Zittermann et al. demonstrated that geographic factors such as latitude, altitude, season and place of residency were associated with different cardiovascular risk, mostly for ischemic heart disease. Interestingly, those factors were also associated with 25-hydroxyvitamin D levels. Cardiovascular disease rates were at their zenith in the winter, when the vitamin D levels were at their nadir. Based on studies done by Holick, PhD, MD, we know that the prevalence of vitamin D deficiency is close to somewhere between 40-100% in healthy individuals at the end of the winter in the New England area. Similar seasonal variations have also been shown for heart failure hospitalization rates and in cerebrovascular disease. The Ludwigshafen Risk and Cardiovascular Health Study (LURIC), a prospective cohort design to genetic polymorphisms and biomarkers associated with cardiovascular risks, showed a correlation between 25-hydroxyvitamin D and C-reactive protein (CRP) and interleukin 6 levels (IL-6), serum phospholipid and gluthatione levels and vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1). Dobnig et al. showed that 25-hydroxyvitamin D levels had a significant hazard ratio of 2.08 for cardiovascular mortality comparing the lowest versus the highest quartiles with a follow up close to eight years, and 1.61 for 1,25-hydroxyvitamin D. Results suggest independent predictive value of 25-hydroxyvitamin D and 1,25-hydroxyvitamin D. The results were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism and New York Heart Association functional class. The hazard ratios increased progressively per lower vitamin D level, suggesting a dose-dependent effect and strengthening the association. However, the study assumed that the patients with non-cardiac death had the same probability of dying of cardiac etiologies than the rest of the population, which may not necessarily be true and may bias the estimates. Research indicates that vitamin D plays a role in preventing or reversing coronary disease. As with cancer incidence, the same qualitative inverse correlations exist between coronary disease incidence and serum vitamin D levels, seasonal solar exposure, in temperate latitudes but not tropical latitudes. A nested case-control study with 18,225 men in the Health Professionals Follow-up Study showed that vitamin D deficient people had a relative risk of 2.09 of developing myocardial infarction. Similar findings were also shown in the researchers from the Framingham Offspring study prospectively collected 25-OH D levels in 1739 white individuals without cardiovascular disease or renal disease. For the primary analysis, vitamin D levels were a categorical variable, with cut-offs chosen a priori based on previously published studies. Participants were classified as deficient (15 ng/ml). Mean level was 19.7 ng/ml among all participants. Low 25-OH D levels were associated with obesity, cigarette smoking, higher systolic blood pressure, diabetes, higher ratio of total to HDL cholesterol, and lower intake of vitamin D or vitamins. Interesting, there was no correlation with physical activity. Over a mean of 7.6 years follow up there were 120 cardiovascular events. A multivariate model was used to correlate 25-OH D status with cardiovascular risk, adjusting for age, sex, blood pressure, medications, diabetes, cigarette smoking, cholesterol, body mass index, and renal function. After adjustment, a 25-OH D level less than 15 ng/ml was independently associated with risk of a cardiovascular event (HR 1.62, CI 1.11 to 2.35, P=0.01). In a three-category model, where participants were classified as sufficient, deficient (10 to 15 ng/ml) or severely deficient (<10 ng/ml), severe deficiency was associated with even greater risk (HR 1.80, CI 1.05 to 3.08, P=0.01). The mechanism by which vitamin D deficiency might increase risk of vascular disease is not entirely known. The authors cite data demonstrating that 1,25-OH D is important for suppression of the renin-angiotensin axis, and possible effects of hyperparathyroidism on myocyte function and vascular inflammation. The possibility always exists that an unmeasured confounder might explain the correlation seen in this study. Nonetheless, it is telling that the majority of participants in this study would qualify as vitamin-D deficient if a cut-off of 20 ng/ml were used, and the body of evidence linking vitamin-D deficiency with chronic illness is impressive. Observational data has shown similar associations of vitamin D not only with coronary artery disease, but with equivalents such as peripheral vascular disease. Differences by race in PVD have also been reported. A retrospective pilot study of hemodialysis patients demonstrated improved diastolic function evaluated with lower E/A ratios on echocardiogram in patients treated with paricalcitol as compared to untreated patients. A cohort of 51 patients was enrolled and followed for 12 months. Treatment was left at discretion of nephrologists. Baseline and 12-month echocardiograms were compared. ### Randomized clinical trials Randomized controlled trials have not found benefit from Vitamin D supplementation. Cardiovascular disease many be increased when calcium supplementation is added to Vitamin D The treatment group M-mode echocardiography showed pronounced reductions in inverventricular wall thickness, left ventricular posterior wall thickness and left ventricle mass index. There were no differences in blood pressure control, and blood pressure medications were not changed. Data regarding distribution of angiotensin converting enzyme inhibitors and angiotensin receptor blockers between groups is not shown. Plasma renin, angiotensin II and atrial natriuretic peptide decreased over time in the calcitriol group. The study is limited due to its sample size, because it does not specify why some patients received treatment and why some did not, and it does not show the hormonal change in the control group. There are two large randomized double-blind placebo-controlled trials in chronic kidney disease assessing the effect of paricalcitol treatment on diastolic dysfunction, left ventricular mass as well as biomarkers and genetic expression ( and ). These trials promise rigorous data to further characterize the effect, and possible mechanisms of the effect, of activated vitamin D in the heart. ## Role in fibromyalgia # Screening for vitamin D deficieny The United States Preventive Services Task Force in 2021 gave an "I" recommendation, " the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults", for screening for vitamin D deficiency. The USPSTF recommendation was based on a systematic review	Vitamin D Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Hector Tamez [3] # Overview Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).[1] The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Vitamin D plays an important role in the maintenance of organ systems.[2] - Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys. - It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton. - It inhibits parathyroid hormone secretion from the parathyroid gland. - Vitamin D affects the immune system by promoting immunosuppression, phagocytosis, and anti-tumor activity. Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. Vitamin D deficiency may also be linked to many forms of cancer. # Forms Several forms of vitamin D have been described. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. - Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1 - Vitamin D2: ergocalciferol or calciferol (made from ergosterol) - Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the skin). - Vitamin D4: 22-dihydroergocalciferol - Vitamin D5: sitocalciferol (made from 7-dehydrositosterol) Chemically, the various forms of vitamin D are secosteroids; i.e. broken-open steroids.[3] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–290 nm.[4] These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3.[5] At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated.[1] In most mammals, including humans, D3 is more effective than D2 at increasing the levels of vitamin D hormone in circulation; D3 is at least 3-fold, and likely closer to 10-fold, more potent than D2.[6] However, in some species, such as rats, vitamin D2 is more effective than D3.[7] Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.[8] Some forms of activated vitamin D like calcitriol, that are commonly used in the chronic kidney disease population, can cause increase absorption of calcium and phosphorus in the gut leading to high serum levels. Some companies modified the structures of the side-chain decreasing the gut effect and maintaining the effect in the parathyroid gland.[9] These group of compounds includes paricalcitol and the one named after Hector DeLuca, hectorol. # Biochemistry Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a hormone 1,25-D which does, through a tightly regulated synthesis mechanism. ## Production in the skin The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.[4] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is reduced. Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths between 270–290 nm and thus the production of vitamin D3 will only occur at those wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum.[4] A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 mg/cm² of skin) are available in the stratum spinosum and stratum basale of human skin to meet the body's vitamin D requirements,[4] and melanin content does not alter the amount of vitamin D that can be produced.[10] Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. ### Synthesis mechanism (form 3) ## Mechanism of action Once vitamin D is produced in the skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs.[3] The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[3] The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The Vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.[11] The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells.[8] # Nutrition Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains.[1] A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D remains a point for debate among medical scientists. The U.S. Dietary Reference Intake for Adequate Intake (AI) of vitamin D for infants, children and men and women aged 19–50 is 5 micrograms/day (200 IU/day).[12] Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women aged 51–70 and to 15 micrograms/day (600 IU/day) past the age of 70.[1][13] ## In food Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet. In some countries, foods such as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.[14] In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50.[1] Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D. Natural sources of vitamin D include:[1] - Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU - Fatty fish species, such as: Catfish, 3 oz provides 425 IU Salmon, cooked, 3.5 oz provides 360 IU Mackerel, cooked, 3.5 oz, 345 IU Sardines, canned in oil, drained, 1.75 oz, 250 IU Tuna, canned in oil, 3 oz, 200 IU Eel, cooked, 3.5 oz, 200 IU - Catfish, 3 oz provides 425 IU - Salmon, cooked, 3.5 oz provides 360 IU - Mackerel, cooked, 3.5 oz, 345 IU - Sardines, canned in oil, drained, 1.75 oz, 250 IU - Tuna, canned in oil, 3 oz, 200 IU - Eel, cooked, 3.5 oz, 200 IU - Mushrooms provide over 2700 IU per serving (approx. 3 oz or 1/2 cup) of vitamin D2, if exposed to just 5 minutes of UV light after being harvested;[15] this is one of a few natural sources of vitamin D for vegans. - One whole egg, 20 IU - Yeast # Deficiency There is no consensus on the serum 25-hydroxyvitamin D levels, "25(OH)D", considered "normal". 12 ng per milliliter (50 nmol per liter) ihas been proposed.[16] However, "a common misconception is that the RDA functions as a “cut point” and that nearly the entire population must have a serum 25(OH)D level above 20 ng per milliliter to achieve good bone health. The reality is that the majority (about 97.5%) of the population has a requirement of 20 ng per milliliter or less. Moreover, by definition of an average requirement, approximately half the population has a requirement of 16 ng per milliliter (the EAR) or less. " (italics added)[17] Previous opinions suggested a value equal or less than 20 ng per milliliter (50 nmol per liter) is in the deficient range.[18], [19], [20], [21] The definition can be based on the point at which the parathyroid hormone (PTH) levels off as the cutoff point, which may be at 12 ng per milliliter (30 nmol per liter)[22] or is close to 30 ng per milliliter (75 nmol per liter). [23] The Institute of Medicine states (page 13): [24]* Levels over 20 ng/ml: "Practically all persons are sufficient" - Levels 12-20 ng/ml: "Some, but not all, persons are potentially at risk for inadequacy." - Levels below 12 ng/ml: "persons are at risk of deficiency." # Causes of vitamin D deficiency Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis.[2] ## Diseases caused by deficiency The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920.[25] In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D.[25] The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid, 7-dehydrocholesterol, the precursor of vitamin D. Vitamin D deficiency is known to cause several bone diseases[26] including: - Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. - Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterised by proximal muscle weakness and bone fragility. - Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases.[11] Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder and several autoimmune diseases (see role in immunomodulation).[11] ## Vitamin D dosage for deficiencies There are 2 major forms of vitamin D available, Vitamin D2 and D3. We prefer Vitamin D3 supplements as it is naturally available form and very effective. 25OHD is measured in blood if you suspect vitamin D deficiency and based on the value supplements are given. Normal value of 25OHD is 30-80 ng/ml. If 25OHD is less than 20 ng/ml-50,000 IU Vitamin D3 per week for 6-8 weeks, followed by 800 to 100 IU/ day daily thereafter. If 25OHD is 20 to 30 ng/ml-800-1000 IU vitamin D3 per day for 3 months, after 25OHD reached normal values continue with 800 IU it D per day. In adults with normal 25OHD more than 30 ng/ml- 800 IU of Vitamin D3 daily is recommended. For children and infants with 25OHD less than 20 ng/ml-vitamin D3 1000-500 IU per day for 3 months. During pregnancy vitamin D3 400IU/day is recommended. [27] ## Groups at greater risk of deficiency Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 decreases.[28] In addition the ability of the kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L.[29] The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards.[1] Health Canada recommends 400IU/day (10μg/d).[30] While infant formula is generally fortified with vitamin D, breast milk does not contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes.[30] Liquid "drops" of vitamin D, as a single nutrient or combined with other vitamins, are available in water based or oil-based preparations ("Baby Drops" in North America, or "Vigantol oil" in Europe). However, babies may be safely exposed to sunlight for short periods; as little as 10 minutes a day without a hat can suffice, depending on location and season. The vitamin D found in supplements and infant formula is less easily absorbed than that produced by the body naturally and carries a risk of overdose that is not present with natural exposure to sunlight. Obese individuals may have lower levels of the circulating form of vitamin D, probably because of reduced bioavailability, and are at higher risk of deficiency. To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly renal dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism.[31] Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin.[11][32] Recent studies showed that, following the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient.[14] Ironically, there are indications that vitamin D deficiency may lead to skin cancer.[33] To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use. The reduced pigmentation of light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency.[29] However, at higher latitudes (above 30°) during the winter months, the decreased angle of the sun's rays, reduced daylight hours, protective clothing during cold weather, and fewer hours of outside activity, diminish absorption of sunlight and the production of vitamin D. Because melanin acts like a sun-block, prolonging the time required to generate vitamin D, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required.[5] Individuals clad in full body coverings during all their outdoor activity, most notably women wearing burquas in daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk mostly for female residents of conservative Muslim nations in the Middle East, but also for strict adherents in other parts of the world.[34] # Overdose Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a long half-life (about 20 to 29 days).[8] However, the synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity usually occurs only if excessive doses (prescription or megavitamin) are taken.[35] Although normal food and pill vitamin D concentration levels are too low to be toxic in adults, because of the high vitamin A content in codliver oil it is possible to reach poisonous levels of vitamin A,[36] if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[37] Exposure to sunlight for extended periods of time does not cause Vitamin D toxicity.[37] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[38] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[37] The exact long-term safe dose of vitamin D is not entirely known, but dosages up to 60 micrograms (2,400 IU) /day in healthy adults are believed to be safe.[8], and all known cases of vitamin D toxicity with hypercalcemia involve intake of or over 1,000 micrograms (40,000 IU)/day[37]. The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2,000 IU/day). In adults, sustained intake of 2500 μg/day (100,000 IU) can produce toxicity within a few months.[2] For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death.[39] Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 25 to 40 ng/mL (60 to 100 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose.[2] The symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Gastrointestinal symptoms of vitamin D toxicity can develop including anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[2] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[40] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[41] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[2] # Medical uses The United States Preventive Services Task Force in 2013 concluded "the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins for the prevention of cardiovascular disease or cancer".[42] ## Role in depression prevention The VITAL-DEP analysis of the VITAL randomized controlled trial found no benefit from vitamin D to prevent depression[43] ## Role in diabetes prevention in patients with prediabetes A systematic review of randomized controlled trials, including the D2d trial[44], suggests benefit[45]. In the D2d trial, the results were negative; however, the patients mean baseline vitamin D level (28 nl/ml) was above the Academy of Medicine's definition of at risk of inadequacy (levels 12-20 ng/ml)[24]. The large VITAL randomized controlled, that has previously reported on other outcomes from vitamin D supplementation, has registered an analysis of diabetes prevention[46]. ## Role in fall prevention Vitamin D did not prevent falls in a randomized controlled trial[47]. In this trial of 4 doses of vitamin D (200 [control], 1000, 2000, or 4000 IU of vitamin D3 per day), patients were 70 years and older with vitamin D [25-(OH)D] levels of 25 to 72.5 nmol/L with a mean total 25-(OH)D level of 55.3 nmol/L. The final final vitamin D level achieved was 67.1, 80.3, 87.3, and 119.2 nmol/L for doses of 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. Earlier, in 2012, the USPSTF had recommendated vitamin D supplementation for fall prevention in adults over 65 years old[48]. Subsequently, in 2018, the USPSTF did not make this recommendation[49]. ## Role in fracture prevention ### All patients The large VITAL-D randomized controlled trial used vitamin D3 (2000 IU per day) and found no reduction in fractures[50]. - No benefit among the 8,374 patients with baseline vitamin D level below 30 ng/mL (75 nmol/L). - No subgroup among patients with both low baseline levels and high follow-up levels as done by the Bischoff-Ferrari pooled analysis[51] In prior systematic reviews: - The Cochrane Collaboration concluded that "vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture."[52]. - Vitamin D given in an individual patient analysis of randomized controlled trials of women with mean age of 76 and mean vitamin D level of about 47 nmol/L, affect on fracture rate was a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99)[51] In a subgroup analysis the benefit was statistically significant for women whose intake was > 800 IU per day.[51] There was a strong, but insignificant trend toward benefit among the 106 patients with baseline vitamin D less than 30 ng/mL (75 nmol/L) and who had the highest actual intake of vitamin D. Much of this benefit may have been due to the trial by Chapuy which studied 3270 women (1765 or 54% completed the 18 months of follow-up) in structured living arrangements with baseline levels of 16 ng/mL and a mean post-treatment level of 42 ng/mL[53] - There was a strong, but insignificant trend toward benefit among the 106 patients with baseline vitamin D less than 30 ng/mL (75 nmol/L) and who had the highest actual intake of vitamin D. Much of this benefit may have been due to the trial by Chapuy which studied 3270 women (1765 or 54% completed the 18 months of follow-up) in structured living arrangements with baseline levels of 16 ng/mL and a mean post-treatment level of 42 ng/mL[53] In patients starting long-term corticosteroid therapy, a randomized control trial found that vitamin D can reduce loss of bone densitiy[54]. ### Patients with osteopososis Vitamin D, when combined with calcium, prevents fractures among patients with osteoporosis according to a systematic review by the Cochrane Collaboration. ## Role in immunomodulation The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects.[55] Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns.[56] VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.[57] VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[8] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.[58] Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.[59] These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection.[55] However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosis and other diseases involving vitamin D hypersensitivity.[60][37][61] A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D.[62] In 2022; the VITAL randomized controlled trial reported a reduction autoimmune disease in among subjects randomized to vitamin D[63]. ## Role in cancer prevention and recovery The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. Although the anti-cancer activity of vitamin D is not fully understood, it is thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related to its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer.[8] In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%.[64] Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer.[65]. A recent study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers.[66] In June 2007, The Canadian Cancer Society began recommending that all adult Canadians consider taking 1000 IU of vitamin D during the fall and winter months (when typically the country's northern latitude prevents sufficient sun-stimulated production of vitamin D). This kind of recommendation is a first for cancer agencies.[67] Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight.[68] ### Randomized controlled trials A randomized controlled trial found no benefit[69]. Previously, in 2017, a randomized controlled trial reported no reduction in cancer among postmenopausal women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL from supplementation with vitamin D3.[70]. Earlier, a trial found benefit amond 1,200 women receiving vitamin D supplementation (1,100 international units (IU) / day). This resulted in a 60% reduction in cancer incidence over four-years, rising to a 77% reduction if cancers diagnosed in the first year (and therefore more likely to have originated prior to the intervention) were excluded.[71][72] ## Role in cardiovascular diseases ### History One of the very first indications of the association between cardiovascular diseases and vitamin D was in the most severe form of the vitamin deficiency, Rickets, in which patients had cardiomyopathy.[73] Evidence of an intracellular vitamin D receptor in rat cardiomyocytes was described in the early 1980's[74] and in human heart tissue in the mid 1990s.[75] Xiang W. et al. provided further evidence of the relationship between vitamin D and cardiovascular diseases in his VDR knockout mouse model, in which the mice had severe cardiac hypertrophy.[76] VDR knockout mice also under-express tissue inhibitors of metalloproteinases (TIMP-1 & TIMP-3) in comparison to the wild-type, which may contribute to increased oxidation of the extracellular matrix proteins and perivascular tissues.[77] Interestingly, spontaneous hypertensive rats (SHR) were found to be more vitamin D deficient as measures of blood pressure increased.[78] Contrary to data in the vitamin D receptor knockout mice model, the wild-type had higher blood pressures compared to the knockout.[79] ### In vitro and animal studies In vitro data showed that 1,25-hydroxyvitamin D has a regulatory effect on myoblast proliferation as well as some rapid genomic effect, suggesting some action independent of transcription.[80] To further explore possible non-genomic effects, Tishkoff et al. explored the location of the VDR intracellularly and found signaling in the T-tubules, close to the sarcoendoplasmic reticulum Ca++- ATPase (SERCA).[81] They also reported accelerated rates of myocyte contraction and relaxation in VDR knockout mice cells as compared to the wild-type. Dahl salt-sensitive rats (DSS) are an interesting animal model to study direct cardiac vitamin D effects on the heart since the DSS rats become vitamin D deficient, hypertensive and develop increased heart mass if fed with high-salt diet. Bodyak et al. showed decreased heart size and improved contraction by m-mode echocardiography in rats treated with paricalcitol versus rats treated with placebo.[82] Atrial natriuretic factor (ANP) was lower in the treated group, findings which are similar to those previously described in cardiomyocyte cell cultures.[83] There were differences shown in the gene expression profiles between DSS treated with paricalcitol versus vehicle. ### Observational studies Multiple epidemiologic studies have shown improved in cardiovascular morbidity and mortality in several populations. One of the earliest associations was shown by Teng et al. in the New England Journal of Medicine in 2003, where they showed a benefit in survival independent of calcium, phosphorus and PTH for patients treated with activated vitamin D.[84] There was controversy regarding the activated vitamin D effects in mortality, because of higher risk of hypercalcemia, hyperposphatemia and their effect in the cardiovascular system. Patients treated with Paricalcitol, an activated vitamin D analogue with less effect on calcium and phosphorus, had improved survival compared to those treated with calcitriol. In further studies in the chronic kidney disease population, the vitamin D level was shown to be predictive of 90-day all-cause and cardiovascular mortality[85] and the administration of activated form of vitamin D was shown to improve survival.[86] Recently, in the New England Journal of Medicine Dr. Lee et al. described how the sicker patients in multiple intesive care units have lower levels of vitamin D.[87] There is discrepancy in the prevalence and in the response to treatment of cardiovascular diseases among different races and ethnicities. In the third National Health and Nutrition Examination Survey (NHANES) black people, who have higher cardiovascular risk compared to whites, had lower levels of 25-hydroxyvitamin D.[88] Moreover, multiple risk factors such as obesity, hypertension and diabetes mellitus were associated with lower 25-hydroxyvitamin D levels. In other studies 25-hydroxyvitamin D levels were inversely correlated with the prevalence of metabolic syndrome,[89] type 2 diabetes mellitus[90] and hypertension.[91] In a cohort study with more than five thousand participants that were followed for twenty years the cumulative incidence of heart failure in black woman was 1.1% and in black men 0.9% compared to 0.8% and 0% in white women and men respectively.[92] Interestingly, paradoxically to other scenarios, the african-american population has a survival advantage compared to whites in hemodialysis. Wolf et al. showed that they are more likely to be treated with activated vitamin D.[93] Therefore, if you compare african-american versus whites in the non-treated population their survival advantage is lost. Zittermann et al. demonstrated that geographic factors such as latitude, altitude, season and place of residency were associated with different cardiovascular risk, mostly for ischemic heart disease.[94] Interestingly, those factors were also associated with 25-hydroxyvitamin D levels. Cardiovascular disease rates were at their zenith in the winter, when the vitamin D levels were at their nadir. Based on studies done by Holick, PhD, MD, we know that the prevalence of vitamin D deficiency is close to somewhere between 40-100% in healthy individuals at the end of the winter in the New England area.[95] Similar seasonal variations have also been shown for heart failure hospitalization rates[96] and in cerebrovascular disease.[97] The Ludwigshafen Risk and Cardiovascular Health Study (LURIC), a prospective cohort design to genetic polymorphisms and biomarkers associated with cardiovascular risks, showed a correlation between 25-hydroxyvitamin D and C-reactive protein (CRP) and interleukin 6 levels (IL-6), serum phospholipid and gluthatione levels and vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1).[98] Dobnig et al. showed that 25-hydroxyvitamin D levels had a significant hazard ratio of 2.08 for cardiovascular mortality comparing the lowest versus the highest quartiles with a follow up close to eight years, and 1.61 for 1,25-hydroxyvitamin D. Results suggest independent predictive value of 25-hydroxyvitamin D and 1,25-hydroxyvitamin D. The results were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism and New York Heart Association functional class. The hazard ratios increased progressively per lower vitamin D level, suggesting a dose-dependent effect and strengthening the association. However, the study assumed that the patients with non-cardiac death had the same probability of dying of cardiac etiologies than the rest of the population, which may not necessarily be true and may bias the estimates. Research indicates that vitamin D plays a role in preventing or reversing coronary disease. As with cancer incidence, the same qualitative inverse correlations exist between coronary disease incidence and serum vitamin D levels,[99] seasonal solar exposure,[100] in temperate latitudes[101] but not tropical latitudes.[102] A nested case-control study with 18,225 men in the Health Professionals Follow-up Study showed that vitamin D deficient people had a relative risk of 2.09 of developing myocardial infarction.[103] Similar findings were also shown in the researchers from the Framingham Offspring study prospectively collected 25-OH D levels in 1739 white individuals without cardiovascular disease or renal disease. For the primary analysis, vitamin D levels were a categorical variable, with cut-offs chosen a priori based on previously published studies. Participants were classified as deficient (<15 ng/ml) or sufficient (>15 ng/ml). Mean level was 19.7 ng/ml among all participants. Low 25-OH D levels were associated with obesity, cigarette smoking, higher systolic blood pressure, diabetes, higher ratio of total to HDL cholesterol, and lower intake of vitamin D or vitamins. Interesting, there was no correlation with physical activity. Over a mean of 7.6 years follow up there were 120 cardiovascular events. A multivariate model was used to correlate 25-OH D status with cardiovascular risk, adjusting for age, sex, blood pressure, medications, diabetes, cigarette smoking, cholesterol, body mass index, and renal function. After adjustment, a 25-OH D level less than 15 ng/ml was independently associated with risk of a cardiovascular event (HR 1.62, CI 1.11 to 2.35, P=0.01). In a three-category model, where participants were classified as sufficient, deficient (10 to 15 ng/ml) or severely deficient (<10 ng/ml), severe deficiency was associated with even greater risk (HR 1.80, CI 1.05 to 3.08, P=0.01). The mechanism by which vitamin D deficiency might increase risk of vascular disease is not entirely known. The authors cite data demonstrating that 1,25-OH D is important for suppression of the renin-angiotensin axis, and possible effects of hyperparathyroidism on myocyte function and vascular inflammation. The possibility always exists that an unmeasured confounder might explain the correlation seen in this study. Nonetheless, it is telling that the majority of participants in this study would qualify as vitamin-D deficient if a cut-off of 20 ng/ml were used, and the body of evidence linking vitamin-D deficiency with chronic illness is impressive. Observational data has shown similar associations of vitamin D not only with coronary artery disease, but with equivalents such as peripheral vascular disease.[104] Differences by race in PVD have also been reported.[105] A retrospective pilot study of hemodialysis patients demonstrated improved diastolic function evaluated with lower E/A ratios on echocardiogram in patients treated with paricalcitol as compared to untreated patients.[106] A cohort of 51 patients was enrolled and followed for 12 months. Treatment was left at discretion of nephrologists. Baseline and 12-month echocardiograms were compared. ### Randomized clinical trials Randomized controlled trials have not found benefit from Vitamin D supplementation[69][107][108]. Cardiovascular disease many be increased when calcium supplementation is added to Vitamin D The treatment group M-mode echocardiography showed pronounced reductions in inverventricular wall thickness, left ventricular posterior wall thickness and left ventricle mass index. There were no differences in blood pressure control, and blood pressure medications were not changed. Data regarding distribution of angiotensin converting enzyme inhibitors and angiotensin receptor blockers between groups is not shown. Plasma renin, angiotensin II and atrial natriuretic peptide decreased over time in the calcitriol group. The study is limited due to its sample size, because it does not specify why some patients received treatment and why some did not, and it does not show the hormonal change in the control group. There are two large randomized double-blind placebo-controlled trials in chronic kidney disease assessing the effect of paricalcitol treatment on diastolic dysfunction, left ventricular mass as well as biomarkers and genetic expression (http://clinicaltrials.gov/ct2/show/NCT00497146 and http://clinicaltrials.gov/ct2/show/NCT00616902 ). These trials promise rigorous data to further characterize the effect, and possible mechanisms of the effect, of activated vitamin D in the heart. ## Role in fibromyalgia # Screening for vitamin D deficieny The United States Preventive Services Task Force in 2021 gave an "I" recommendation, " the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults", for screening for vitamin D deficiency[109]. The USPSTF recommendation was based on a systematic review[110]	https://www.wikidoc.org/index.php/Calciferol
2102dd801a50508f4252299a6c54aca4fea4a143	wikidoc	Scheelite	Scheelite Scheelite is a calcium tungstate mineral with the chemical formula CaWO4. It is an important ore of tungsten. Well-formed crystals are sought by collectors and are occasionally fashioned into gemstones when suitably free of flaws. Scheelite has been synthesized via the Czochralski process; the material produced may be used to imitate diamond, as a scintillator, or as a solid state lasing medium. # Properties Its crystals are in the tetragonal crystal system, appearing as dipyramidal pseudo-octahedra. Colors include golden yellow, brownish green to dark brown, pinkish to reddish gray, and colorless. Transparency ranges from translucent to transparent and crystal faces are highly lustrous (vitreous to adamantine). Scheelite possesses distinct cleavage and its fracture may be subconchoidal to uneven. Its specific gravity is high at 5.9–6.1 and its hardness is low at 4.5–5.(Bulletin, p81). Aside from pseudo-octahedra, scheelite may be columnar, granular, tabular or massive in habit. Twinning is also commonly observed and crystal faces may be striated. Scheelite streaks white and is brittle. Gems cut from transparent material are fragile yet attractive: Scheelite's refractive index (1.918–1.937 uniaxial positive, with a maximum birefringence of 0.016) and dispersion (0.026) are both moderately high. These factors combine to result in scheelite's high lustre and perceptible "fire", approaching that of diamond. Owing to low hardness, however, cut scheelites are best enjoyed unset as valuable collector's pieces. Rockhounds treasure scheelite for its fluorescent properties: under shortwave ultraviolet light, the mineral glows a bright sky-blue. The presence of molybdenum trace impurities occasionally results in a green glow. # Composition The scheelite structure consists of isolated tetrahedra. The tetrahedra form (non touching) 1D chains. There are two directions that the "chains" line up (Figure 3). Tungsten deposits only occur where mineralization has taken place at high temperatures and pressures. Research shows these were deposited mostly between 200 to 500 degrees Celsius, and from 200 to 1,500 bars. (Ore deposits of the western states, p518, 535). # Special Characteristics Scheelite is often found to have a grayish white color; yellowish, brownish or translucent (Figure 1). Its streak is white. Scheelite has a greasy luster which helps distinguish it. Moreover, when looking for scheelite, miners use ultraviolet light which causes it to fluoresce with a bright blue color. Many prospectors for scheelite have made good use of scheelite's typically bright blue fluorescence by searching for scheelite deposits by night with ultraviolet lamps (Figure 2). Many old mines have even been reopened after examination of the mine shafts with ultraviolet lamps have proven that the ore is not quite yet exhausted. Tungsten can be combined with carbon, and when it does, it forms tungsten carbide. This substance is one of the hardest known other than diamond. This substance is used in abrasive wheels and cutting tools, which the demand for is steadily increasing. (Bulletin, p81). # Synthetics Although it is now uncommon as a diamond imitation—much more convincing products, like cubic zirconia and moissanite have long since superseded it—synthetic scheelite is occasionally offered as natural scheelite, and collectors may thus be fooled into paying high prices for them. Gemmologists distinguish natural scheelite from synthetic material mainly by microscopic examination: Natural material is very seldom without internal growth features and inclusions (imperfections), while synthetic material is usually very clean. Distinctly artificial curved striae and clouds of minute gas bubbles may also be obvserved in synthetic scheelite. The visible absorption spectrum of scheelite, as seen by a hand-held (direct vision) spectroscope, may also be of use: Most natural stones show a number of faint absorption lines in the yellow region of the spectrum (~585 nm) due to praseodymium and neodymium trace impurities. Conversely, synthetic scheelite is often without such a spectrum. Some synthetics may however be doped with neodymium or other rare earth elements, but the spectrum produced is unlike that of natural stones. # History Named in 1821 after Carl Wilhelm Scheele (1742-1786).(The Manual of Mineral Science, p426). The Swedish chemist and apothecary, proved the existence of tungstic oxide in the mineral in 1781. Born in Stralsund, Pomerania, he grew up studying chemistry. He then opened a pharmacy where he continued his research and soon made many original discoveries. Some of the papers he wrote were related to many important minerals today such as quartz, alum and clay. He also made many important discoveries not related to minerals such as lactic acid being the source of the acidity of sour milk. His discovery in 1781 was probably his call to fame, where a mineral was named after him. This discovery was about the composition of the mineral Tungsten, later called Scheelite (Calcium Tungstate). From this he obtained tungstic acid, which he is also famous for discovering.	Scheelite Template:Infobox mineral Scheelite is a calcium tungstate mineral with the chemical formula CaWO4. It is an important ore of tungsten. Well-formed crystals are sought by collectors and are occasionally fashioned into gemstones when suitably free of flaws. Scheelite has been synthesized via the Czochralski process; the material produced may be used to imitate diamond, as a scintillator, or as a solid state lasing medium. # Properties Its crystals are in the tetragonal crystal system, appearing as dipyramidal pseudo-octahedra. Colors include golden yellow, brownish green to dark brown, pinkish to reddish gray, and colorless. Transparency ranges from translucent to transparent and crystal faces are highly lustrous (vitreous to adamantine). Scheelite possesses distinct cleavage and its fracture may be subconchoidal to uneven. Its specific gravity is high at 5.9–6.1 and its hardness is low at 4.5–5.(Bulletin, p81). Aside from pseudo-octahedra, scheelite may be columnar, granular, tabular or massive in habit. Twinning is also commonly observed and crystal faces may be striated. Scheelite streaks white and is brittle. Gems cut from transparent material are fragile yet attractive: Scheelite's refractive index (1.918–1.937 uniaxial positive, with a maximum birefringence of 0.016) and dispersion (0.026) are both moderately high. These factors combine to result in scheelite's high lustre and perceptible "fire", approaching that of diamond. Owing to low hardness, however, cut scheelites are best enjoyed unset as valuable collector's pieces. Rockhounds treasure scheelite for its fluorescent properties: under shortwave ultraviolet light, the mineral glows a bright sky-blue. The presence of molybdenum trace impurities occasionally results in a green glow. # Composition The scheelite structure consists of isolated tetrahedra. The tetrahedra form (non touching) 1D chains. There are two directions that the "chains" line up (Figure 3). Tungsten deposits only occur where mineralization has taken place at high temperatures and pressures. Research shows these were deposited mostly between 200 to 500 degrees Celsius, and from 200 to 1,500 bars. (Ore deposits of the western states, p518, 535). # Special Characteristics Scheelite is often found to have a grayish white color; yellowish, brownish or translucent (Figure 1). Its streak is white. Scheelite has a greasy luster which helps distinguish it. Moreover, when looking for scheelite, miners use ultraviolet light which causes it to fluoresce with a bright blue color. Many prospectors for scheelite have made good use of scheelite's typically bright blue fluorescence by searching for scheelite deposits by night with ultraviolet lamps (Figure 2). Many old mines have even been reopened after examination of the mine shafts with ultraviolet lamps have proven that the ore is not quite yet exhausted. Tungsten can be combined with carbon, and when it does, it forms tungsten carbide. This substance is one of the hardest known other than diamond. This substance is used in abrasive wheels and cutting tools, which the demand for is steadily increasing. (Bulletin, p81). # Synthetics Although it is now uncommon as a diamond imitation—much more convincing products, like cubic zirconia and moissanite have long since superseded it—synthetic scheelite is occasionally offered as natural scheelite, and collectors may thus be fooled into paying high prices for them. Gemmologists distinguish natural scheelite from synthetic material mainly by microscopic examination: Natural material is very seldom without internal growth features and inclusions (imperfections), while synthetic material is usually very clean. Distinctly artificial curved striae and clouds of minute gas bubbles may also be obvserved in synthetic scheelite. The visible absorption spectrum of scheelite, as seen by a hand-held (direct vision) spectroscope, may also be of use: Most natural stones show a number of faint absorption lines in the yellow region of the spectrum (~585 nm) due to praseodymium and neodymium trace impurities. Conversely, synthetic scheelite is often without such a spectrum. Some synthetics may however be doped with neodymium or other rare earth elements, but the spectrum produced is unlike that of natural stones. # History Named in 1821 after Carl Wilhelm Scheele (1742-1786).(The Manual of Mineral Science, p426). The Swedish chemist and apothecary, proved the existence of tungstic oxide in the mineral in 1781. Born in Stralsund, Pomerania, he grew up studying chemistry. He then opened a pharmacy where he continued his research and soon made many original discoveries. Some of the papers he wrote were related to many important minerals today such as quartz, alum and clay. He also made many important discoveries not related to minerals such as lactic acid being the source of the acidity of sour milk. His discovery in 1781 was probably his call to fame, where a mineral was named after him. This discovery was about the composition of the mineral Tungsten, later called Scheelite (Calcium Tungstate). From this he obtained tungstic acid, which he is also famous for discovering.	https://www.wikidoc.org/index.php/Calcium_tungstate
50d020c0655c4b6f195ce2ddf6dedbfbe8b4aeb3	wikidoc	Caldesmon	Caldesmon Caldesmon is a protein that in humans is encoded by the CALD1 gene. Caldesmon is a calmodulin binding protein. Like calponin, caldesmon tonically inhibits the ATPase activity of myosin in smooth muscle. This gene encodes a calmodulin- and actin-binding protein that plays an essential role in the regulation of smooth muscle and nonmuscle contraction. The conserved domain of this protein possesses the binding activities to Ca++-calmodulin, actin, tropomyosin, myosin, and phospholipids. This protein is a potent inhibitor of the actin-tropomyosin activated myosin MgATPase, and serves as a mediating factor for Ca++-dependent inhibition of smooth muscle contraction. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. # Immunochemistry In diagnostic immunochemistry, caldesmon is a marker for smooth muscle differentiation.	Caldesmon Caldesmon is a protein that in humans is encoded by the CALD1 gene.[1][2] Caldesmon is a calmodulin binding protein. Like calponin, caldesmon tonically inhibits the ATPase activity of myosin in smooth muscle. This gene encodes a calmodulin- and actin-binding protein that plays an essential role in the regulation of smooth muscle and nonmuscle contraction. The conserved domain of this protein possesses the binding activities to Ca++-calmodulin, actin, tropomyosin, myosin, and phospholipids. This protein is a potent inhibitor of the actin-tropomyosin activated myosin MgATPase, and serves as a mediating factor for Ca++-dependent inhibition of smooth muscle contraction. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms.[2] # Immunochemistry In diagnostic immunochemistry, caldesmon is a marker for smooth muscle differentiation.	https://www.wikidoc.org/index.php/Caldesmon
97d4b74f95dc3a3130a382b666d676c4d83dcbc4	wikidoc	Camazepam	Camazepam # Overview Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties. # Pharmacology Camazepam, like others benzodiazepines, produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the GABAA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of camazepam on the nervous system. Compared to other benzodiazepines, it has reduced side effects such as impaired cognition, reaction times and coordination. which makes it best suited as an anxiolytic because of these reduced sides effects. Animal studies have shown camazepam and its active metabolites possess anticonvulsant properties. Unlike other benzodiazepines it does not disrupt normal sleep patterns. Camazepam has been shown in animal experiments to have a very low affinity for benzodiazepine receptors compared to other benzodiazepines. Compared to temazepam, camazepam has shown roughly equal anxiolytic properties, and less anticonvulsant, sedative and motor-impairing properties. # Pharmacokinetics Following oral administration, camazepam is almost completely absorbed into the bloodstream, with 90 percent bioavailability achieved in humans. In the human camazepam is metabolised into the active metabolite temazepam. Studies in dogs have shown that the half-life of the terminal elimination phase ranged from 6.4 to 10.5 h. # Medical uses Camazepam is indicated for the short-term treatment of insomnia and anxiety. As with other benzodiazepines, its use should be reserved for those patients in which the sleep disorder is severe, disabling or causes marked distress. # Adverse effects With higher doses such as 40 mg of camazepam, impairments similar to those caused by other benzodiazepines manifest as disrupted sleep patterns and impaired cognitive performance. Skin disorders have been reported with use of camazepam however. Camazepam is believed to increase attention. # Contraindications Use of camazepam is contraindicated in subjects with known hypersensitivity to drug or allergy to other drugs in the benzodiazepine class or any excipients contained in the pharmaceutical form. Use of camazepam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression or cronic pulmonary insufficiency.	Camazepam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Camazepam[1] is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam.[2] While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties[3] it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties. # Pharmacology Camazepam, like others benzodiazepines, produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the GABAA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of camazepam on the nervous system. Compared to other benzodiazepines, it has reduced side effects such as impaired cognition, reaction times and coordination.[4][5][6][7][8] which makes it best suited as an anxiolytic because of these reduced sides effects. Animal studies have shown camazepam and its active metabolites possess anticonvulsant properties.[9] Unlike other benzodiazepines it does not disrupt normal sleep patterns.[10] Camazepam has been shown in animal experiments to have a very low affinity for benzodiazepine receptors compared to other benzodiazepines.[11] Compared to temazepam, camazepam has shown roughly equal anxiolytic properties, and less anticonvulsant, sedative and motor-impairing properties. # Pharmacokinetics Following oral administration, camazepam is almost completely absorbed into the bloodstream, with 90 percent bioavailability achieved in humans.[12] In the human camazepam is metabolised into the active metabolite temazepam.[13] Studies in dogs have shown that the half-life of the terminal elimination phase ranged from 6.4 to 10.5 h.[14] # Medical uses Camazepam is indicated for the short-term treatment of insomnia and anxiety. As with other benzodiazepines, its use should be reserved for those patients in which the sleep disorder is severe, disabling or causes marked distress. # Adverse effects With higher doses such as 40 mg of camazepam, impairments similar to those caused by other benzodiazepines manifest as disrupted sleep patterns and impaired cognitive performance.[15] Skin disorders have been reported with use of camazepam however.[16] Camazepam is believed to increase attention.[17] # Contraindications Use of camazepam is contraindicated in subjects with known hypersensitivity to drug or allergy to other drugs in the benzodiazepine class or any excipients contained in the pharmaceutical form. Use of camazepam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression or cronic pulmonary insufficiency.	https://www.wikidoc.org/index.php/Camazepam
61a503ca0d2ac1b2b29aaaef620c532224961650	wikidoc	Cand.med.	Cand.med. Candidatus medicinæ (male), Candidata medicinæ (female), abbreviated cand. med. is a academic degree awarded in Denmark and Norway following a six year medical school education. The education is offered at the Norwegian University of Science and Technology, University of Bergen, University of Oslo and University of Tromsø. Following the education, candidates are permitted to work as rotation doctor, first at a hospital for one year and then six months as a general practitioner. After the rotation service, the candidate may receive formal qualifications as a medical doctor. The first Norwegian to receive this degree was Carl Schultz in 1817. Along with the cand. med. vet., cand. psychol. and cand. theol. it is the only Latin title to survive the "Quality Reform" in Norway. no:Candidatus medicinæ	Cand.med. Candidatus medicinæ (male), Candidata medicinæ (female), abbreviated cand. med. is a academic degree awarded in Denmark and Norway following a six year medical school education. The education is offered at the Norwegian University of Science and Technology, University of Bergen, University of Oslo and University of Tromsø. Following the education, candidates are permitted to work as rotation doctor, first at a hospital for one year and then six months as a general practitioner. After the rotation service, the candidate may receive formal qualifications as a medical doctor. The first Norwegian to receive this degree was Carl Schultz in 1817. Along with the cand. med. vet., cand. psychol. and cand. theol. it is the only Latin title to survive the "Quality Reform" in Norway. Template:Cand.nav.box. no:Candidatus medicinæ Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Cand.med.
426158b7a17ff7905dc98325560537c7600a3049	wikidoc	Cangrelor	Cangrelor # 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 Cangrelor is a P2Y12 platelet inhibitor that is FDA approved for the prevention of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor and undergoing percutaneous coronary intervention (PCI). Common adverse reactions include bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cangrelor is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. The recommended dosage of Cangrelor is a 30 mcg/kg IV bolus followed immediately by a 4 mcg/kg/min IV infusion. Initiate the bolus infusion prior to PCI. The maintenance infusion should ordinarily be continued for at least 2 hours or for the duration of PCI, whichever is longer. - Transitioning Patients to Oral P2Y12 Therapy To maintain platelet inhibition after discontinuation of Cangrelor infusion, an oral P2Y12 platelet inhibitor should be administered. Administer one as described below: - Ticagrelor: 180 mg at any time during Cangrelor infusion or immediately after discontinuation. - Prasugrel: 60 mg immediately after discontinuation of Cangrelor. Do not administer prasugrel prior to discontinuation of Cangrelor. - Clopidogrel: 600 mg immediately after discontinuation of Cangrelor. Do not administer clopidogrel prior to discontinuation of Cangrelor. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) # Contraindications Cangrelor is contraindicated in patients with significant active bleeding. Cangrelor is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to Cangrelor or any component of the product. # Warnings Drugs that inhibit platelet P2Y12 function, including Cangrelor, increase the risk of bleeding. In CHAMPION PHOENIX bleeding events of all severities were more common with Cangrelor than with clopidogrel. Bleeding complications with Cangrelor were consistent across a variety of clinically important subgroups (see Figure 1). Once Cangrelor is discontinued, there is no antiplatelet effect after an hour. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Cangrelor has been evaluated in 13,301 subjects in controlled trials, in whom, 5,529 were in the CHAMPION PHOENIX trial. Bleeding There was a greater incidence of bleeding with Cangrelor than with clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Cangrelor (see Table 1 and Figure 1). - Table 1: Major Bleeding Results in the CHAMPION PHOENIX Study (Non-CABG related Bleeding)(a) KENGREAL: Cangrelor's Brand name - Figure 1:Bleeding Results in the CHAMPION PHOENIX Study(a) (All Non-CABG related) KENGREAL: Cangrelor's Brand name Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Drug Discontinuation In CHAMPION PHOENIX the rate of discontinuation for bleeding events was 0.3% for Cangrelor and 0.1% for clopidogrel. Discontinuation for non-bleeding adverse events was low and similar for Cangrelor (0.6%) and for clopidogrel (0.4%). Coronary artery dissection, coronary artery perforation, and dyspnea were the most frequent events leading to discontinuation in patients treated with Cangrelor. Non-Bleeding Adverse Reactions - Hypersensitivity Serious cases of hypersensitivity were more frequent with Cangrelor (7/13301) than with control (2/12861). These included anaphylactic reactions, anaphylactic shock, bronchospasm, angioedema, and stridor. - Decreased renal function Worsening renal function was reported in 3.2% of Cangrelor patients with severe renal impairment (creatinine clearance <30 mL/min) compared to 1.4% of clopidogrel patients with severe renal impairment. - Dyspnea Dyspnea was reported more frequently in patients treated with Cangrelor (1.3%) than with control (0.4%). ## Postmarketing Experience There is limited information regarding Cangrelor Postmarketing Experience in the drug label. # Drug Interactions If clopidogrel or prasugrel are administered during Cangrelor infusion, they will have no antiplatelet effect until the next dose is administered. Clopidogrel and prasugrel, therefore, should not be administered until Cangrelor infusion is discontinued. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C . There are no adequate and well-controlled studies of Cangrelor in pregnant women. Cangrelor did not produce malformations in either the rat or rabbit reproductive studies, and is not considered to be a teratogen. In embryo-fetal development studies in rats, Cangrelor produced dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals at plasma concentration of approximately 5 times lower than that achieved in the PCI setting at the maximum recommended human dose (MRHD). In rabbits, Cangrelor was associated with increased incidences of abortion and intrauterine losses, as well as fetal growth retardation at plasma concentrations of approximately 12 times higher than the PCI setting at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cangrelor in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cangrelor during labor and delivery. ### Nursing Mothers It is not known whether Cangrelor is excreted in human milk. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use In CHAMPION PHOENIX, 18% of patients were ≥75 years. No overall differences in safety or effectiveness were observed between these patients and those patients <75 years. ### Gender There is no FDA guidance on the use of Cangrelor with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cangrelor with respect to specific racial populations. ### Renal Impairment No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. ### Hepatic Impairment Cangrelor has not been studied in patients with hepatic impairment. However, the metabolism of Cangrelor is not dependent of hepatic function, so that dosage adjustment is not required for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cangrelor in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cangrelor in patients who are immunocompromised. # Administration and Monitoring ### Administration Cangrelor is intended for IV administration, after reconstitution and dilution. Preparation For each 50 mg/vial, reconstitute by adding 5 mL of Sterile Water for Injection. Swirl gently until all material is dissolved. Avoid vigorous mixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and the reconstituted material is a clear, colorless to pale yellow solution. Reconstitute the vial prior to dilution in a bag. Parenteral drug products should be inspected visually for particulate matter after reconstitution. Do not use without dilution. Before administration, each reconstituted vial must be diluted further with Normal Saline (Sodium Chloride Injection 0.9% USP) or 5% Dextrose Injection USP. Withdraw the contents from one reconstituted vial and add to one 250 mL saline bag. Mix the bag thoroughly. This dilution will result in a concentration of 200 mcg/mL and should be sufficient for at least 2 hours of dosing. Patients 100 kg and over will require a minimum of 2 bags. Reconstituted Cangrelor should be diluted immediately. Diluted Cangrelor is stable for up to 12 hours in 5% Dextrose Injection and 24 hours in Normal Saline at Room Temperature. Discard any unused portion of reconstituted solution remaining in the vial. Administration Administer Cangrelor via a dedicated IV line. Administer the bolus volume rapidly (<1 minute), from the diluted bag via manual IV push or pump. Ensure the bolus is completely administered before the start of PCI. Start the infusion immediately after administration of the bolus. ### Monitoring There is limited information regarding Cangrelor Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cangrelor and IV administrations. # Overdosage There is no specific treatment to reverse the antiplatelet effect of Cangrelor but the effect is gone within one hour after the drug is discontinued. In clinical trials, 36 patients received an overdose of Cangrelor, ranging from 36 to 300 mcg/kg (bolus dose) or 4.8 to 13.7 mcg/kg/min (infusion dose). The maximum overdose received was 10 times the PCI bolus dose or 3.5 times the PCI infusion dose in 4 patients. No clinical sequela were noted as a result of overdose following completion of Cangrelor therapy. # Pharmacology ## Mechanism of Action Cangrelor is a direct P2Y12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent further signaling and platelet activation. ## Structure There is limited information regarding Cangrelor Structure in the drug label. ## Pharmacodynamics Cangrelor inhibits activation and aggregation of platelets. After administration of a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2 minutes. Figure 2 shows the effect on platelet activity, and its relation to Cangrelor plasma concentration, of administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV infusion, of Cangrelor. The anti-platelet effect is maintained for the duration of the infusion. After discontinuation of the infusion, the anti-platelet effect decreases rapidly and platelet function returns to normal within 1 hour. - Figure 2: Cangrelor PD Characteristics ## Pharmacokinetics Cangrelor administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. Cangrelor is rapidly distributed and metabolized, reaching Cmax within 2 minutes after administration of an intravenous bolus followed by infusion. - Distribution In a study in healthy volunteers, Cangrelor administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of 3.9 L. Plasma protein binding of Cangrelor is about 97-98%. - Metabolism Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity. Cangrelor’s metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes. - Elimination Following IV administration of Cangrelor 58% of radioactivity was recovered in urine. The remaining 35% of radioactivity was in feces, presumably following biliary excretion. The average elimination half-life of Cangrelor is about 3-6 minutes. - Specific Populations Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function. No dose adjustment is needed for these factors. - Weight Although weight was a significant covariate for PK with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. - Drug-Drug Interactions Co-administration of Cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the PK/PD of Cangrelor. In clinical trials Cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions. The expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a Cangrelor infusion. In contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during Cangrelor infusion. - Figure 3: Inhibition (Mean) of 20 µM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Cangrelor 30 mcg/kg Bolus and 120-minute 4 mcg/kg Infusion with Transition to Other Oral P2Y12 Platelet Inhibitors. As shown in Figure 3, discontinuation of Cangrelor infusion, followed by administration of the irreversible P2Y12 platelet inhibitors clopidogrel and prasugrel led to a 1-hour decrease in IPA followed by an increase in inhibition of platelet aggregation beginning at about one hour. This time course of platelet inhibition reflects the pharmacokinetics of Cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). Administration of ticagrelor, a reversible P2Y12 platelet inhibitor, during the Cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hours following discontinuation of the Cangrelor infusion. Administering ticagrelor during Cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor. In vitro studies suggest that neither Cangrelor nor its major metabolites inhibit the activity of the hepatic CYP isoenzymes at therapeutic concentrations. Therefore, Cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents. ## Nonclinical Toxicology Carcinogenesis No carcinogenicity studies were conducted. Mutagenesis Cangrelor was non-mutagenic and non-clastogenic in genetic toxicology studies, including in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice. Impairment of Fertility Cangrelor had no significant effect on male or female rats fertility treated for 28 days, or on early embryonic development at steady state plasma concentration (Css) of approximately the same as that achieved in the PCI setting at the MRHD. # Clinical Studies The CHAMPION PHOENIX trial was intended to test whether faster platelet inhibition with Cangrelor at the time of PCI would reduce the rate of periprocedural thrombotic events compared to a drug with a slower antiplatelet effect, clopidogrel, given at about the time of PCI. It was a randomized, double-blind study in which patients with coronary artery disease (stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy including aspirin and heparin or bivalirudin were randomized 1:1 to Cangrelor (n=5472) or to clopidogrel 300 or 600 mg (n=5470). Patients who had already taken an oral P2Y12 platelet inhibitor were not eligible to enroll. Patients administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was planned were also not eligible to enroll. PHOENIX was thus a study of people undergoing PCI who had not been previously treated with anti-platelet therapy other than aspirin. The primary outcome measure was the first occurrence of any one of the composite endpoint of all-cause mortality, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) within 48 hours after randomization. Cangrelor was administered as 30 mcg/kg bolus followed by 4 mcg/kg/min infusion for 2 to 4 hours. Clopidogrel 600 mg was administered immediately at the end of the Cangrelor infusion in patients randomized to Cangrelor. Clopidogrel 300 mg or 600 mg was administered shortly before PCI or shortly afterward, in patients randomized to clopidogrel. Cangrelor significantly reduced the occurrence of primary composite endpoint events compared to clopidogrel (relative risk reduction 22%). Most of the effect was a reduction in post-procedural MIs detected solely by elevations in CK-MB (type 4a MI). Cangrelor did not reduce the risk of death. Table 2 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. - Table 2: Primary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population(a)) KENGREAL: Cangrelor's Brand name A supplementary analysis was also performed omitting two subcomponent events of the primary endpoint that were of lesser clinical significance: intraprocedural stent thrombosis (defined as a new or increasing thrombus within or adjacent to a deployed stent occurring during the index PCI procedure), and myocardial infarction with less than a 10-fold increase in CK-MB, or with less than a 5-fold increase in CK-MB in the presence of new Q waves or new left bundle branch block (LBBB). These results are shown in Table 3. - Table 3: Supplementary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population) KENGREAL: Cangrelor's Brand name The effect of Cangrelor appeared to be consistent in a variety of pre-specified and other clinically important subgroups (see Figure 4). - Figure 4: CHAMPION PHOENIX Study: Primary Efficacy Endpoint by Subgroup (mITT Population(a)) KENGREAL: Cangrelor's Brand name Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Two additional concurrent clinical trials of the effect of Cangrelor in patients undergoing percutaneous coronary intervention, CHAMPION PCI and CHAMPION PLATFORM were conducted and terminated early for futility. They were completed prior to the design and conduct of CHAMPION PHOENIX. The comparative characteristics and outcomes of each trial are shown in Table 4. - Table 4: Summary of the CHAMPION Trials # How Supplied Cangrelor is supplied as a sterile lyophilized powder in single-use 10 mL vials. - NDC # 65293-003-01: 10 mL vial containing 50 mg Cangrelor - NDC # 65293-003-10: 10 count of 10 mL vials containing 50 mg Cangrelor ## Storage Vials of Cangrelor should be stored at USP Controlled Room Temperature, . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cangrelor Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cangrelor interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names KENGREAL® # Look-Alike Drug Names There is limited information regarding Cangrelor Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cangrelor Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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 Cangrelor is a P2Y12 platelet inhibitor that is FDA approved for the prevention of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor and undergoing percutaneous coronary intervention (PCI). Common adverse reactions include bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cangrelor is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. The recommended dosage of Cangrelor is a 30 mcg/kg IV bolus followed immediately by a 4 mcg/kg/min IV infusion. Initiate the bolus infusion prior to PCI. The maintenance infusion should ordinarily be continued for at least 2 hours or for the duration of PCI, whichever is longer. - Transitioning Patients to Oral P2Y12 Therapy To maintain platelet inhibition after discontinuation of Cangrelor infusion, an oral P2Y12 platelet inhibitor should be administered. Administer one as described below: - Ticagrelor: 180 mg at any time during Cangrelor infusion or immediately after discontinuation. - Prasugrel: 60 mg immediately after discontinuation of Cangrelor. Do not administer prasugrel prior to discontinuation of Cangrelor. - Clopidogrel: 600 mg immediately after discontinuation of Cangrelor. Do not administer clopidogrel prior to discontinuation of Cangrelor. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) # Contraindications Cangrelor is contraindicated in patients with significant active bleeding. Cangrelor is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to Cangrelor or any component of the product. # Warnings Drugs that inhibit platelet P2Y12 function, including Cangrelor, increase the risk of bleeding. In CHAMPION PHOENIX bleeding events of all severities were more common with Cangrelor than with clopidogrel. Bleeding complications with Cangrelor were consistent across a variety of clinically important subgroups (see Figure 1). Once Cangrelor is discontinued, there is no antiplatelet effect after an hour. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Cangrelor has been evaluated in 13,301 subjects in controlled trials, in whom, 5,529 were in the CHAMPION PHOENIX trial. Bleeding There was a greater incidence of bleeding with Cangrelor than with clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Cangrelor (see Table 1 and Figure 1). - Table 1: Major Bleeding Results in the CHAMPION PHOENIX Study (Non-CABG related Bleeding)(a) KENGREAL: Cangrelor's Brand name - Figure 1:Bleeding Results in the CHAMPION PHOENIX Study(a) (All Non-CABG related) KENGREAL: Cangrelor's Brand name Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Drug Discontinuation In CHAMPION PHOENIX the rate of discontinuation for bleeding events was 0.3% for Cangrelor and 0.1% for clopidogrel. Discontinuation for non-bleeding adverse events was low and similar for Cangrelor (0.6%) and for clopidogrel (0.4%). Coronary artery dissection, coronary artery perforation, and dyspnea were the most frequent events leading to discontinuation in patients treated with Cangrelor. Non-Bleeding Adverse Reactions - Hypersensitivity Serious cases of hypersensitivity were more frequent with Cangrelor (7/13301) than with control (2/12861). These included anaphylactic reactions, anaphylactic shock, bronchospasm, angioedema, and stridor. - Decreased renal function Worsening renal function was reported in 3.2% of Cangrelor patients with severe renal impairment (creatinine clearance <30 mL/min) compared to 1.4% of clopidogrel patients with severe renal impairment. - Dyspnea Dyspnea was reported more frequently in patients treated with Cangrelor (1.3%) than with control (0.4%). ## Postmarketing Experience There is limited information regarding Cangrelor Postmarketing Experience in the drug label. # Drug Interactions If clopidogrel or prasugrel are administered during Cangrelor infusion, they will have no antiplatelet effect until the next dose is administered. Clopidogrel and prasugrel, therefore, should not be administered until Cangrelor infusion is discontinued. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C . There are no adequate and well-controlled studies of Cangrelor in pregnant women. Cangrelor did not produce malformations in either the rat or rabbit reproductive studies, and is not considered to be a teratogen. In embryo-fetal development studies in rats, Cangrelor produced dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals at plasma concentration of approximately 5 times lower than that achieved in the PCI setting at the maximum recommended human dose (MRHD). In rabbits, Cangrelor was associated with increased incidences of abortion and intrauterine losses, as well as fetal growth retardation at plasma concentrations of approximately 12 times higher than the PCI setting at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cangrelor in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cangrelor during labor and delivery. ### Nursing Mothers It is not known whether Cangrelor is excreted in human milk. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use In CHAMPION PHOENIX, 18% of patients were ≥75 years. No overall differences in safety or effectiveness were observed between these patients and those patients <75 years. ### Gender There is no FDA guidance on the use of Cangrelor with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cangrelor with respect to specific racial populations. ### Renal Impairment No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. ### Hepatic Impairment Cangrelor has not been studied in patients with hepatic impairment. However, the metabolism of Cangrelor is not dependent of hepatic function, so that dosage adjustment is not required for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cangrelor in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cangrelor in patients who are immunocompromised. # Administration and Monitoring ### Administration Cangrelor is intended for IV administration, after reconstitution and dilution. Preparation For each 50 mg/vial, reconstitute by adding 5 mL of Sterile Water for Injection. Swirl gently until all material is dissolved. Avoid vigorous mixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and the reconstituted material is a clear, colorless to pale yellow solution. Reconstitute the vial prior to dilution in a bag. Parenteral drug products should be inspected visually for particulate matter after reconstitution. Do not use without dilution. Before administration, each reconstituted vial must be diluted further with Normal Saline (Sodium Chloride Injection 0.9% USP) or 5% Dextrose Injection USP. Withdraw the contents from one reconstituted vial and add to one 250 mL saline bag. Mix the bag thoroughly. This dilution will result in a concentration of 200 mcg/mL and should be sufficient for at least 2 hours of dosing. Patients 100 kg and over will require a minimum of 2 bags. Reconstituted Cangrelor should be diluted immediately. Diluted Cangrelor is stable for up to 12 hours in 5% Dextrose Injection and 24 hours in Normal Saline at Room Temperature. Discard any unused portion of reconstituted solution remaining in the vial. Administration Administer Cangrelor via a dedicated IV line. Administer the bolus volume rapidly (<1 minute), from the diluted bag via manual IV push or pump. Ensure the bolus is completely administered before the start of PCI. Start the infusion immediately after administration of the bolus. ### Monitoring There is limited information regarding Cangrelor Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cangrelor and IV administrations. # Overdosage There is no specific treatment to reverse the antiplatelet effect of Cangrelor but the effect is gone within one hour after the drug is discontinued. In clinical trials, 36 patients received an overdose of Cangrelor, ranging from 36 to 300 mcg/kg (bolus dose) or 4.8 to 13.7 mcg/kg/min (infusion dose). The maximum overdose received was 10 times the PCI bolus dose or 3.5 times the PCI infusion dose in 4 patients. No clinical sequela were noted as a result of overdose following completion of Cangrelor therapy. # Pharmacology ## Mechanism of Action Cangrelor is a direct P2Y12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent further signaling and platelet activation. ## Structure There is limited information regarding Cangrelor Structure in the drug label. ## Pharmacodynamics Cangrelor inhibits activation and aggregation of platelets. After administration of a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2 minutes. Figure 2 shows the effect on platelet activity, and its relation to Cangrelor plasma concentration, of administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV infusion, of Cangrelor. The anti-platelet effect is maintained for the duration of the infusion. After discontinuation of the infusion, the anti-platelet effect decreases rapidly and platelet function returns to normal within 1 hour. - Figure 2: Cangrelor PD Characteristics ## Pharmacokinetics Cangrelor administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. Cangrelor is rapidly distributed and metabolized, reaching Cmax within 2 minutes after administration of an intravenous bolus followed by infusion. - Distribution In a study in healthy volunteers, Cangrelor administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of 3.9 L. Plasma protein binding of Cangrelor is about 97-98%. - Metabolism Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity. Cangrelor’s metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes. - Elimination Following IV administration of [3H] Cangrelor 58% of radioactivity was recovered in urine. The remaining 35% of radioactivity was in feces, presumably following biliary excretion. The average elimination half-life of Cangrelor is about 3-6 minutes. - Specific Populations Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function. No dose adjustment is needed for these factors. - Weight Although weight was a significant covariate for PK with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. - Drug-Drug Interactions Co-administration of Cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the PK/PD of Cangrelor. In clinical trials Cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions. The expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a Cangrelor infusion. In contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during Cangrelor infusion. - Figure 3: Inhibition (Mean) of 20 µM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Cangrelor 30 mcg/kg Bolus and 120-minute 4 mcg/kg Infusion with Transition to Other Oral P2Y12 Platelet Inhibitors. As shown in Figure 3, discontinuation of Cangrelor infusion, followed by administration of the irreversible P2Y12 platelet inhibitors clopidogrel and prasugrel led to a 1-hour decrease in IPA followed by an increase in inhibition of platelet aggregation beginning at about one hour. This time course of platelet inhibition reflects the pharmacokinetics of Cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). Administration of ticagrelor, a reversible P2Y12 platelet inhibitor, during the Cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hours following discontinuation of the Cangrelor infusion. Administering ticagrelor during Cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor. In vitro studies suggest that neither Cangrelor nor its major metabolites inhibit the activity of the hepatic CYP isoenzymes at therapeutic concentrations. Therefore, Cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents. ## Nonclinical Toxicology Carcinogenesis No carcinogenicity studies were conducted. Mutagenesis Cangrelor was non-mutagenic and non-clastogenic in genetic toxicology studies, including in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice. Impairment of Fertility Cangrelor had no significant effect on male or female rats fertility treated for 28 days, or on early embryonic development at steady state plasma concentration (Css) of approximately the same as that achieved in the PCI setting at the MRHD. # Clinical Studies The CHAMPION PHOENIX trial was intended to test whether faster platelet inhibition with Cangrelor at the time of PCI would reduce the rate of periprocedural thrombotic events compared to a drug with a slower antiplatelet effect, clopidogrel, given at about the time of PCI. It was a randomized, double-blind study in which patients with coronary artery disease (stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy including aspirin and heparin or bivalirudin were randomized 1:1 to Cangrelor (n=5472) or to clopidogrel 300 or 600 mg (n=5470). Patients who had already taken an oral P2Y12 platelet inhibitor were not eligible to enroll. Patients administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was planned were also not eligible to enroll. PHOENIX was thus a study of people undergoing PCI who had not been previously treated with anti-platelet therapy other than aspirin. The primary outcome measure was the first occurrence of any one of the composite endpoint of all-cause mortality, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) within 48 hours after randomization. Cangrelor was administered as 30 mcg/kg bolus followed by 4 mcg/kg/min infusion for 2 to 4 hours. Clopidogrel 600 mg was administered immediately at the end of the Cangrelor infusion in patients randomized to Cangrelor. Clopidogrel 300 mg or 600 mg was administered shortly before PCI or shortly afterward, in patients randomized to clopidogrel. Cangrelor significantly reduced the occurrence of primary composite endpoint events compared to clopidogrel (relative risk reduction [RRR] 22%). Most of the effect was a reduction in post-procedural MIs detected solely by elevations in CK-MB (type 4a MI). Cangrelor did not reduce the risk of death. Table 2 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. - Table 2: Primary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population(a)) KENGREAL: Cangrelor's Brand name A supplementary analysis was also performed omitting two subcomponent events of the primary endpoint that were of lesser clinical significance: intraprocedural stent thrombosis (defined as a new or increasing thrombus within or adjacent to a deployed stent occurring during the index PCI procedure), and myocardial infarction with less than a 10-fold increase in CK-MB, or with less than a 5-fold increase in CK-MB in the presence of new Q waves or new left bundle branch block (LBBB). These results are shown in Table 3. - Table 3: Supplementary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population) KENGREAL: Cangrelor's Brand name The effect of Cangrelor appeared to be consistent in a variety of pre-specified and other clinically important subgroups (see Figure 4). - Figure 4: CHAMPION PHOENIX Study: Primary Efficacy Endpoint by Subgroup (mITT Population(a)) KENGREAL: Cangrelor's Brand name Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Two additional concurrent clinical trials of the effect of Cangrelor in patients undergoing percutaneous coronary intervention, CHAMPION PCI and CHAMPION PLATFORM were conducted and terminated early for futility. They were completed prior to the design and conduct of CHAMPION PHOENIX. The comparative characteristics and outcomes of each trial are shown in Table 4. - Table 4: Summary of the CHAMPION Trials # How Supplied Cangrelor is supplied as a sterile lyophilized powder in single-use 10 mL vials. - NDC # 65293-003-01: 10 mL vial containing 50 mg Cangrelor - NDC # 65293-003-10: 10 count of 10 mL vials containing 50 mg Cangrelor ## Storage Vials of Cangrelor should be stored at USP Controlled Room Temperature, [20°C to 25°C (68°F to 77°F) with excursions between 15°C and 30°C (59°F and 86°F) permitted]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cangrelor Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cangrelor interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names KENGREAL® # Look-Alike Drug Names There is limited information regarding Cangrelor Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cangrelor
1e34caf2073e8bef07f5ec0693478d3d8104547c	wikidoc	Capacitor	Capacitor A capacitor is an electrical/electronic device that can store energy in the electric field between a pair of conductors (called "plates"). The process of storing energy in the capacitor is known as "charging", and involves electric charges of equal magnitude, but opposite polarity, building up on each plate. Capacitors are often used in electric and electronic circuits as energy-storage devices. They can also be used to differentiate between high-frequency and low-frequency signals. This property makes them useful in electronic filters. Capacitors are occasionally referred to as condensers. This is considered an antiquated term in English, but most other languages use an equivalent, like "Kondensator" in German, "condensador" in Spanish, or "Kondensa" in Japanese. # History In October 1745, Ewald Georg von Kleist of Pomerania in Germany invented the first recorded capacitor: a glass jar with water inside as one plate was held on the hand as the other plate. A wire in the mouth of the bottle received charge from an electric machine, and released it as a spark. In the same year, Dutch physicist Pieter van Musschenbroek independently invented a very similar capacitor. It was named the Leyden jar, after the University of Leyden where van Musschenbroek worked. Daniel Gralath was the first to combine several jars in parallel into a "battery" to increase the charge storage capacity. Benjamin Franklin investigated the Leyden jar, and proved that the charge was stored on the glass, not in the water as others had assumed. The earliest unit of capacitance was the 'jar', equivalent to about 1 nanofarad. Early capacitors were also known as condensers, a term that is still occasionally used today. It was coined by Alessandro Volta in 1782 (derived from the Italian condensatore), with reference to the device's ability to store a higher density of electric charge than a normal isolated conductor. Most non-English European languages still use a word derived from "condensatore". # Physics A capacitor consists of two conductive electrodes, or plates, separated by a dielectric. ## Capacitance The capacitor's capacitance (C) is a measure of the amount of charge (Q) stored on each plate for a given potential difference or voltage (V) which appears between the plates: In SI units, a capacitor has a capacitance of one farad when one coulomb of charge is stored due to one volt applied potential difference across the plates. Since the farad is a very large unit, values of capacitors are usually expressed in microfarads (µF), nanofarads (nF), or picofarads (pF). The capacitance is proportional to the surface area of the conducting plate and inversely proportional to the distance between the plates. It is also proportional to the permittivity of the dielectric (that is, non-conducting) substance that separates the plates. The capacitance of a parallel-plate capacitor is given by: where ε is the permittivity of the dielectric (see Dielectric constant), A is the area of the plates and d is the spacing between them. In the diagram, the rotated molecules create an opposing electric field that partially cancels the field created by the plates, a process called dielectric polarization. ## Stored energy As opposite charges accumulate on the plates of a capacitor due to the separation of charge, a voltage develops across the capacitor due to the electric field of these charges. Ever-increasing work must be done against this ever-increasing electric field as more charge is separated. The energy (measured in joules, in SI) stored in a capacitor is equal to the amount of work required to establish the voltage across the capacitor, and therefore the electric field. The energy stored is given by: where V is the voltage across the capacitor. The maximum energy that can be (safely) stored in a particular capacitor is limited by the maximum electric field that the dielectric can withstand before it breaks down. Therefore, capacitors made with the same dielectric have about the same maximum energy density (joules of energy per cubic meter), if the dielectric volume dominates the total volume. ## Hydraulic model As electrical circuitry can be modeled by fluid flow, a capacitor can be modeled as a chamber with a flexible diaphragm separating the input from the output. As can be determined intuitively as well as mathematically, this provides the correct characteristics: - The pressure difference (voltage difference) across the unit is proportional to the integral of the flow (current). - A steady state current cannot pass through it because the pressure will build up across the diaphragm until it equally opposes the source pressure, - but a transient pulse or alternating current can be transmitted. - An overpressure results in bursting of the diaphragm, analogous to dielectric breakdown. - The capacitance of units connected in parallel is equivalent to the sum of their individual capacitances. ## Aging Certain types of capacitors exhibit decreased capacitance over time. The behavior is different for different types: ceramic capacitors change most near the beginning of life, whereas electrolytic capacitors change most near the end of life. ### Ceramic capacitor aging In ceramic capacitors, the change in capacitance over time, called aging, is due to physical changes over time of the dielectric material used in their construction. The critical factors in this type of aging are - The type of dielectric material used in their construction (with many types this effect is negligible), - The temperature of the storage and operation environment, and - (to a small extent) the voltage of operation. The rate of change of capacitance decreases over time, so the main concern is the initial stabilization, not the long-term lifetime. Ceramic capacitor aging can be reversed by heating the capacitor above the Curie Point. ### Electrolytic capacitor aging Electrolytic capacitors' capacitance can decrease as the capacitor approaches end of life due to electrolyte evaporation. # Electric circuits ## DC sources The dielectric between the plates is an insulator and blocks the flow of electrons. A steady current through a capacitor deposits electrons on one plate and removes the same quantity of electrons from the other plate. This process is commonly called 'charging' the capacitor. The current through the capacitor results in the separation of electric charge within the capacitor, which develops an electric field between the plates of the capacitor, equivalently, developing a voltage difference between the plates. This voltage V is directly proportional to the amount of charge separated Q. Since the current I through the capacitor is the rate at which charge Q is forced through the capacitor (dQ/dt), this can be expressed mathematically as: where I is the current flowing in the conventional direction measured in amperes, dV/dt is the time derivative of voltage measured in volts per second, and C is the capacitance in farads. For circuits with a constant (DC) voltage source and consisting of only resistors and capacitors, the voltage across the capacitor cannot exceed the voltage of the source. Thus, an equilibrium is reached where the voltage across the capacitor is constant and the current through the capacitor is zero. For this reason, it is commonly said that capacitors block DC. ## AC sources The current through a capacitor due to an AC source reverses direction periodically. That is, the alternating current alternately charges the plates: first in one direction and then the other. With the exception of the instant that the current changes direction, the capacitor current is non-zero at all times during a cycle. For this reason, it is commonly said that capacitors "pass" AC. However, at no time do electrons actually cross between the plates, unless the dielectric breaks down. Such a situation would involve physical damage to the capacitor and likely to the circuit involved as well. Since the voltage across a capacitor is proportional to the integral of the current, as shown above, with sine waves in AC or signal circuits this results in a phase difference of 90 degrees, the current leading the voltage phase angle. It can be shown that the AC voltage across the capacitor is in quadrature with the alternating current through the capacitor. That is, the voltage and current are 'out-of-phase' by a quarter cycle. The amplitude of the voltage depends on the amplitude of the current divided by the product of the frequency of the current with the capacitance, C. ### Impedance The ratio of the phasor voltage across a circuit element to the phasor current through that element is called the impedance Z. For a capacitor, the impedance is given by Z_C = \frac{V_C}{I_C} = \frac{-j}{2 \pi f C} = -j X_C , where X_C = \frac{1}{\omega C} is the capacitive reactance, \omega = 2 \pi f \, is the angular frequency, f is the frequency), C is the capacitance in farads, and j is the imaginary unit. While this relation (between the frequency domain voltage and current associated with a capacitor) is always true, the ratio of the time domain voltage and current amplitudes is equal to X_C only for sinusoidal (AC) circuits in steady state. See derivation Deriving capacitor impedance. Hence, capacitive reactance is the negative imaginary component of impedance. The negative sign indicates that the current leads the voltage by 90° for a sinusoidal signal, as opposed to the inductor, where the current lags the voltage by 90°. The impedance is analogous to the resistance of a resistor. The impedance of a capacitor is inversely proportional to the frequency -- that is, for very high-frequency alternating currents the reactance approaches zero -- so that a capacitor is nearly a short circuit to a very high frequency AC source. Conversely, for very low frequency alternating currents, the reactance increases without bound so that a capacitor is nearly an open circuit to a very low frequency AC source. This frequency dependent behaviour accounts for most uses of the capacitor (see "Applications", below). Reactance is so called because the capacitor doesn't dissipate power, but merely stores energy. In electrical circuits, as in mechanics, there are two types of load, resistive and reactive. Resistive loads (analogous to an object sliding on a rough surface) dissipate the energy delivered by the circuit as heat, while reactive loads (analogous to a spring or frictionless moving object) store this energy, ultimately delivering the energy back to the circuit. Also significant is that the impedance is inversely proportional to the capacitance, unlike resistors and inductors for which impedances are linearly proportional to resistance and inductance respectively. This is why the series and shunt impedance formulae (given below) are the inverse of the resistive case. In series, impedances sum. In parallel, conductances sum. ### Laplace equivalent (s-domain) When using the Laplace transform in circuit analysis, the capacitive impedance is represented in the s domain by: Z(s)=\frac{1}{Cs} where C is the capacitance, and s (= σ+jω) is the complex frequency. ## Displacement current The physicist James Clerk Maxwell invented the concept of displacement current, dD/dt, to make Ampère's law consistent with conservation of charge in cases where charge is accumulating as in a capacitor. He interpreted this as a real motion of charges, even in vacuum, where he supposed that it corresponded to motion of dipole charges in the aether. Although this interpretation has been abandoned, Maxwell's correction to Ampère's law remains valid. ## Networks ### Series or parallel arrangements Capacitors in a parallel configuration each have the same potential difference (voltage). Their total capacitance (Ceq) is given by: The reason for putting capacitors in parallel is to increase the total amount of charge stored. In other words, increasing the capacitance also increases the amount of energy that can be stored. Its expression is: The current through capacitors in series stays the same, but the voltage across each capacitor can be different. The sum of the potential differences (voltage) is equal to the total voltage. Their total capacitance is given by: In parallel the effective area of the combined capacitor has increased, increasing the overall capacitance. While in series, the distance between the plates has effectively been increased, reducing the overall capacitance. In practice capacitors will be placed in series as a means of economically obtaining very high voltage capacitors, for example for smoothing ripples in a high voltage power supply. Three "600 volt maximum" capacitors in series, will increase their overall working voltage to 1800 volts. This is of course offset by the capacitance obtained being only one third of the value of the capacitors used. This can be countered by connecting 3 of these series set-ups in parallel, resulting in a 3x3 matrix of capacitors with the same overall capacitance as an individual capacitor but operable under three times the voltage. In this application, a large resistor would be connected across each capacitor to ensure that the total voltage is divided equally across each capacitor and also to discharge the capacitors for safety when the equipment is not in use. Another application is for use of polarized capacitors in alternating current circuits; the capacitors are connected in series, in reverse polarity, so that at any given time one of the capacitors is not conducting... ## Capacitor/inductor duality In mathematical terms, the ideal capacitor can be considered as an inverse of the ideal inductor, because the voltage-current equations of the two devices can be transformed into one another by exchanging the voltage and current terms. Just as two or more inductors can be magnetically coupled to make a transformer, two or more charged conductors can be electrostatically coupled to make a capacitor. The mutual capacitance of two conductors is defined as the current that flows in one when the voltage across the other changes by unit voltage in unit time. # Capacitor types ## By dielectric material - Vacuum : Two metal, usually copper, electrodes are separated by a vacuum. The insulating envelope is usually glass or ceramic. Typically of low capacitance - 10 - 1000 pF and high voltage, up to tens of kilovolts, they are most often used in radio transmitters and other high voltage power devices. Both fixed and variable types are available. Vacuum variable capacitors can have a minimum to maximum capacitance ratio of up to 100, allowing any tuned circuit to cover a full decade of frequency. Vacuum is the most perfect of dielectrics with a zero loss tangent. This allows very high powers to be transmitted without significant loss and consequent heating. - Air : Air dielectric capacitors consist of metal plates separated by an air gap. The metal plates, of which there may be many interleaved, are most often made of aluminium or silver-plated brass. Nearly all air dielectric capacitors are variable and are used in radio tuning circuits. - Plastic film: Made from high quality polymer film (usually polycarbonate, polystyrene, polypropylene, polyester (Mylar), and for high quality capacitors polysulfone), and metal foil or a layer of metal deposited on surface of the plastic film in a the metalized film type. They have good quality and stability, and are suitable for timer circuits. Their inductance limits use at high frequencies. - Mica: Similar to glass. Often high voltage. Suitable for high frequencies. Expensive. Excellent tolerance & stability. - Paper: Used for relatively high voltages. Known for long term failures. - Glass: Used for high voltages. Expensive. Stable temperature coefficient in a wide range of temperatures. - Ceramic: Chips of alternating layers of metal and ceramic, or disks of ceramic with metal on both sides of the disk. Characteristics vary widely depending on the type of ceramic dielectric. The dielectrics are broadly categorized as Class 1 or Class 2. Class 2 ceramic capacitors have strong variation of capacitance with temperature, high dissipation factor, high frequency coefficient of dissipation, and their capacitance depends on applied voltage and changes with aging. However they find massive use in common low-precision coupling and filtering applications. Suitable for high frequencies. - Aluminum electrolytic: Polarized. One electrode made of aluminum foil, etched aluminium to acquire much larger surface area. The dielectric is oxide grown on the etched aluminum plate, and the second electrode is a liquid electrolyte. They can achieve high capacitance but suffer from poor tolerances, high instability, gradual loss of capacitance especially when subjected to heat, and high leakage current. The conductivity of the electrolyte drops at low temperatures, increasing equivalent series resistance. Bad frequency characteristics make them unsuited for high-frequency applications. Special types with low equivalent series resistance are available. - Tantalum electrolytic: Similar to the aluminum electrolytic capacitor but with better frequency and temperature characteristics. High dielectric absorption and high leakage . Although they share many of the disadvantages of aluminum electrolytics, they perform better on most attributes; for example, they have much better performance at low temperatures. - OS-CON (or OC-CON) capacitors are a polymerized organic semiconductor solid-electrolyte type that offer longer life at higher cost than standard electrolytics. - Supercapacitors: Made from carbon aerogel, carbon nanotubes, or highly porous electrode materials. Extremely high capacity. Can be used in some applications instead of rechargeable batteries. - Varactors or varicap capacitors are specialized, reverse-biased diodes whose capacitance varies with voltage. Used in phase-locked loops, amongst other applications. - AC capacitors are capacitors specifically designed to work on line (mains) voltage ac power circuits. These are commonly used electric motor circuits. They are often designed to handle large currents so they tend to be physically large. They are usually ruggedly packaged, often in metal cases that can be easily grounded/earthed. They also tend to have rather high DC breakdown voltages; ## By construction - Axial capacitors - Feedthrough capacitors for RF decoupling usage - Gimmick capacitors, made from two insulated wires that have been twisted together - Radial capacitors - Surface mount (leadless) capacitors - Trimmer capacitors Beehive types Compression types - Beehive types - Compression types - Tuning capacitor (air spaced) - Discoidal capacitors # Applications Capacitors have various uses in electronic and electrical systems. ## Energy storage A capacitor can store electric energy when disconnected from its charging circuit, so it can be used like a temporary battery. Capacitors are commonly used in electronic devices to maintain power supply while batteries are being changed. (This prevents loss of information in volatile memory.) ## Power conditioning Reservoir capacitors are used in power supplies where they smooth the output of a full or half wave rectifier. They can also be used in charge pump circuits as the energy storage element in the generation of higher voltages than the input voltage. Capacitors are connected in parallel with the power circuits of most electronic devices and larger systems (such as factories) to shunt away and conceal current fluctuations from the primary power source to provide a "clean" power supply for signal or control circuits. Audio equipment, for example, uses several capacitors in this way, to shunt away power line hum before it gets into the signal circuitry. The capacitors act as a local reserve for the DC power source, and bypass AC currents from the power supply. This is used in car audio applications, when a stiffening capacitor compensates for the inductance and resistance of the leads to the lead-acid car battery. ### Power factor correction Capacitors are used in power factor correction. Such capacitors often come as three capacitors connected as a three phase load. Usually, the values of these capacitors are given not in farads but rather as a reactive power in volt-amperes reactive (VAr). The purpose is to counteract inductive loading from electric motors and fluorescent lighting in order to make the load appear to be mostly resistive. ## Filtering ### Signal coupling Because capacitors pass AC but block DC signals (when charged up to the applied dc voltage), they are often used to separate the AC and DC components of a signal. This method is known as AC coupling or "capacitive coupling". Here, a large value of capacitance, whose value need not be accurately controlled, but whose reactance is small at the signal frequency, is employed. ### Decoupling A decoupling capacitor is a capacitor used to decouple one part of a circuit from another. Noise caused by other circuit elements is shunted through the capacitor reducing the effect they have on the rest of the circuit. It is most commonly used between the power supply and ground. An alternative name is bypass capacitor as it is used to bypass the power supply or other high impedance component of a circuit. ### Noise filters, motor starters, and snubbers When an inductive circuit is opened, the current through the inductance collapses quickly, creating a large voltage across the open circuit of the switch or relay. If the inductance is large enough, the energy will generate a spark, causing the contact points to oxidize, deteriorate, or sometimes weld together, or destroying a solid-state switch. A snubber capacitor across the newly opened circuit creates a path for this impulse to bypass the contact points, thereby preserving their life; these were commonly found in contact breaker ignition systems, for instance. Similarly, in smaller scale circuits, the spark may not be enough to damage the switch but will still radiate undesirable radio frequency interference (RFI), which a filter capacitor absorbs. Snubber capacitors are usually employed with a low-value resistor in series, to dissipate energy and minimize RFI. Such resistor-capacitor combinations are available in a single package. In an inverse fashion, to initiate current quickly through an inductive circuit requires a greater voltage than required to maintain it; in uses such as large motors, this can cause undesirable startup characteristics, and a motor starting capacitor is used to increase the coil current to help start the motor. Capacitors are also used in parallel to interrupt units of a high-voltage circuit breaker in order to equally distribute the voltage between these units. In this case they are called grading capacitors. In schematic diagrams, a capacitor used primarily for DC charge storage is often drawn vertically in circuit diagrams with the lower, more negative, plate drawn as an arc. The straight plate indicates the positive terminal of the device, if it is polarized (see electrolytic capacitor). ## Signal processing The energy stored in a capacitor can be used to represent information, either in binary form, as in DRAMs, or in analogue form, as in analog sampled filters and CCDs. Capacitors can be used in analog circuits as components of integrators or more complex filters and in negative feedback loop stabilization. Signal processing circuits also use capacitors to integrate a current signal. ### Tuned circuits Capacitors and inductors are applied together in tuned circuits to select information in particular frequency bands. For example, radio receivers rely on variable capacitors to tune the station frequency. Speakers use passive analog crossovers, and analog equalizers use capacitors to select different audio bands. In a tuned circuit such as a radio receiver, the frequency selected is a function of the inductance (L) and the capacitance (C) in series, and is given by: This is the frequency at which resonance occurs in an LC circuit. ## Other applications ### Sensing Most capacitors are designed to maintain a fixed physical structure. However, various factors can change the structure of the capacitor; the resulting change in capacitance can be used to sense those factors. Changing the dielectric: the effects of varying the physical and/or electrical characteristics of the dielectric can also be of use. Capacitors with an exposed and porous dielectric can be used to measure humidity in air. Changing the distance between the plates: Capacitors are used to accurately measure the fuel level in airplanes. Capacitors with a flexible plate can be used to measure strain or pressure. Capacitors are used as the sensor in condenser microphones, where one plate is moved by air pressure, relative to the fixed position of the other plate. Some accelerometers use MEMS capacitors etched on a chip to measure the magnitude and direction of the acceleration vector. They are used to detect changes in acceleration, eg. as tilt sensors or to detect free fall, as sensors triggering airbag deployment, and in many other applications. Some fingerprint sensors use capacitors. Additionally, a user can adjust the pitch of a theremin musical instrument by moving his hand since this changes the effective capacitance between the user's hand and the antenna. Changing the effective area of the plates: capacitive touch switches ### Pulsed power and weapons Groups of large, specially constructed, low-inductance high-voltage capacitors (capacitor banks) are used to supply huge pulses of current for many pulsed power applications. These include electromagnetic forming, Marx generators, pulsed lasers (especially TEA lasers), pulse forming networks, radar, fusion research, and particle accelerators. Large capacitor banks(Reservoir) are used as energy sources for the exploding-bridgewire detonators or slapper detonators in nuclear weapons and other specialty weapons. Experimental work is under way using banks of capacitors as power sources for electromagnetic armour and electromagnetic railguns or coilguns. See also Explosively pumped flux compression generator. # Hazards and safety Capacitors may retain a charge long after power is removed from a circuit; this charge can cause shocks (sometimes fatal) or damage to connected equipment. For example, even a seemingly innocuous device such as a disposable camera flash unit powered by a 1.5 volt AA battery contains a capacitor which may be charged to over 300 volts. This is easily capable of delivering an extremely painful shock. Care must be taken to ensure that any large or high-voltage capacitor is properly discharged before servicing the containing equipment. For board-level capacitors, this is done by placing a bleeder resistor across the terminals, whose resistance is large enough that the leakage current will not affect the circuit, but small enough to discharge the capacitor shortly after power is removed. High-voltage capacitors should be stored with the terminals shorted, since temporarily discharged capacitors can develop potentially dangerous voltages when the terminals are left open-circuited. Large oil-filled old capacitors must be disposed of properly as some contain polychlorinated biphenyls (PCBs). It is known that waste PCBs can leak into groundwater under landfills. If consumed by drinking contaminated water, PCBs are carcinogenic, even in very tiny amounts. If the capacitor is physically large it is more likely to be dangerous and may require precautions in addition to those described above. New electrical components are no longer produced with PCBs. ("PCB" in electronics usually means printed circuit board, but the above usage is an exception.) Capacitors containing PCB were labelled as containing "Askarel" and several other trade names. ## High-voltage Above and beyond usual hazards associated with working with high voltage, high energy circuits, there are a number of dangers that are specific to high voltage capacitors. High voltage capacitors may catastrophically fail when subjected to voltages or currents beyond their rating, or as they reach their normal end of life. Dielectric or metal interconnection failures may create arcing called an arc fault, within oil-filled units that vaporizes dielectric fluid, resulting in case bulging, rupture, or even an explosion that disperses flammable oil, starts fires, and damages nearby equipment, called flash - melt down, Rigid cased cylindrical glass or plastic cases are more prone to explosive rupture than rectangular cases due to an inability to easily expand under pressure. Capacitors used in RF or sustained high current applications can overheat, especially in the center of the capacitor rolls. The trapped heat may cause rapid interior heating and destruction, even though the outer case remains relatively cool. Capacitors used within high energy capacitor banks can violently explode when a fault in one capacitor causes sudden dumping of energy stored in the rest of the bank into the failing unit. And, high voltage vacuum capacitors can generate soft X-rays even during normal operation. Proper containment, fusing, and preventative maintenance can help to minimize these hazards. High voltage capacitors can benefit from a pre-charge to limit in-rush currents at power-up of HVDC circuits. This will extend the life of the component and may mitigate high voltage hazards.	Capacitor A capacitor is an electrical/electronic device that can store energy in the electric field between a pair of conductors (called "plates"). The process of storing energy in the capacitor is known as "charging", and involves electric charges of equal magnitude, but opposite polarity, building up on each plate. Capacitors are often used in electric and electronic circuits as energy-storage devices. They can also be used to differentiate between high-frequency and low-frequency signals. This property makes them useful in electronic filters. Capacitors are occasionally referred to as condensers. This is considered an antiquated term in English, but most other languages use an equivalent, like "Kondensator" in German, "condensador" in Spanish, or "Kondensa" in Japanese. # History In October 1745, Ewald Georg von Kleist of Pomerania in Germany invented the first recorded capacitor: a glass jar with water inside as one plate was held on the hand as the other plate. A wire in the mouth of the bottle received charge from an electric machine, and released it as a spark.[1] In the same year, Dutch physicist Pieter van Musschenbroek independently invented a very similar capacitor. It was named the Leyden jar, after the University of Leyden where van Musschenbroek worked. Daniel Gralath was the first to combine several jars in parallel into a "battery" to increase the charge storage capacity. Benjamin Franklin investigated the Leyden jar, and proved that the charge was stored on the glass, not in the water as others had assumed. The earliest unit of capacitance was the 'jar', equivalent to about 1 nanofarad. Early capacitors were also known as condensers, a term that is still occasionally used today. It was coined by Alessandro Volta in 1782 (derived from the Italian condensatore), with reference to the device's ability to store a higher density of electric charge than a normal isolated conductor. Most non-English European languages still use a word derived from "condensatore". # Physics A capacitor consists of two conductive electrodes, or plates, separated by a dielectric. ## Capacitance The capacitor's capacitance (C) is a measure of the amount of charge (Q) stored on each plate for a given potential difference or voltage (V) which appears between the plates: In SI units, a capacitor has a capacitance of one farad when one coulomb of charge is stored due to one volt applied potential difference across the plates. Since the farad is a very large unit, values of capacitors are usually expressed in microfarads (µF), nanofarads (nF), or picofarads (pF). The capacitance is proportional to the surface area of the conducting plate and inversely proportional to the distance between the plates. It is also proportional to the permittivity of the dielectric (that is, non-conducting) substance that separates the plates. The capacitance of a parallel-plate capacitor is given by: where ε is the permittivity of the dielectric (see Dielectric constant), A is the area of the plates and d is the spacing between them. In the diagram, the rotated molecules create an opposing electric field that partially cancels the field created by the plates, a process called dielectric polarization. ## Stored energy As opposite charges accumulate on the plates of a capacitor due to the separation of charge, a voltage develops across the capacitor due to the electric field of these charges. Ever-increasing work must be done against this ever-increasing electric field as more charge is separated. The energy (measured in joules, in SI) stored in a capacitor is equal to the amount of work required to establish the voltage across the capacitor, and therefore the electric field. The energy stored is given by: where V is the voltage across the capacitor. The maximum energy that can be (safely) stored in a particular capacitor is limited by the maximum electric field that the dielectric can withstand before it breaks down. Therefore, capacitors made with the same dielectric have about the same maximum energy density (joules of energy per cubic meter), if the dielectric volume dominates the total volume. ## Hydraulic model As electrical circuitry can be modeled by fluid flow, a capacitor can be modeled as a chamber with a flexible diaphragm separating the input from the output. As can be determined intuitively as well as mathematically, this provides the correct characteristics: - The pressure difference (voltage difference) across the unit is proportional to the integral of the flow (current). - A steady state current cannot pass through it because the pressure will build up across the diaphragm until it equally opposes the source pressure, - but a transient pulse or alternating current can be transmitted. - An overpressure results in bursting of the diaphragm, analogous to dielectric breakdown. - The capacitance of units connected in parallel is equivalent to the sum of their individual capacitances. ## Aging Certain types of capacitors exhibit decreased capacitance over time. The behavior is different for different types: ceramic capacitors change most near the beginning of life, whereas electrolytic capacitors change most near the end of life. ### Ceramic capacitor aging In ceramic capacitors, the change in capacitance over time, called aging, is due to physical changes over time of the dielectric material used in their construction. The critical factors in this type of aging are - The type of dielectric material used in their construction (with many types this effect is negligible), - The temperature of the storage and operation environment, and - (to a small extent) the voltage of operation. The rate of change of capacitance decreases over time, so the main concern is the initial stabilization, not the long-term lifetime. [3] Ceramic capacitor aging can be reversed by heating the capacitor above the Curie Point. ### Electrolytic capacitor aging Electrolytic capacitors' capacitance can decrease as the capacitor approaches end of life due to electrolyte evaporation. # Electric circuits ## DC sources The dielectric between the plates is an insulator and blocks the flow of electrons. A steady current through a capacitor deposits electrons on one plate and removes the same quantity of electrons from the other plate. This process is commonly called 'charging' the capacitor. The current through the capacitor results in the separation of electric charge within the capacitor, which develops an electric field between the plates of the capacitor, equivalently, developing a voltage difference between the plates. This voltage V is directly proportional to the amount of charge separated Q. Since the current I through the capacitor is the rate at which charge Q is forced through the capacitor (dQ/dt), this can be expressed mathematically as: where I is the current flowing in the conventional direction measured in amperes, dV/dt is the time derivative of voltage measured in volts per second, and C is the capacitance in farads. For circuits with a constant (DC) voltage source and consisting of only resistors and capacitors, the voltage across the capacitor cannot exceed the voltage of the source. Thus, an equilibrium is reached where the voltage across the capacitor is constant and the current through the capacitor is zero. For this reason, it is commonly said that capacitors block DC. ## AC sources The current through a capacitor due to an AC source reverses direction periodically. That is, the alternating current alternately charges the plates: first in one direction and then the other. With the exception of the instant that the current changes direction, the capacitor current is non-zero at all times during a cycle. For this reason, it is commonly said that capacitors "pass" AC. However, at no time do electrons actually cross between the plates, unless the dielectric breaks down. Such a situation would involve physical damage to the capacitor and likely to the circuit involved as well. Since the voltage across a capacitor is proportional to the integral of the current, as shown above, with sine waves in AC or signal circuits this results in a phase difference of 90 degrees, the current leading the voltage phase angle. It can be shown that the AC voltage across the capacitor is in quadrature with the alternating current through the capacitor. That is, the voltage and current are 'out-of-phase' by a quarter cycle. The amplitude of the voltage depends on the amplitude of the current divided by the product of the frequency of the current with the capacitance, C. ### Impedance The ratio of the phasor voltage across a circuit element to the phasor current through that element is called the impedance <math>Z</math>. For a capacitor, the impedance is given by <math>Z_C = \frac{V_C}{I_C} = \frac{-j}{2 \pi f C} = -j X_C ,</math> where <math>X_C = \frac{1}{\omega C}</math> is the capacitive reactance, <math>\omega = 2 \pi f \,</math> is the angular frequency, f is the frequency), C is the capacitance in farads, and j is the imaginary unit. While this relation (between the frequency domain voltage and current associated with a capacitor) is always true, the ratio of the time domain voltage and current amplitudes is equal to <math>X_C</math> only for sinusoidal (AC) circuits in steady state. See derivation Deriving capacitor impedance. Hence, capacitive reactance is the negative imaginary component of impedance. The negative sign indicates that the current leads the voltage by 90° for a sinusoidal signal, as opposed to the inductor, where the current lags the voltage by 90°. The impedance is analogous to the resistance of a resistor. The impedance of a capacitor is inversely proportional to the frequency -- that is, for very high-frequency alternating currents the reactance approaches zero -- so that a capacitor is nearly a short circuit to a very high frequency AC source. Conversely, for very low frequency alternating currents, the reactance increases without bound so that a capacitor is nearly an open circuit to a very low frequency AC source. This frequency dependent behaviour accounts for most uses of the capacitor (see "Applications", below). Reactance is so called because the capacitor doesn't dissipate power, but merely stores energy. In electrical circuits, as in mechanics, there are two types of load, resistive and reactive. Resistive loads (analogous to an object sliding on a rough surface) dissipate the energy delivered by the circuit as heat, while reactive loads (analogous to a spring or frictionless moving object) store this energy, ultimately delivering the energy back to the circuit. Also significant is that the impedance is inversely proportional to the capacitance, unlike resistors and inductors for which impedances are linearly proportional to resistance and inductance respectively. This is why the series and shunt impedance formulae (given below) are the inverse of the resistive case. In series, impedances sum. In parallel, conductances sum. ### Laplace equivalent (s-domain) When using the Laplace transform in circuit analysis, the capacitive impedance is represented in the s domain by: <math>Z(s)=\frac{1}{Cs}</math> where C is the capacitance, and s (= σ+jω) is the complex frequency. ## Displacement current The physicist James Clerk Maxwell invented the concept of displacement current, dD/dt, to make Ampère's law consistent with conservation of charge in cases where charge is accumulating as in a capacitor. He interpreted this as a real motion of charges, even in vacuum, where he supposed that it corresponded to motion of dipole charges in the aether. Although this interpretation has been abandoned, Maxwell's correction to Ampère's law remains valid. ## Networks ### Series or parallel arrangements Capacitors in a parallel configuration each have the same potential difference (voltage). Their total capacitance (Ceq) is given by: The reason for putting capacitors in parallel is to increase the total amount of charge stored. In other words, increasing the capacitance also increases the amount of energy that can be stored. Its expression is: The current through capacitors in series stays the same, but the voltage across each capacitor can be different. The sum of the potential differences (voltage) is equal to the total voltage. Their total capacitance is given by: In parallel the effective area of the combined capacitor has increased, increasing the overall capacitance. While in series, the distance between the plates has effectively been increased, reducing the overall capacitance. In practice capacitors will be placed in series as a means of economically obtaining very high voltage capacitors, for example for smoothing ripples in a high voltage power supply. Three "600 volt maximum" capacitors in series, will increase their overall working voltage to 1800 volts. This is of course offset by the capacitance obtained being only one third of the value of the capacitors used. This can be countered by connecting 3 of these series set-ups in parallel, resulting in a 3x3 matrix of capacitors with the same overall capacitance as an individual capacitor but operable under three times the voltage. In this application, a large resistor would be connected across each capacitor to ensure that the total voltage is divided equally across each capacitor and also to discharge the capacitors for safety when the equipment is not in use. Another application is for use of polarized capacitors in alternating current circuits; the capacitors are connected in series, in reverse polarity, so that at any given time one of the capacitors is not conducting... ## Capacitor/inductor duality In mathematical terms, the ideal capacitor can be considered as an inverse of the ideal inductor, because the voltage-current equations of the two devices can be transformed into one another by exchanging the voltage and current terms. Just as two or more inductors can be magnetically coupled to make a transformer, two or more charged conductors can be electrostatically coupled to make a capacitor. The mutual capacitance of two conductors is defined as the current that flows in one when the voltage across the other changes by unit voltage in unit time. # Capacitor types Template:Mergeto Template:Cleanup-section ## By dielectric material - Vacuum : Two metal, usually copper, electrodes are separated by a vacuum. The insulating envelope is usually glass or ceramic. Typically of low capacitance - 10 - 1000 pF and high voltage, up to tens of kilovolts, they are most often used in radio transmitters and other high voltage power devices. Both fixed and variable types are available. Vacuum variable capacitors can have a minimum to maximum capacitance ratio of up to 100, allowing any tuned circuit to cover a full decade of frequency. Vacuum is the most perfect of dielectrics with a zero loss tangent. This allows very high powers to be transmitted without significant loss and consequent heating. - Air : Air dielectric capacitors consist of metal plates separated by an air gap. The metal plates, of which there may be many interleaved, are most often made of aluminium or silver-plated brass. Nearly all air dielectric capacitors are variable and are used in radio tuning circuits. - Plastic film: Made from high quality polymer film (usually polycarbonate, polystyrene, polypropylene, polyester (Mylar), and for high quality capacitors polysulfone), and metal foil or a layer of metal deposited on surface of the plastic film in a the metalized film type. They have good quality and stability, and are suitable for timer circuits. Their inductance limits use at high frequencies. - Mica: Similar to glass. Often high voltage. Suitable for high frequencies. Expensive. Excellent tolerance & stability. - Paper: Used for relatively high voltages. Known for long term failures. - Glass: Used for high voltages. Expensive. Stable temperature coefficient in a wide range of temperatures. - Ceramic: Chips of alternating layers of metal and ceramic, or disks of ceramic with metal on both sides of the disk. Characteristics vary widely depending on the type of ceramic dielectric. The dielectrics are broadly categorized as Class 1 or Class 2. Class 2 ceramic capacitors have strong variation of capacitance with temperature, high dissipation factor, high frequency coefficient of dissipation, and their capacitance depends on applied voltage and changes with aging. However they find massive use in common low-precision coupling and filtering applications. Suitable for high frequencies. - Aluminum electrolytic: Polarized. One electrode made of aluminum foil, etched aluminium to acquire much larger surface area. The dielectric is oxide grown on the etched aluminum plate, and the second electrode is a liquid electrolyte. They can achieve high capacitance but suffer from poor tolerances, high instability, gradual loss of capacitance especially when subjected to heat, and high leakage current. The conductivity of the electrolyte drops at low temperatures, increasing equivalent series resistance. Bad frequency characteristics make them unsuited for high-frequency applications. Special types with low equivalent series resistance are available. - Tantalum electrolytic: Similar to the aluminum electrolytic capacitor but with better frequency and temperature characteristics. High dielectric absorption and high leakage [4]. Although they share many of the disadvantages of aluminum electrolytics, they perform better on most attributes; for example, they have much better performance at low temperatures. - OS-CON (or OC-CON) capacitors are a polymerized organic semiconductor solid-electrolyte type that offer longer life at higher cost than standard electrolytics. - Supercapacitors: Made from carbon aerogel, carbon nanotubes, or highly porous electrode materials. Extremely high capacity. Can be used in some applications instead of rechargeable batteries. - Varactors or varicap capacitors are specialized, reverse-biased diodes whose capacitance varies with voltage. Used in phase-locked loops, amongst other applications. - AC capacitors are capacitors specifically designed to work on line (mains) voltage ac power circuits. These are commonly used electric motor circuits. They are often designed to handle large currents so they tend to be physically large. They are usually ruggedly packaged, often in metal cases that can be easily grounded/earthed. They also tend to have rather high DC breakdown voltages; ## By construction - Axial capacitors - Feedthrough capacitors for RF decoupling usage - Gimmick capacitors, made from two insulated wires that have been twisted together [2] - Radial capacitors - Surface mount (leadless) capacitors - Trimmer capacitors Beehive types Compression types - Beehive types - Compression types - Tuning capacitor (air spaced) - Discoidal capacitors # Applications Capacitors have various uses in electronic and electrical systems. ## Energy storage A capacitor can store electric energy when disconnected from its charging circuit, so it can be used like a temporary battery. Capacitors are commonly used in electronic devices to maintain power supply while batteries are being changed. (This prevents loss of information in volatile memory.) ## Power conditioning Reservoir capacitors are used in power supplies where they smooth the output of a full or half wave rectifier. They can also be used in charge pump circuits as the energy storage element in the generation of higher voltages than the input voltage. Capacitors are connected in parallel with the power circuits of most electronic devices and larger systems (such as factories) to shunt away and conceal current fluctuations from the primary power source to provide a "clean" power supply for signal or control circuits. Audio equipment, for example, uses several capacitors in this way, to shunt away power line hum before it gets into the signal circuitry. The capacitors act as a local reserve for the DC power source, and bypass AC currents from the power supply. This is used in car audio applications, when a stiffening capacitor compensates for the inductance and resistance of the leads to the lead-acid car battery. ### Power factor correction Capacitors are used in power factor correction. Such capacitors often come as three capacitors connected as a three phase load. Usually, the values of these capacitors are given not in farads but rather as a reactive power in volt-amperes reactive (VAr). The purpose is to counteract inductive loading from electric motors and fluorescent lighting in order to make the load appear to be mostly resistive. ## Filtering ### Signal coupling Because capacitors pass AC but block DC signals (when charged up to the applied dc voltage), they are often used to separate the AC and DC components of a signal. This method is known as AC coupling or "capacitive coupling". Here, a large value of capacitance, whose value need not be accurately controlled, but whose reactance is small at the signal frequency, is employed. ### Decoupling A decoupling capacitor is a capacitor used to decouple one part of a circuit from another. Noise caused by other circuit elements is shunted through the capacitor reducing the effect they have on the rest of the circuit. It is most commonly used between the power supply and ground. An alternative name is bypass capacitor as it is used to bypass the power supply or other high impedance component of a circuit. ### Noise filters, motor starters, and snubbers When an inductive circuit is opened, the current through the inductance collapses quickly, creating a large voltage across the open circuit of the switch or relay. If the inductance is large enough, the energy will generate a spark, causing the contact points to oxidize, deteriorate, or sometimes weld together, or destroying a solid-state switch. A snubber capacitor across the newly opened circuit creates a path for this impulse to bypass the contact points, thereby preserving their life; these were commonly found in contact breaker ignition systems, for instance. Similarly, in smaller scale circuits, the spark may not be enough to damage the switch but will still radiate undesirable radio frequency interference (RFI), which a filter capacitor absorbs. Snubber capacitors are usually employed with a low-value resistor in series, to dissipate energy and minimize RFI. Such resistor-capacitor combinations are available in a single package. In an inverse fashion, to initiate current quickly through an inductive circuit requires a greater voltage than required to maintain it; in uses such as large motors, this can cause undesirable startup characteristics, and a motor starting capacitor is used to increase the coil current to help start the motor. Capacitors are also used in parallel to interrupt units of a high-voltage circuit breaker in order to equally distribute the voltage between these units. In this case they are called grading capacitors. In schematic diagrams, a capacitor used primarily for DC charge storage is often drawn vertically in circuit diagrams with the lower, more negative, plate drawn as an arc. The straight plate indicates the positive terminal of the device, if it is polarized (see electrolytic capacitor). ## Signal processing The energy stored in a capacitor can be used to represent information, either in binary form, as in DRAMs, or in analogue form, as in analog sampled filters and CCDs. Capacitors can be used in analog circuits as components of integrators or more complex filters and in negative feedback loop stabilization. Signal processing circuits also use capacitors to integrate a current signal. ### Tuned circuits Capacitors and inductors are applied together in tuned circuits to select information in particular frequency bands. For example, radio receivers rely on variable capacitors to tune the station frequency. Speakers use passive analog crossovers, and analog equalizers use capacitors to select different audio bands. In a tuned circuit such as a radio receiver, the frequency selected is a function of the inductance (L) and the capacitance (C) in series, and is given by: This is the frequency at which resonance occurs in an LC circuit. ## Other applications ### Sensing Most capacitors are designed to maintain a fixed physical structure. However, various factors can change the structure of the capacitor; the resulting change in capacitance can be used to sense those factors. Changing the dielectric: the effects of varying the physical and/or electrical characteristics of the dielectric can also be of use. Capacitors with an exposed and porous dielectric can be used to measure humidity in air. Changing the distance between the plates: Capacitors are used to accurately measure the fuel level in airplanes. Capacitors with a flexible plate can be used to measure strain or pressure. Capacitors are used as the sensor in condenser microphones, where one plate is moved by air pressure, relative to the fixed position of the other plate. Some accelerometers use MEMS capacitors etched on a chip to measure the magnitude and direction of the acceleration vector. They are used to detect changes in acceleration, eg. as tilt sensors or to detect free fall, as sensors triggering airbag deployment, and in many other applications. Some fingerprint sensors use capacitors. Additionally, a user can adjust the pitch of a theremin musical instrument by moving his hand since this changes the effective capacitance between the user's hand and the antenna. Changing the effective area of the plates: capacitive touch switches [3] [4] [5]. ### Pulsed power and weapons Groups of large, specially constructed, low-inductance high-voltage capacitors (capacitor banks) are used to supply huge pulses of current for many pulsed power applications. These include electromagnetic forming, Marx generators, pulsed lasers (especially TEA lasers), pulse forming networks, radar, fusion research, and particle accelerators. Large capacitor banks(Reservoir) are used as energy sources for the exploding-bridgewire detonators or slapper detonators in nuclear weapons and other specialty weapons. Experimental work is under way using banks of capacitors as power sources for electromagnetic armour and electromagnetic railguns or coilguns. See also Explosively pumped flux compression generator. # Hazards and safety Capacitors may retain a charge long after power is removed from a circuit; this charge can cause shocks (sometimes fatal) or damage to connected equipment. For example, even a seemingly innocuous device such as a disposable camera flash unit powered by a 1.5 volt AA battery contains a capacitor which may be charged to over 300 volts. This is easily capable of delivering an extremely painful shock. Care must be taken to ensure that any large or high-voltage capacitor is properly discharged before servicing the containing equipment. For board-level capacitors, this is done by placing a bleeder resistor across the terminals, whose resistance is large enough that the leakage current will not affect the circuit, but small enough to discharge the capacitor shortly after power is removed. High-voltage capacitors should be stored with the terminals shorted, since temporarily discharged capacitors can develop potentially dangerous voltages when the terminals are left open-circuited. Large oil-filled old capacitors must be disposed of properly as some contain polychlorinated biphenyls (PCBs). It is known that waste PCBs can leak into groundwater under landfills. If consumed by drinking contaminated water, PCBs are carcinogenic, even in very tiny amounts. If the capacitor is physically large it is more likely to be dangerous and may require precautions in addition to those described above. New electrical components are no longer produced with PCBs. ("PCB" in electronics usually means printed circuit board, but the above usage is an exception.) Capacitors containing PCB were labelled as containing "Askarel" and several other trade names. ## High-voltage Above and beyond usual hazards associated with working with high voltage, high energy circuits, there are a number of dangers that are specific to high voltage capacitors. High voltage capacitors may catastrophically fail when subjected to voltages or currents beyond their rating, or as they reach their normal end of life. Dielectric or metal interconnection failures may create arcing called an arc fault, within oil-filled units that vaporizes dielectric fluid, resulting in case bulging, rupture, or even an explosion that disperses flammable oil, starts fires, and damages nearby equipment, called flash - melt down, Rigid cased cylindrical glass or plastic cases are more prone to explosive rupture than rectangular cases due to an inability to easily expand under pressure. Capacitors used in RF or sustained high current applications can overheat, especially in the center of the capacitor rolls. The trapped heat may cause rapid interior heating and destruction, even though the outer case remains relatively cool. Capacitors used within high energy capacitor banks can violently explode when a fault in one capacitor causes sudden dumping of energy stored in the rest of the bank into the failing unit. And, high voltage vacuum capacitors can generate soft X-rays even during normal operation. Proper containment, fusing, and preventative maintenance can help to minimize these hazards. High voltage capacitors can benefit from a pre-charge to limit in-rush currents at power-up of HVDC circuits. This will extend the life of the component and may mitigate high voltage hazards.	https://www.wikidoc.org/index.php/Capacitor
d9cbc82d8005fb198c7c71ba2bb8a1fa0d93ea0d	wikidoc	Captopril	Captopril # 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 Captopril is an Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension, heart failure, left ventricular dysfunction after myocardial infarction, diabetic nephropathy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, rash, hyperkalemia (11% ), disorder of taste, cough (0.5% to 2%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose: Captopril 25 mg PO bid or Captopril 25 mg PO tid ; may be increased after 1 to 2 weeks to Captopril 50 mg PO bid or Captopril 50 mg PO tid , then to Captopril 100 to 150 mg PO bid/tid (in combination with a thiazide diuretic) if needed (MAX 450 mg daily) Captopril tablets, USP are indicated for the treatment of hypertension. In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis. Captopril may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations. Captopril is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. - Dosing Information - Initial dose: (patients with normal or low blood pressure, vigorous diuretic therapy, volume depletion) Captopril 6.25 to 12.5 mg PO tid - Initial dose: Captopril PO 25 mg tid - Maintenance dose: Captopril 50 to 100 mg PO tid (MAX 450 mg PO daily) Captopril tablets, USP are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. - Dosing Information - Initial dose: Captopril 6.25 mg PO for one dose starting as early as 3 days after myocardial infarction, - Maintenance dose: Captopril 12.5 mg tid a day increased to 25 mg PO tid a day in several days; target dose 50 mg PO tid over the next several weeks as tolerated Captopril tablets, USP are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients. - Dosing Information - (type 1 diabetes mellitus) Captopril 25 mg PO tid - (type 2 diabetes mellitus) Captopril 12.5 mg bid , increased to Captopril 12.5 mg tid after 3 months Captopril tablets, USP are indicated for the treatment of diabetic nephropathy (proteinuria >500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Captopril decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis). In considering use of captopril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Dosing Information - An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated. ### Non–Guideline-Supported Use - Dosing information - Case report 1: 150 mg/day for 26 weeks followed by 75 mg for 9 weeks - Case report 2: 25 mg bid (titrated to achieve a concentration of urinary cystine of less than 200 mg/liter, or to a maximum of 150 mg/day) - Dosing information - Case report: 12.5 mg bid for 3 months followed by 12.5 mg tid - Dosing information - 25 mg qd This beneficial effect may not be sustained. - Dosing information - RCT report: - Initial dosage: 12.5 mg bid - Followed-up treatment: increase the dosage bi-weekly - Final aim: either blood pressure normalization or reach the maximum of 50 mg bid - Research 1 - Dosage for the first month: 6.25 mg/day - Dosage for the second month: titrated to 12.5 mg/day - Finally dosage: titrated to 25 mg/day - Research 2 - Initial dosage: 6.25 mg tid - Followed-up treatment: 25 mg tid - Case report: 25 mg/day, max: 75 mg/day - Dosing information - 25 mg/day - Dosing information - Case report 1: long time treatment for 6 months, maximum dose 200 mg/day - Case reprot 2: 25 mg tid ### Renovascular Hypertension - Dosing information - As an alternative therapy in patients with contraindications to surgery or renal artery angioplasty. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for captopril contains no information regarding safety and efficacy in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about the guideline-supported off-label use. ### Non–Guideline-Supported Use ### Chronic Heart Failure(infants) - Dosing Information - 4 mg/kg via nasogastric tube ### Kidney Imaging - Dosing Information - 0.2-0.4 mg/kg PO qd # Contraindications - Hypersensitivity to this product or any other angiotensin-converting enzyme inhibitor - History of angioedema during therapy with any other ACE inhibitor) # Warnings ### Anaphylactoid and Possibly Related Reactions - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including captopril) may be subject to a variety of adverse reactions, some of them serious. - Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted. - Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of captopril; some cases required medical therapy. - Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. - Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. ### Neutropenia/Agranulocytosis - Neutropenia (<1000/mm3) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. - The risk of neutropenia is dependent on the clinical status of the patient. - In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed. - In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports. - In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. - While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine ≥1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present. - The neutropenia has usually been detected within three months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen. - In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors. ### Evaluation of the hypertensive or heart failure patient should always include assessment of renal function - If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically. - In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution. - All patients treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay. - Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm3) the physician should withdraw captopril and closely follow the patient's course. ### Proteinuria - Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. - The nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria. ### Hypotension - Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis. - In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6 percent of patients with heart failure. - Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure. - Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood pressure is a common and desirable observation upon initiation of captopril tablets, USP treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months. ### Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. # Adverse Reactions ## Clinical Trials Experience Reported incidences are based on clinical trials involving approximately 7000 patients. ### Renal - About one of 100 patients developed proteinuria. - Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency. ### Hematologic - Neutropenia/agranulocytosis has occurred. Cases of anemia, thrombocytopenia, and pancytopenia have been reported. ### Dermatologic - Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistamine agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported. - Flushing or pallor has been reported in 2 to 5 of 1000 patients. ### Cardiovascular - Hypotension may occur; for discussion of hypotension with captopril therapy. - Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients. - Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. ### Dysgeusia - Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste. ### Angioedema - Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. ### Cough - Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials. The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: - Gastric irritation - Abdominal pain - Nausea - Vomiting - Diarrhea - Anorexia - Constipation - Aphthous ulcers - Peptic ulcer - Dizziness - Headache - Malaise - Fatigue - Insomnia - Dry mouth - Dyspnea - Alopecia - Paresthesias ## Postmarketing Experience ### Body As A Whole - Anaphylactoid reactions. ### General - Asthenia, gynecomastia. ### Cardiovascular - Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope. ### Dermatologic - Bullous pemphigoid, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis. ### Gastrointestinal - Pancreatitis, glossitis, dyspepsia. ### Hematologic - Anemia, including aplastic and hemolytic. ### Hepatobiliary - Jaundice, hepatitis, including rare cases of necrosis, cholestasis. ### Metabolic - Symptomatic hyponatremia. ### Musculoskeletal - Myalgia, myasthenia. ### Nervous/Psychiatric - Ataxia, confusion, depression, nervousness, somnolence. ### Respiratory - Bronchospasm, eosinophilic pneumonitis, rhinitis. ### Special Senses - Blurred vision. ### Urogenital - Impotence. - As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. ### Altered Laboratory Findings - Hyperkalemia - Small increases in serum potassium, especially in patients with renal impairment. - Hyponatremia - Particularly in patients receiving a low sodium diet or concomitant diuretics. - Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. - A positive ANA has been reported. - Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred. # Drug Interactions ### Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on captopril and other agents that affect the RAS. - Do not co-administer aliskiren with captopril in patients with diabetes. Avoid use of aliskiren with captopril in patients with renal impairment (GFR <60 ml/min). ### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase – 2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including captopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving captopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including captopril, may be attenuated by NSAIDs. ### Hypotension - Patients On Diuretic Therapy - Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril. - The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril tablets, USP or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion. ### Agents Having Vasodilator Activity - Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously, and perhaps at lower dosage. ### Agents Causing Renin Release - Captopril's effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system. ### Agents Affecting Sympathetic Activity - The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive. ### Agents Increasing Serum Potassium - Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution. ### Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. ### Cardiac Glycosides - In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril-digoxin interaction could be found. ### Loop Diuretics - Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renal impaired hypertensive patients. ### Allopurinol - In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days. ### Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including captopril. ### Drug /Laboratory Test Interaction - Captopril may cause a false-positive urine test for acetone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue captopril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mothers and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue, captopril unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to captopril for hypotension, oliguria, and hyperkalemia. - When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose. Pregnancy Category (AUS): D Drugs which have caused, are suspected to have caused, or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. ### Labor and Delivery FDA Package Insert for captopril contains no information regarding Labor and Delivery. ### Nursing Mothers - Concentrations of captopril in human milk are approximately one percent of those in maternal blood. Because of the potential for serious adverse reactions in nursing infants from captopril, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of captopril to the mother. ### Pediatric Use - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. - Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril form the general circulation. - Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults. - Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported. - Captopril should be used in pediatric patients only if other measures for controlling blood pressure have not been effective. ### Geriatic Use FDA Package Insert for Captopril contains no information regarding the drug in Geriatrics. ### Gender FDA Package Insert for Captopril contains no information regarding the use of the drug and Gender. ### Race FDA Package Insert for Captopril contains no information regarding the Race. ### Renal Impairment - Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. - Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. - Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels. - Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration. - Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis). - Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on a surface-area basis) for only 5 to 7 days. - In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing. ### Hepatic Impairment FDA Package Insert for Captopril contains no information regarding Hepatic Impairment. ### Females of Reproductive Potential and Males FDA Package Insert for Captopril contains no information regarding Females of Reproductive Potential and Males. ### Immunocompromised Patients FDA Package Insert for Captopril contains no information regarding Immunocompromised Patients. # Administration and Monitoring ### Administration Captopril should be taken one hour before meals. Dosage must be individualized. ## Hypertension - Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient's previous antihypertensive drug regimen for one week before starting captopril. - The initial dose of captopril tablets, USP is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when captopril is used alone. - The dose of captopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one- to two-week intervals until its highest usual antihypertensive dose is reached. - If captopril is being started in a patient already receiving a diuretic, captopril therapy should be initiated under close medical supervision, with dosage and titration of captopril as noted above. - If further blood pressure reduction is required, the dose of captopril may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril should not be exceeded. - For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision. - When necessitated by the patient's clinical condition, the daily dose of captopril may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated. - Beta-blockers may also be used in conjunction with captopril therapy, but the effects of the two drugs are less than additive. ## Heart Failure - Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect; for these patients, titration to the usual daily dosage can then occur within the next several days. - For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of captopril should not be exceeded. - Captopril should generally be used in conjunction with a diuretic and digitalis. Captopril therapy must be initiated under very close medical supervision. ## Left Ventricular Dysfunction After Myocardial Infarction - The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d. - Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg t.i.d. Captopril should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated. - Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers. ### Diabetic Nephropathy - The recommended dose of captopril for long term use to treat diabetic nephropathy is 25 mg t.i.d. - Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril if additional therapy is required to further lower blood pressure. ## Dosage Adjustment in Renal Impairment - Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. - Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. ### Monitoring - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. # IV Compatibility FDA Package Insert for captopril contains no information regarding IV Compatibility. # Overdosage - Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure. - While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. - Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation. # Pharmacology ## Mechanism of Action The mechanism of action of captopril has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention. Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by captopril. In animal studies, captopril did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action. ACE is identical to "bradykininase", and captopril may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril. Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss. The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood. ## Structure Captopril is a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to angiotensin II. Captopril is designated chemically as 1-((2S)-3-mercapto-2-methylpropionyl)-L-proline (MW 217.29) and has the following structural formula: Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in chloroform and ethyl acetate. Each captopril tablet, USP 12.5 mg, 25 mg, 50 mg and 100 mg for oral administration contains 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide NF, croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF and microcrystalline cellulose NF. ## Pharmacodynamics Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of captopril and glomerular filtration rate is usually unchanged. Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of captopril. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics are additive. In contrast, captopril and beta-blockers have a less than additive effect. Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of captopril has not been associated with a rapid increase in blood pressure. ## Pharmacokinetics After oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide. Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged captopril is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of captopril occurs. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum recommended human dose of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, the high doses for mice and rats are 13 and 26 times the maximum recommended human dose, respectively. Studies in rats have revealed no impairment of fertility. ### Animal Toxicology Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels. Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration. Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis). Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on surface-area basis) for only 5 to 7 days. In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing. # Clinical Studies ### Myocardial Infarction Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics and digitalis show no tolerance to beneficial effects on exercise tolerance time (ETT), open studies, with exposure up to 18 months in some cases, also indicate that ETT benefit is maintained. Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal. The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 2,231 patients (age 21 to 79 years) who survived the acute phase of myocardial infarction and did not have active ischemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤40%, but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half of the patients had symptoms of heart failure in the past. Patients were given a test dose of 6.25 mg oral captopril and were randomized within 3 to 16 days post-infarction to receive either captopril or placebo in addition to conventional therapy. Captopril was initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg t.i.d. About 80% of patients were receiving the target dose at the end of the study. Patients were followed for a minimum of two years and for up to five years, with an average follow-up of 3.5 years. Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and captopril groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the captopril group (119/74 vs. 125/77 mmHg at 1 yr). Therapy with captopril improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular death was 21% (P=0.014). Captopril treated subjects had 22% (P=0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving captopril developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2056 placebo; 2036 captopril). Captopril was well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics. In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18 to 49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤ 2.5 mg/dL, were randomized to placebo or captopril (25 mg t.i.d.) and followed for up to 4.8 years (median 3 years). To achieve blood pressure control, additional antihypertensive agents (diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for patients in both groups. The captopril group had a 51% reduction in risk of doubling of serum creatinine (P<0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or transplantation) or death (P<0.01). captopril treatment resulted in a 30% reduction in urine protein excretion within the first 3 months (P<0.05), which was maintained throughout the trial. The captopril group had somewhat better blood pressure control than the placebo group, but the effects of captopril on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Captopril was well tolerated in this patient population. In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20 to 200 mcg/min) were randomized to placebo or captopril (50 mg b.i.d.) and followed for up to 2 years. Captopril delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P<0.05). Captopril also reduced the albumin excretion rate. However, the long term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established. Studies in rats and cats indicate that captopril does not cross the blood-brain barrier to any significant extent. # How Supplied - 12.5 mg tablets in bottles of 100 (NDC 60505-0003-6) and 1000 (NDC 60505-0003-9) - 25 mg tablets in bottles of 100 (NDC 60505-0004-6) and 1000 (NDC 60505-0004-9) - 50 mg tablets in bottles of 100 (NDC 60505-0005-6) and 1000 (NDC 60505-0005-9) - 100 mg tablets in bottles of 100 (NDC 60505-0006-6) and 1000 (NDC 60505-0006-9) - The 12.5 mg tablet is a round, biconvex tablet, coded “APO 003” with a bisect score on one side and a plain face on the other - The 25 mg tablet is a round, biconvex tablet, coded “APO 004” on one side and a quadrisect score on the other - The 50 mg tablet is capsule shaped, biconvex tablet, coded “APO 005” with a bisect score on one side and a plain face on the other - The 100 mg tablet is capsule shaped, biconvex tablet, coded “APO 006” with a bisect score on one side and a plain face on the other. All captopril tablets are white to off-white and may exhibit a slight sulfurous odor. ## Storage Do not store above 86°F. Keep bottles tightly closed (protect from moisture). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign on neutropenia, or of progressive edema which might be related to proteinuria and nephrotic syndrome. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Patients should be advised not to use potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes without consulting their physician. Patients should be warned against interruption or discontinuation of medication unless instructed by the physician. Heart failure patients on captopril therapy should be cautioned against rapid increases in physical activity. Patients should be informed that captopril tablets should be taken one hour before meals. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to captopril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible # Precautions with Alcohol Alcohol-captopril interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Capoten # Look-Alike Drug Names Captopril - carvedilol # Drug Shortage Status # Price	Captopril Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2], Amr Marawan, M.D. [3], Alejandro Lemor, M.D. [4] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Captopril is an Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension, heart failure, left ventricular dysfunction after myocardial infarction, diabetic nephropathy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, rash, hyperkalemia (11% ), disorder of taste, cough (0.5% to 2%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose: Captopril 25 mg PO bid or Captopril 25 mg PO tid ; may be increased after 1 to 2 weeks to Captopril 50 mg PO bid or Captopril 50 mg PO tid , then to Captopril 100 to 150 mg PO bid/tid (in combination with a thiazide diuretic) if needed (MAX 450 mg daily) Captopril tablets, USP are indicated for the treatment of hypertension. In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis. Captopril may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations. Captopril is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. - Dosing Information - Initial dose: (patients with normal or low blood pressure, vigorous diuretic therapy, volume depletion) Captopril 6.25 to 12.5 mg PO tid - Initial dose: Captopril PO 25 mg tid - Maintenance dose: Captopril 50 to 100 mg PO tid (MAX 450 mg PO daily) Captopril tablets, USP are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. - Dosing Information - Initial dose: Captopril 6.25 mg PO for one dose starting as early as 3 days after myocardial infarction, - Maintenance dose: Captopril 12.5 mg tid a day increased to 25 mg PO tid a day in several days; target dose 50 mg PO tid over the next several weeks as tolerated Captopril tablets, USP are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients. - Dosing Information - (type 1 diabetes mellitus) Captopril 25 mg PO tid - (type 2 diabetes mellitus) Captopril 12.5 mg bid , increased to Captopril 12.5 mg tid after 3 months Captopril tablets, USP are indicated for the treatment of diabetic nephropathy (proteinuria >500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Captopril decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis). In considering use of captopril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Dosing Information - An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated.[1] ### Non–Guideline-Supported Use - Dosing information - Case report 1: 150 mg/day for 26 weeks followed by 75 mg for 9 weeks[2] - Case report 2: 25 mg bid (titrated to achieve a concentration of urinary cystine of less than 200 mg/liter, or to a maximum of 150 mg/day)[3] - Dosing information - Case report: 12.5 mg bid for 3 months followed by 12.5 mg tid[4] - Dosing information - 25 mg qd [5]This beneficial effect may not be sustained. - Dosing information - RCT report: - Initial dosage: 12.5 mg bid - Followed-up treatment: increase the dosage bi-weekly - Final aim: either blood pressure normalization or reach the maximum of 50 mg bid [6] - Research 1 - Dosage for the first month: 6.25 mg/day - Dosage for the second month: titrated to 12.5 mg/day - Finally dosage: titrated to 25 mg/day[7] - Research 2 - Initial dosage: 6.25 mg tid - Followed-up treatment: 25 mg tid[8] - Case report: 25 mg/day, max: 75 mg/day[9] - Dosing information - 25 mg/day[10] - Dosing information - Case report 1: long time treatment for 6 months, maximum dose 200 mg/day[11] - Case reprot 2: 25 mg tid [12] ### Renovascular Hypertension - Dosing information - As an alternative therapy in patients with contraindications to surgery or renal artery angioplasty. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for captopril contains no information regarding safety and efficacy in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about the guideline-supported off-label use. ### Non–Guideline-Supported Use ### Chronic Heart Failure(infants) - Dosing Information - 4 mg/kg via nasogastric tube[13] ### Kidney Imaging - Dosing Information - 0.2-0.4 mg/kg PO qd[14] # Contraindications - Hypersensitivity to this product or any other angiotensin-converting enzyme inhibitor - History of angioedema during therapy with any other ACE inhibitor) # Warnings ### Anaphylactoid and Possibly Related Reactions - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including captopril) may be subject to a variety of adverse reactions, some of them serious. - Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted. - Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of captopril; some cases required medical therapy. - Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. - Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. ### Neutropenia/Agranulocytosis - Neutropenia (<1000/mm3) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. - The risk of neutropenia is dependent on the clinical status of the patient. - In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed. - In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports. - In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. - While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine ≥1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present. - The neutropenia has usually been detected within three months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen. - In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors. ### Evaluation of the hypertensive or heart failure patient should always include assessment of renal function - If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically. - In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution. - All patients treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay. - Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm3) the physician should withdraw captopril and closely follow the patient's course. ### Proteinuria - Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. - The nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria. ### Hypotension - Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis. - In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6 percent of patients with heart failure. - Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure. - Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood pressure is a common and desirable observation upon initiation of captopril tablets, USP treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months. ### Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. # Adverse Reactions ## Clinical Trials Experience Reported incidences are based on clinical trials involving approximately 7000 patients. ### Renal - About one of 100 patients developed proteinuria. - Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency. ### Hematologic - Neutropenia/agranulocytosis has occurred. Cases of anemia, thrombocytopenia, and pancytopenia have been reported. ### Dermatologic - Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistamine agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported. - Flushing or pallor has been reported in 2 to 5 of 1000 patients. ### Cardiovascular - Hypotension may occur; for discussion of hypotension with captopril therapy. - Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients. - Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. ### Dysgeusia - Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste. ### Angioedema - Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. ### Cough - Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials. The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: - Gastric irritation - Abdominal pain - Nausea - Vomiting - Diarrhea - Anorexia - Constipation - Aphthous ulcers - Peptic ulcer - Dizziness - Headache - Malaise - Fatigue - Insomnia - Dry mouth - Dyspnea - Alopecia - Paresthesias ## Postmarketing Experience ### Body As A Whole - Anaphylactoid reactions. ### General - Asthenia, gynecomastia. ### Cardiovascular - Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope. ### Dermatologic - Bullous pemphigoid, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis. ### Gastrointestinal - Pancreatitis, glossitis, dyspepsia. ### Hematologic - Anemia, including aplastic and hemolytic. ### Hepatobiliary - Jaundice, hepatitis, including rare cases of necrosis, cholestasis. ### Metabolic - Symptomatic hyponatremia. ### Musculoskeletal - Myalgia, myasthenia. ### Nervous/Psychiatric - Ataxia, confusion, depression, nervousness, somnolence. ### Respiratory - Bronchospasm, eosinophilic pneumonitis, rhinitis. ### Special Senses - Blurred vision. ### Urogenital - Impotence. - As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. ### Altered Laboratory Findings - Hyperkalemia - Small increases in serum potassium, especially in patients with renal impairment. - Hyponatremia - Particularly in patients receiving a low sodium diet or concomitant diuretics. - Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. - A positive ANA has been reported. - Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred. # Drug Interactions ### Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on captopril and other agents that affect the RAS. - Do not co-administer aliskiren with captopril in patients with diabetes. Avoid use of aliskiren with captopril in patients with renal impairment (GFR <60 ml/min). ### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase – 2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including captopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving captopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including captopril, may be attenuated by NSAIDs. ### Hypotension - Patients On Diuretic Therapy - Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril. - The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril tablets, USP or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion. ### Agents Having Vasodilator Activity - Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously, and perhaps at lower dosage. ### Agents Causing Renin Release - Captopril's effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system. ### Agents Affecting Sympathetic Activity - The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive. ### Agents Increasing Serum Potassium - Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution. ### Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. ### Cardiac Glycosides - In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril-digoxin interaction could be found. ### Loop Diuretics - Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renal impaired hypertensive patients. ### Allopurinol - In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days. ### Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including captopril. ### Drug /Laboratory Test Interaction - Captopril may cause a false-positive urine test for acetone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue captopril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mothers and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue, captopril unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to captopril for hypotension, oliguria, and hyperkalemia. - When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose. Pregnancy Category (AUS): D Drugs which have caused, are suspected to have caused, or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. ### Labor and Delivery FDA Package Insert for captopril contains no information regarding Labor and Delivery. ### Nursing Mothers - Concentrations of captopril in human milk are approximately one percent of those in maternal blood. Because of the potential for serious adverse reactions in nursing infants from captopril, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of captopril to the mother. ### Pediatric Use - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. - Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril form the general circulation. - Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults. - Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported. - Captopril should be used in pediatric patients only if other measures for controlling blood pressure have not been effective. ### Geriatic Use FDA Package Insert for Captopril contains no information regarding the drug in Geriatrics. ### Gender FDA Package Insert for Captopril contains no information regarding the use of the drug and Gender. ### Race FDA Package Insert for Captopril contains no information regarding the Race. ### Renal Impairment - Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. - Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. - Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels. - Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration. - Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis). - Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on a surface-area basis) for only 5 to 7 days. - In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing. ### Hepatic Impairment FDA Package Insert for Captopril contains no information regarding Hepatic Impairment. ### Females of Reproductive Potential and Males FDA Package Insert for Captopril contains no information regarding Females of Reproductive Potential and Males. ### Immunocompromised Patients FDA Package Insert for Captopril contains no information regarding Immunocompromised Patients. # Administration and Monitoring ### Administration Captopril should be taken one hour before meals. Dosage must be individualized. ## Hypertension - Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient's previous antihypertensive drug regimen for one week before starting captopril. - The initial dose of captopril tablets, USP is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when captopril is used alone. - The dose of captopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one- to two-week intervals until its highest usual antihypertensive dose is reached. - If captopril is being started in a patient already receiving a diuretic, captopril therapy should be initiated under close medical supervision, with dosage and titration of captopril as noted above. - If further blood pressure reduction is required, the dose of captopril may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril should not be exceeded. - For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision. - When necessitated by the patient's clinical condition, the daily dose of captopril may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated. - Beta-blockers may also be used in conjunction with captopril therapy, but the effects of the two drugs are less than additive. ## Heart Failure - Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect; for these patients, titration to the usual daily dosage can then occur within the next several days. - For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of captopril should not be exceeded. - Captopril should generally be used in conjunction with a diuretic and digitalis. Captopril therapy must be initiated under very close medical supervision. ## Left Ventricular Dysfunction After Myocardial Infarction - The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d. - Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg t.i.d. Captopril should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated. - Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers. ### Diabetic Nephropathy - The recommended dose of captopril for long term use to treat diabetic nephropathy is 25 mg t.i.d. - Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril if additional therapy is required to further lower blood pressure. ## Dosage Adjustment in Renal Impairment - Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. - Accordingly, for patients with significant renal impairment, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. ### Monitoring - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity. # IV Compatibility FDA Package Insert for captopril contains no information regarding IV Compatibility. # Overdosage - Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure. - While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. - Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation. # Pharmacology ## Mechanism of Action The mechanism of action of captopril has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention. Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by captopril. In animal studies, captopril did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action. ACE is identical to "bradykininase", and captopril may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril. Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss. The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood. ## Structure Captopril is a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to angiotensin II. Captopril is designated chemically as 1-((2S)-3-mercapto-2-methylpropionyl)-L-proline (MW 217.29) and has the following structural formula: Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in chloroform and ethyl acetate. Each captopril tablet, USP 12.5 mg, 25 mg, 50 mg and 100 mg for oral administration contains 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide NF, croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF and microcrystalline cellulose NF. ## Pharmacodynamics Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of captopril and glomerular filtration rate is usually unchanged. Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of captopril. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics are additive. In contrast, captopril and beta-blockers have a less than additive effect. Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of captopril has not been associated with a rapid increase in blood pressure. ## Pharmacokinetics After oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide. Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged captopril is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of captopril occurs. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum recommended human dose of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, the high doses for mice and rats are 13 and 26 times the maximum recommended human dose, respectively. Studies in rats have revealed no impairment of fertility. ### Animal Toxicology Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels. Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration. Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis). Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on surface-area basis) for only 5 to 7 days. In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing. # Clinical Studies ### Myocardial Infarction Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics and digitalis show no tolerance to beneficial effects on exercise tolerance time (ETT), open studies, with exposure up to 18 months in some cases, also indicate that ETT benefit is maintained. Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal. The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 2,231 patients (age 21 to 79 years) who survived the acute phase of myocardial infarction and did not have active ischemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤40%, but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half of the patients had symptoms of heart failure in the past. Patients were given a test dose of 6.25 mg oral captopril and were randomized within 3 to 16 days post-infarction to receive either captopril or placebo in addition to conventional therapy. Captopril was initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg t.i.d. About 80% of patients were receiving the target dose at the end of the study. Patients were followed for a minimum of two years and for up to five years, with an average follow-up of 3.5 years. Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and captopril groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the captopril group (119/74 vs. 125/77 mmHg at 1 yr). Therapy with captopril improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular death was 21% (P=0.014). Captopril treated subjects had 22% (P=0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving captopril developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2056 placebo; 2036 captopril). Captopril was well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics. In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18 to 49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤ 2.5 mg/dL, were randomized to placebo or captopril (25 mg t.i.d.) and followed for up to 4.8 years (median 3 years). To achieve blood pressure control, additional antihypertensive agents (diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for patients in both groups. The captopril group had a 51% reduction in risk of doubling of serum creatinine (P<0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or transplantation) or death (P<0.01). captopril treatment resulted in a 30% reduction in urine protein excretion within the first 3 months (P<0.05), which was maintained throughout the trial. The captopril group had somewhat better blood pressure control than the placebo group, but the effects of captopril on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Captopril was well tolerated in this patient population. In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20 to 200 mcg/min) were randomized to placebo or captopril (50 mg b.i.d.) and followed for up to 2 years. Captopril delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P<0.05). Captopril also reduced the albumin excretion rate. However, the long term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established. Studies in rats and cats indicate that captopril does not cross the blood-brain barrier to any significant extent. # How Supplied - 12.5 mg tablets in bottles of 100 (NDC 60505-0003-6) and 1000 (NDC 60505-0003-9) - 25 mg tablets in bottles of 100 (NDC 60505-0004-6) and 1000 (NDC 60505-0004-9) - 50 mg tablets in bottles of 100 (NDC 60505-0005-6) and 1000 (NDC 60505-0005-9) - 100 mg tablets in bottles of 100 (NDC 60505-0006-6) and 1000 (NDC 60505-0006-9) - The 12.5 mg tablet is a round, biconvex tablet, coded “APO 003” with a bisect score on one side and a plain face on the other - The 25 mg tablet is a round, biconvex tablet, coded “APO 004” on one side and a quadrisect score on the other - The 50 mg tablet is capsule shaped, biconvex tablet, coded “APO 005” with a bisect score on one side and a plain face on the other - The 100 mg tablet is capsule shaped, biconvex tablet, coded “APO 006” with a bisect score on one side and a plain face on the other. All captopril tablets are white to off-white and may exhibit a slight sulfurous odor. ## Storage Do not store above 86°F. Keep bottles tightly closed (protect from moisture). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign on neutropenia, or of progressive edema which might be related to proteinuria and nephrotic syndrome. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Patients should be advised not to use potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes without consulting their physician. Patients should be warned against interruption or discontinuation of medication unless instructed by the physician. Heart failure patients on captopril therapy should be cautioned against rapid increases in physical activity. Patients should be informed that captopril tablets should be taken one hour before meals. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to captopril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible # Precautions with Alcohol Alcohol-captopril interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Capoten # Look-Alike Drug Names Captopril - carvedilol # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Capoten
215adc344c59f23edbe3602a16d2f0a44290910c	wikidoc	Carbachol	Carbachol # 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 Carbachol is a cholinergic drug that is FDA approved for the procedure of glaucoma, ocular hypertension, miosis induction. Common adverse reactions include corneal clouding, bullous keratopathy, retinal detachment, postoperative iritis, flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Intraocular use for obtaining miosis during surgery. In addition, MIOSTAT (carbachol intraocular solution, USP) reduces the intensity of intraocular pressure elevation in the first 24 hours after cataract surgery. # Dosage - Glaucoma: 2 drops 0.75-3% solution in affected eye(s) up to 3 times daily - Miosis induction - Surgical procedure: 0.5 mL of 0.01% solution INTRAOCULARLY, instilled into anterior chamber of the eye before or after securing sutures ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbachol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbachol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Carbachol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbachol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbachol in pediatric patients. # Contraindications - Should not be used in those persons showing hypersensitivity to any of the components of this preparation. # Warnings - For single-dose intraocular use only. Discard unused portion. Intraocular carbachol 0.01% should be used with caution in patients with acute cardiac failure, bronchial asthma, peptic ulcer, hyperthyroidism, G.I. spasm, urinary tract obstruction and Parkinson's disease. # Adverse Reactions ## Clinical Trials Experience Ocular: Corneal clouding, persistent bullous keratopathy, retinal detachment and postoperative iritis following cataract extraction have been reported. Systemic: Side effects such as flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, and headache have been reported with topical or systemic application of carbachol. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carbachol in the drug label. # Drug Interactions There is limited information regarding Carbachol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. MIOSTAT® (carbachol intraocular solution, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbachol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbachol during labor and delivery. ### Nursing Mothers - It is not known if this medication is excreted in breast milk. Exercise caution when administering to a nursing woman. ### Pediatric Use - Safety and efficacy in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Carbachol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbachol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbachol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbachol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbachol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbachol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Aseptically remove the sterile vial from the blister package by peeling the backing paper and dropping the vial onto a sterile tray. Withdraw the contents into a dry sterile syringe, and replace the needle with an atraumatic cannula prior to intraocular instillation. No more than one-half milliliter should be gently instilled into the anterior chamber for the production of satisfactory miosis. It may be instilled before or after securing sutures. Miosis is usually maximal within two to five minutes after application. ### Monitoring There is limited information regarding Monitoring of Carbachol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Carbachol in the drug label. # Overdosage There is limited information regarding Carbachol overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. ## Structure - MIOSTAT® (carbachol intraocular solution, USP) is a sterile balanced salt solution of carbachol for intraocular injection. The active ingredient is represented by the chemical structure: Established name: Carbachol Chemical name: Ethanaminium, 2--N,N,Ntrimethyl-, chloride. Molecular Formula: C6H15CIN2O2 Molecular Weight: 182.65 Each mL contains: Active: carbachol 0.01%. Inactives: sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride dehydrate 0.048%, magnesium chloride hexahydrate 0.03%, sodium acetate trihydrate 0.39%, sodium citrate dihydrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH) and Water for Injection. pH range is 6.5-7.5. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carbachol in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Carbachol in the drug label. ## Nonclinical Toxicology Carcinogenesis - Studies in animals to evaluate the carcinogenic potential have not been conducted. # Clinical Studies There is limited information regarding Clinical Studies of Carbachol in the drug label. # How Supplied - In a 2.0 mL glass vial with a 1.5 mL fill, grey butyl stopper and aluminum seal packaged twelve to a carton. - NDC 0065-0023-15 ## Storage - STORAGE: Store at 15° - 30°C (59° - 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Carbachol in the drug label. # Precautions with Alcohol - Alcohol-Carbachol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names MIOSTAT # Look-Alike Drug Names There is limited information regarding Carbachol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Carbachol 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 Carbachol is a cholinergic drug that is FDA approved for the procedure of glaucoma, ocular hypertension, miosis induction. Common adverse reactions include corneal clouding, bullous keratopathy, retinal detachment, postoperative iritis, flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Intraocular use for obtaining miosis during surgery. In addition, MIOSTAT (carbachol intraocular solution, USP) reduces the intensity of intraocular pressure elevation in the first 24 hours after cataract surgery. # Dosage - Glaucoma: 2 drops 0.75-3% solution in affected eye(s) up to 3 times daily - Miosis induction - Surgical procedure: 0.5 mL of 0.01% solution INTRAOCULARLY, instilled into anterior chamber of the eye before or after securing sutures ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbachol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbachol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Carbachol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbachol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbachol in pediatric patients. # Contraindications - Should not be used in those persons showing hypersensitivity to any of the components of this preparation. # Warnings - For single-dose intraocular use only. Discard unused portion. Intraocular carbachol 0.01% should be used with caution in patients with acute cardiac failure, bronchial asthma, peptic ulcer, hyperthyroidism, G.I. spasm, urinary tract obstruction and Parkinson's disease. # Adverse Reactions ## Clinical Trials Experience Ocular: Corneal clouding, persistent bullous keratopathy, retinal detachment and postoperative iritis following cataract extraction have been reported. Systemic: Side effects such as flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, and headache have been reported with topical or systemic application of carbachol. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carbachol in the drug label. # Drug Interactions There is limited information regarding Carbachol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. MIOSTAT® (carbachol intraocular solution, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbachol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbachol during labor and delivery. ### Nursing Mothers - It is not known if this medication is excreted in breast milk. Exercise caution when administering to a nursing woman. ### Pediatric Use - Safety and efficacy in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Carbachol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbachol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbachol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbachol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbachol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbachol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Aseptically remove the sterile vial from the blister package by peeling the backing paper and dropping the vial onto a sterile tray. Withdraw the contents into a dry sterile syringe, and replace the needle with an atraumatic cannula prior to intraocular instillation. No more than one-half milliliter should be gently instilled into the anterior chamber for the production of satisfactory miosis. It may be instilled before or after securing sutures. Miosis is usually maximal within two to five minutes after application. ### Monitoring There is limited information regarding Monitoring of Carbachol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Carbachol in the drug label. # Overdosage There is limited information regarding Carbachol overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. ## Structure - MIOSTAT® (carbachol intraocular solution, USP) is a sterile balanced salt solution of carbachol for intraocular injection. The active ingredient is represented by the chemical structure: Established name: Carbachol Chemical name: Ethanaminium, 2-[(aminocarbonyl)oxy]-N,N,Ntrimethyl-, chloride. Molecular Formula: C6H15CIN2O2 Molecular Weight: 182.65 Each mL contains: Active: carbachol 0.01%. Inactives: sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride dehydrate 0.048%, magnesium chloride hexahydrate 0.03%, sodium acetate trihydrate 0.39%, sodium citrate dihydrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH) and Water for Injection. pH range is 6.5-7.5. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carbachol in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Carbachol in the drug label. ## Nonclinical Toxicology Carcinogenesis - Studies in animals to evaluate the carcinogenic potential have not been conducted. # Clinical Studies There is limited information regarding Clinical Studies of Carbachol in the drug label. # How Supplied - In a 2.0 mL glass vial with a 1.5 mL fill, grey butyl stopper and aluminum seal packaged twelve to a carton. - NDC 0065-0023-15 ## Storage - STORAGE: Store at 15° - 30°C (59° - 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Carbachol in the drug label. # Precautions with Alcohol - Alcohol-Carbachol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names MIOSTAT # Look-Alike Drug Names There is limited information regarding Carbachol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carbachol
208325c341407745a296dce7451c84ad42182b8f	wikidoc	Carbamate	Carbamate # Overview Carbamates or urethanes are a group of organic compounds sharing a common functional group with the general structure -NH(CO)O-. Carbamates are esters of carbamic acid, NH2COOH, an unstable compound. Since carbamic acid contains a nitrogen attached to a carboxyl group it is also an amide. Therefore, carbamate esters may have alkyl or aryl groups substituted on the nitrogen, or the amide function. For example, urethane or ethyl carbamate, is unsubstituted, while ethyl N–methylcarbamate has a methyl group attached to the nitrogen (see methyl isocyanate for formation of N-methylcarbamates). # Carbamates in biochemistry A nitrogen substituted carbamic acid is formed when a carbon dioxide molecule reacts with the amino terminus of a peptide chain or an amino group of an amino acid, adding a COO− group to it and releasing a cation (H+ ion) to form a carbamate ion. "R" stands for the atoms attached to the other end of the nitrogen molecule of the amino group. Note that the COO− group is a resonance structure, so the single bonds both show a degree of double bond character, and the charge is delocalised over the two oxygen atoms. This reaction is reversible (with equilibrium constant K << 1 in the above reaction), as the N–C bond is highly labile. # Some occurrences of carbamate groups in nature In hemoglobin, carbamate groups are formed when carbon dioxide molecules bond with the amino termini of the globin chains. This helps to stabilise the protein when it becomes deoxyhaemoglobin and increases the likelihood of the release of remaining oxygen molecules bound to the protein. Ribulose 1,5-bisphosphate carboxylase/oxygenase (the enzyme required to fix a carbon dioxide molecule at the start of the Calvin cycle) also requires the formation of a carbamate to function. At the active site of the enzyme, a Mg2+ ion is bound to a glutamate residue, an aspartate residue and a lysine carbamate, which hold the ion in place. The carbamate is formed when an uncharged lysine side chain near the ion reacts with a carbon dioxide molecule from the air (not the substrate carbon dioxide molecule), which then renders it charged, and so therefore able to bind the Mg2+ ion. # Commercial carbamate compounds A group of insecticides also contain the carbamate functional group for example Aldicarb, Carbofuran, Furadan, Fenoxycarb, Carbaryl, Sevin, Ethienocarb and 2-(1-Methylpropyl)phenyl N-methylcarbamate. These insecticides can cause cholinesterase inhibition poisoning by reversibly inactivating the enzyme acetylcholinesterase. The organophosphate pesticides also inhibit this enzyme, though irreversibly, and cause a more severe form of cholinergic poisoning. Polyurethanes contain multiple carbamate groups as part of their structure, but urethane is not a component of polyurethanes. These polymers have a wide range of properties and are commercially available as foams, elastomers, and solids. Urethane or ethyl carbamate is occasionally used as a veterinary medicine. In addition, some carbamates are used in human pharmacotherapy, for example the cholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine.	Carbamate # Overview Carbamates or urethanes are a group of organic compounds sharing a common functional group with the general structure -NH(CO)O-. Carbamates are esters of carbamic acid, NH2COOH, an unstable compound. Since carbamic acid contains a nitrogen attached to a carboxyl group it is also an amide. Therefore, carbamate esters may have alkyl or aryl groups substituted on the nitrogen, or the amide function. For example, urethane or ethyl carbamate, is unsubstituted, while ethyl N–methylcarbamate has a methyl group attached to the nitrogen (see methyl isocyanate for formation of N-methylcarbamates). # Carbamates in biochemistry A nitrogen substituted carbamic acid is formed when a carbon dioxide molecule reacts with the amino terminus of a peptide chain or an amino group of an amino acid, adding a COO− group to it and releasing a cation (H+ ion) to form a carbamate ion. "R" stands for the atoms attached to the other end of the nitrogen molecule of the amino group. Note that the COO− group is a resonance structure, so the single bonds both show a degree of double bond character, and the charge is delocalised over the two oxygen atoms. This reaction is reversible (with equilibrium constant K << 1 in the above reaction), as the N–C bond is highly labile. # Some occurrences of carbamate groups in nature In hemoglobin, carbamate groups are formed when carbon dioxide molecules bond with the amino termini of the globin chains. This helps to stabilise the protein when it becomes deoxyhaemoglobin and increases the likelihood of the release of remaining oxygen molecules bound to the protein. Ribulose 1,5-bisphosphate carboxylase/oxygenase (the enzyme required to fix a carbon dioxide molecule at the start of the Calvin cycle) also requires the formation of a carbamate to function. At the active site of the enzyme, a Mg2+ ion is bound to a glutamate residue, an aspartate residue and a lysine carbamate, which hold the ion in place. The carbamate is formed when an uncharged lysine side chain near the ion reacts with a carbon dioxide molecule from the air (not the substrate carbon dioxide molecule), which then renders it charged, and so therefore able to bind the Mg2+ ion. # Commercial carbamate compounds A group of insecticides also contain the carbamate functional group for example Aldicarb, Carbofuran, Furadan, Fenoxycarb, Carbaryl, Sevin, Ethienocarb and 2-(1-Methylpropyl)phenyl N-methylcarbamate. These insecticides can cause cholinesterase inhibition poisoning by reversibly inactivating the enzyme acetylcholinesterase. The organophosphate pesticides also inhibit this enzyme, though irreversibly, and cause a more severe form of cholinergic poisoning. Polyurethanes contain multiple carbamate groups as part of their structure, but urethane is not a component of polyurethanes. These polymers have a wide range of properties and are commercially available as foams, elastomers, and solids. Urethane or ethyl carbamate is occasionally used as a veterinary medicine. In addition, some carbamates are used in human pharmacotherapy, for example the cholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine.	https://www.wikidoc.org/index.php/Carbamate
27c48e4c3dc11b54969f19c7de1d4f7e65d80b87	wikidoc	Carbamide	Carbamide # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Carbamide is a OTC emollient that is FDA approved for the treatment of excessive ear wax. Common adverse reactions include allergic reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - For occasional use as an aid to soften, loosen, and remove excessive ear wax. ### Dosage - FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt head sideways and place 5 to 10 drops into ear. Tip of applicator should not enter ear canal. Keep drops in ear for several minutes by keeping head tilted or placing cotton in ear. Use twice daily for up to four days if needed, or as directed by a doctor. Any wax remaining after treatment may be removed by gently flushing the ear with warm water, using a soft rubber bulb ear syringe. Children under 12 years of age: consult a doctor. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - For occasional use as an aid to soften, loosen, and remove excessive ear wax. ### Dosage - FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt head sideways and place 5 to 10 drops into ear. Tip of applicator should not enter ear canal. Keep drops in ear for several minutes by keeping head tilted or placing cotton in ear. Use twice daily for up to four days if needed, or as directed by a doctor. Any wax remaining after treatment may be removed by gently flushing the ear with warm water, using a soft rubber bulb ear syringe. Children under 12 years of age: consult a doctor. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbamide in pediatric patients. # Contraindications There is limited information regarding Carbamide Contraindications in the drug label. # Warnings - Do not use: if you have ear drainage or discharge, ear pain, irritation or rash in the ear, or are dizzy; consult a doctor. If you have an injury or perforation (hole) of the eardrum or after ear surgery, unless directed by a doctor. For more than four consecutive days. - When using this product: avoid contact with the eyes. - Stop use and ask a doctor if: excessive ear wax remains after use of this product for four consecutive days. - Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. If accidental contact with eyes occurs, flush eyes with water and consult a doctor. # Adverse Reactions ## Clinical Trials Experience - allergic reactions ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carbamide in the drug label. # Drug Interactions There is limited information regarding Carbamide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbamide during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Carbamide with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Carbamide with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Carbamide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Carbamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ear drops ### Monitoring There is limited information regarding Monitoring of Carbamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Carbamide in the drug label. # Overdosage There is limited information regarding Overdose of Carbamide in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Carbamide Mechanism of Action in the drug label. ## Structure - Active Ingredient - Carbamide Peroxide 6.5% - Inactive ingredients - Glycerin, Oxyquinoline, Aloe Barbadensis Leaf Extract, Anthemis Nobilis Flower Oil ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carbamide in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Carbamide in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Carbamide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Carbamide in the drug label. # How Supplied There is limited information regarding Carbamide How Supplied in the drug label. ## Storage There is limited information regarding Carbamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Ear Wax Cleansing Kit Step 1 Ear Wax Removing Drops Step 2 Ear Cleansing Spray ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Carbamide in the drug label. # Precautions with Alcohol - Alcohol-Carbamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EAR WAX REMOVING DROPS CARBAMIDE PEROXIDE® # Look-Alike Drug Names There is limited information regarding Carbamide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Carbamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Carbamide is a OTC emollient that is FDA approved for the treatment of excessive ear wax. Common adverse reactions include allergic reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - For occasional use as an aid to soften, loosen, and remove excessive ear wax. ### Dosage - FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt head sideways and place 5 to 10 drops into ear. Tip of applicator should not enter ear canal. Keep drops in ear for several minutes by keeping head tilted or placing cotton in ear. Use twice daily for up to four days if needed, or as directed by a doctor. Any wax remaining after treatment may be removed by gently flushing the ear with warm water, using a soft rubber bulb ear syringe. Children under 12 years of age: consult a doctor. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - For occasional use as an aid to soften, loosen, and remove excessive ear wax. ### Dosage - FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt head sideways and place 5 to 10 drops into ear. Tip of applicator should not enter ear canal. Keep drops in ear for several minutes by keeping head tilted or placing cotton in ear. Use twice daily for up to four days if needed, or as directed by a doctor. Any wax remaining after treatment may be removed by gently flushing the ear with warm water, using a soft rubber bulb ear syringe. Children under 12 years of age: consult a doctor. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbamide in pediatric patients. # Contraindications There is limited information regarding Carbamide Contraindications in the drug label. # Warnings - Do not use: if you have ear drainage or discharge, ear pain, irritation or rash in the ear, or are dizzy; consult a doctor. If you have an injury or perforation (hole) of the eardrum or after ear surgery, unless directed by a doctor. For more than four consecutive days. - When using this product: avoid contact with the eyes. - Stop use and ask a doctor if: excessive ear wax remains after use of this product for four consecutive days. - Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. If accidental contact with eyes occurs, flush eyes with water and consult a doctor. # Adverse Reactions ## Clinical Trials Experience - allergic reactions ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carbamide in the drug label. # Drug Interactions There is limited information regarding Carbamide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbamide during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Carbamide with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Carbamide with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Carbamide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Carbamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ear drops ### Monitoring There is limited information regarding Monitoring of Carbamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Carbamide in the drug label. # Overdosage There is limited information regarding Overdose of Carbamide in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Carbamide Mechanism of Action in the drug label. ## Structure - Active Ingredient - Carbamide Peroxide 6.5% - Inactive ingredients - Glycerin, Oxyquinoline, Aloe Barbadensis Leaf Extract, Anthemis Nobilis Flower Oil ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carbamide in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Carbamide in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Carbamide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Carbamide in the drug label. # How Supplied There is limited information regarding Carbamide How Supplied in the drug label. ## Storage There is limited information regarding Carbamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Ear Wax Cleansing Kit Step 1 Ear Wax Removing Drops Step 2 Ear Cleansing Spray ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Carbamide in the drug label. # Precautions with Alcohol - Alcohol-Carbamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EAR WAX REMOVING DROPS CARBAMIDE PEROXIDE®[1] # Look-Alike Drug Names There is limited information regarding Carbamide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carbamide
16b3e3e66c7f66c002c2acfc97ddf30524be837e	wikidoc	Carbenoid	Carbenoid In chemistry a carbenoid is a reactive intermediate that shares reaction characteristics with a carbene . In the Simmons-Smith reaction the carbenoid intermediate is a zinc / iodine complex that takes the form of This complex reacts with an alkene to form a cyclopropane just as a carbene would do. Carbenoids appear as intermediates in many other reactions. In one system a carbenoid chloroalkyllithium reagent is prepared in situ from a sulfoxide and t-BuLi which reacts by an insertion reaction into the C-B bond of a pinacol boronic ester . The enantiopurity of the chiral sulfoxide is preserved in the ultimate product after oxidation of the boronic ester to the alcohol indicating that a true carbene was never involved in the sequence.	Carbenoid In chemistry a carbenoid is a reactive intermediate that shares reaction characteristics with a carbene [1]. In the Simmons-Smith reaction the carbenoid intermediate is a zinc / iodine complex that takes the form of This complex reacts with an alkene to form a cyclopropane just as a carbene would do. Carbenoids appear as intermediates in many other reactions. In one system a carbenoid chloroalkyllithium reagent is prepared in situ from a sulfoxide and t-BuLi which reacts by an insertion reaction into the C-B bond of a pinacol boronic ester [2]. The enantiopurity of the chiral sulfoxide is preserved in the ultimate product after oxidation of the boronic ester to the alcohol indicating that a true carbene was never involved in the sequence.	https://www.wikidoc.org/index.php/Carbenoid
b45c641c0293b5f5041b9c5f47bf6fc31b146bd8	wikidoc	Carbidopa	Carbidopa # 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 Carbidopa is an anti-dyskinesia agent and antiparkinson agent that is FDA approved for the treatment of idiopathic Parkinson's disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism. Common adverse reactions include dyskinesia and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Carbidopa Tablets are indicated for use with carbidopa-levodopa or with levodopa in the treatment of the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication. Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of Carbidopa must be determined by careful titration. Most patients respond to a 1:10 proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa, the amount of carbidopa in carbidopa-levodopa should be considered when calculating the total amount of Carbidopa to be administered each day. ### Patients Receiving Carbidopa-Levodopa Who Require Additional Carbidopa Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of Carbidopa may be given with the first dose of carbidopa-levodopa each day. Additional doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa-levodopa. Carbidopa may be given with any dose carbidopa-levodopa as required for optimum therapeutic response. The maximum daily dosage of carbidopa, given as Carbidopa and as carbidopa- levodopa), should not exceed 200 mg. ### Patients Requiring Individual Titration of Carbidopa and Levodopa Dosage Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa administration, there may be an occasional patient who requires individually titrated doses of these two drugs. In these patients, carbidopa should be initiated at a dosage of 25 mg three or four times a day. The two drugs should be given at the same time, starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or recommended daily dosage of levodopa when given without Carbidopa. In patients already receiving levodopa therapy, at least twelve hours should elapse between the last dose of levodopa and initiation of therapy with Carbidopa and levodopa. A convenient way to initiate therapy in these patients is in the morning following a night when the patient has not taken levodopa for at least twelve hours. Health care providers who prescribe separate doses of Carbidopa and levodopa should be thoroughly familiar with the directions for use of each drug. ### Dosage Adjustment Dosage of Carbidopa may be adjusted by adding or omitting one-half or one tablet a day. Because both therapeutic and adverse responses occur more rapidly with combined therapy than when only levodopa is given, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly when Carbidopa and levodopa are given concomitantly than when levodopa is given without Carbidopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients. Current evidence indicates other standard antiparkinsonian drugs may be continued while carbidopa and levodopa are being administered. However, the dosage of such other standard antiparkinsonian drugs may require adjustment. ### Interruption of Therapy Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and withdrawal of carbidopa-levodopa) or carbidopa-levodopa Extended Release. Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or carbidopa-levodopa Extended-Release is required, especially if the patient is receiving neuroleptics. If general anesthesia is required, therapy may be continued as long as the patient is permitted to take fluids and medication by mouth. When therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual daily dosage may be resumed as soon as the patient is able to take medication orally. Carbidopa is for use with carbidopa-levodopa in patients for whom the dosage of carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of carbidopa. Carbidopa is for use with levodopa in the occasional patient whose dosage requirement of carbidopa and levodopa necessitates separate titration of each medication Carbidopa is used with carbidopa-levodopa or with levodopa to permit the administration of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration, and with a somewhat smoother response. However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from the addition of carbidopa. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and levodopa concomitantly or as carbidopa-levodopa. Although the administration of Carbidopa permits control of parkinsonism and Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa. Certain patients who responded poorly to levodopa alone have improved when carbidopa and levodopa were given concurrently. This was most likely due to decreased peripheral decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa. In deciding whether to give Carbidopa with carbidopa-levodopa or with levodopa to patients who have nausea and/orvomiting, the physician should be aware that, while many patients may be expected to improve, some may not. Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy. It should be further noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about half the patients with nausea and/or vomiting on levodopa alone improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbidopa in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbidopa in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbidopa in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbidopa in pediatric patients. # Contraindications - Carbidopa is contraindicated in patients with known hypersensitivity to any component of this drug. - Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with levodopa or carbidopa-levodopa combination products with or without Carbidopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa. Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl). - Levodopa or carbidopa-levodopa products, with or without Carbidopa, are contraindicated in patients with narrow-angle glaucoma. # Warnings Carbidopa has no antiparkinsonian effect when given alone. It is indicated for use with carbidopa-levodopa or levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa. When Carbidopa is to be given to carbidopa-naive patients who are being treated with levodopa alone, the two drugs should be given at the same time. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with Carbidopa and levodopa in combination. Start with no more than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when given without Carbidopa. The addition of Carbidopa with levodopa or carbidopa-levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, Carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because Carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with levodopa in combination with Carbidopa than with levodopa alone. ### Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on dopaminergic medications, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with Carbidopa when taking it with other carbidopa-levodopa products. Before initiating treatment with Carbidopa, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with Carbidopa such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing Carbidopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with Carbidopa continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. ### Hyperpyrexia and Confusion Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release. Therefore, patients should be observed carefully when the dosage of levodopa or arbidopalevodopa 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. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation,leukocytosis, myoglobinuria, and increased serum myoglobin, have been reported. 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. # Precautions ### General As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended concomitant therapy with Carbidopa and levodopa, or with Carbidopa and carbidopa-levodopa or any combination of these drugs. ### Impulse Control/Compulsive Behaviors Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including Carbidopa taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Carbidopa. Physicians should consider dose reduction or stopping Carbidopa or levodopa if a patient develops such urges while taking Carbidopa with carbidopa/levodopa. ### Hallucinations/Psychotic-Like Behavior Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. Carbidopa when taken with carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Ordinarily, patients with a major psychotic disorder should not be treated with Carbidopa and carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of Carbidopa. ### Dyskinesia Carbidopa may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. ### Depression Patients treated with Carbidopa and carbidopa-levodopa should be observed carefully for the development of depression with concomitant suicidal tendencies. ### Melanoma 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 observed increased risk 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 Carbidopa tablets for Parkinson’s disease. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). ### Laboratory Tests Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during concomitant administration of carbidopa and levodopa than with levodopa alone. Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis There were no significant differences between treated and control rats with respect to mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135 mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia was seen when compared to concurrent controls. - Mutagenesis Mutagenicity studies have not been performed with either carbidopa or the combination of carbidopa and levodopa. - Fertility Carbidopa had no effect on the mating performance, fertility, or survival of the young when administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a moderate decrease in body weight gain in males. The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100 mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive performance, or the growth and survival of the young. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Carbidopa Clinical Trials Experience in the drug label. ## Postmarketing Experience Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. The only adverse reactions that have been observed have been with concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa-levodopa combination products. When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa combination products, the most common adverse reactions have included dyskinesias such as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions reported with LODOSYN when administered concomitantly with levodopa alone or carbidopa-levodopa combination products were psychotic episodes including delusions, hallucinations, and paranoid ideation, depression with or without development of suicidal tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with concomitant use of LODOSYN and levodopa has not been established. The following other adverse reactions have been reported with levodopa and carbidopa-levodopa combination products. These same adverse reactions may also occur when LODOSYN is administered with these products. - Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue. - Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension including orthostatic hypotension, palpitation, phlebitis, syncope. - Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste alterations, vomiting. - Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia, agranulocytosis. - Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions (including pemphigus-like reactions). - Metabolic: edema, weight gain, weight loss. - Musculoskeletal: ], leg pain, muscle cramps, shoulder pain. - Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and paranoid ideation,neuroleptic malignant syndrome, bradykinetic episodes (“on-off”phenomenon),confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares,insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with LODOSYN and levodopa, has not been established. - Skin: flushing, increased sweating, malignant melanoma, rash, alopecia, dark sweat. - Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils. - Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention, urinary tract infection. - Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose; decreased hemoglobin and hematocrit; decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in the urine; protein and glucose in the urine. - Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise, neuroleptic malignant syndrome, sense of stimulation. # Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with Carbidopa given with levodopa or carbidopa-levodopa fixed-dose combination products. Symptomatic postural hypotension has occurred when Carbidopa, given with levodopa or carbidopa-levodopa combination products, was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with Carbidopa, given with or without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of the antihypertensive drug may be required. For patients receiving monoamine oxidase inhibitors (Type A or B). Concomitant therapy with selegiline and rasigiline and carbidopa and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with Carbidopa and levodopa or carbidopa-levodopa combination products should be carefully observed for loss of therapeutic response. Carbidopa and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa. Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies with Carbidopa in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Carbidopa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by the concomitant administration of carbidopa. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbidopa in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbidopa during labor and delivery. ### Nursing Mothers t is not known whether carbidopa is excreted in human milk. Because many drugs are excreted in human milk, and because of their potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended. ### Geriatic Use Clinical studies of Carbidopa did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other 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 concomitant disease and other drug therapy. ### Gender There is no FDA guidance on the use of Carbidopa with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbidopa with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbidopa in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbidopa in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbidopa in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbidopa in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Carbidopa tablets for Parkinson’s disease. - In the event of overdosage, electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias. - Because both therapeutic and adverse responses occur more rapidly with combined therapy than when only levodopa is given, patients should be monitored closely during the dose adjustment period. # IV Compatibility There is limited information regarding the compatibility of Carbidopa and IV administrations. # Overdosage No reports of overdose with Carbidopa have been received. Management of overdosage with carbidopa is the same as that with levodopa or carbidopa-levodopa preparations. In the event of overdosage, general supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously, and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Carbidopa should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not effective in reversing the actions of Carbidopa. Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg. # Pharmacology ## Mechanism of Action Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease. ## Structure Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4H2O, and its structural formula is: Chemical Structure Carbidopa tablets contain 25 mg of carbidopa. Inactive ingredients are cellulose, FD&C Yellow 6, magnesium stearate and starch. Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3. ## Pharmacodynamics When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues. The incidence of levodopa-induced nausea and vomiting is less when Carbidopa is used with levodopa than when levodopa is used without Carbidopa. In many patients this reduction in nausea and vomiting will permit more rapid dosage titration. Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does not appear to cross the blood-brain barrier readily and does not affect the metabolism of levodopa within the central nervous system at doses of carbidopa that are recommended for maximum effective inhibition of peripheral decarboxylation of levodopa. Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. However, since levodopa and carbidopa compete with certain amino acids for transport across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients on a high protein diet. ## Pharmacokinetics Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. In clinical pharmacologic studies, simultaneous administration of separate tablets of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine when compared to the two drugs administered at separate times. Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving carbidopa and levodopa concomitantly or the fixed combination carbidopa-levodopa or carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that high doses of vitamin B6 should not be taken by patients on levodopa therapy alone because exogenously administered pyridoxine would enhance the metabolism of levodopa to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of pyridoxine. Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa extended release tablets. ## Nonclinical Toxicology There is limited information regarding Carbidopa Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Carbidopa Clinical Studies in the drug label. # How Supplied carbidopa Tablets, 25 mg, are orange, round, compressed tablets that are scored and coded 711 on one side and LODOSYN on the other. They are supplied as follows: NDC 68682-200-25 bottles of 100. ## Storage Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Information for Patients It is important that Carbidopa with levodopa be taken at regular intervals according to the schedule outlined by the health care provider. Caution patients not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa-levodopa preparations without first consulting a physician. Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing Interval. Tell patients to notify the prescriber if such response poses a problem to lifestyle. Patients should be advised that occasionally dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of Carbidopa and levodopa. Although the color appears to be clinically insignificant, garments may become discolored. The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available in the body. The above factors may reduce the clinical effectiveness of the Carbidopa and levodopa therapy. Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Advise patients to exercise caution while driving or operating machinery and that if they have experience somnolence and/or sudden sleep onset, they must refrain from these activities. 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 Carbidopa and levodopa. 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 intense urges while taking Carbidopa and levodopa. Physicians should consider dose reduction or stopping Carbidopa and levodopa if a patient develops such urges while taking Carbidopa with carbidopa/levodopa. # Precautions with Alcohol Alcohol-Carbidopa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Lodosyn # Look-Alike Drug Names There is limited information regarding Carbidopa Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Carbidopa Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anusha Vege, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Carbidopa is an anti-dyskinesia agent and antiparkinson agent that is FDA approved for the treatment of idiopathic Parkinson's disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism. Common adverse reactions include dyskinesia and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Carbidopa Tablets are indicated for use with carbidopa-levodopa or with levodopa in the treatment of the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication. Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of Carbidopa must be determined by careful titration. Most patients respond to a 1:10 proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa, the amount of carbidopa in carbidopa-levodopa should be considered when calculating the total amount of Carbidopa to be administered each day. ### Patients Receiving Carbidopa-Levodopa Who Require Additional Carbidopa Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of Carbidopa may be given with the first dose of carbidopa-levodopa each day. Additional doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa-levodopa. Carbidopa may be given with any dose carbidopa-levodopa as required for optimum therapeutic response. The maximum daily dosage of carbidopa, given as Carbidopa and as carbidopa- levodopa), should not exceed 200 mg. ### Patients Requiring Individual Titration of Carbidopa and Levodopa Dosage Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa administration, there may be an occasional patient who requires individually titrated doses of these two drugs. In these patients, carbidopa should be initiated at a dosage of 25 mg three or four times a day. The two drugs should be given at the same time, starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or recommended daily dosage of levodopa when given without Carbidopa. In patients already receiving levodopa therapy, at least twelve hours should elapse between the last dose of levodopa and initiation of therapy with Carbidopa and levodopa. A convenient way to initiate therapy in these patients is in the morning following a night when the patient has not taken levodopa for at least twelve hours. Health care providers who prescribe separate doses of Carbidopa and levodopa should be thoroughly familiar with the directions for use of each drug. ### Dosage Adjustment Dosage of Carbidopa may be adjusted by adding or omitting one-half or one tablet a day. Because both therapeutic and adverse responses occur more rapidly with combined therapy than when only levodopa is given, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly when Carbidopa and levodopa are given concomitantly than when levodopa is given without Carbidopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients. Current evidence indicates other standard antiparkinsonian drugs may be continued while carbidopa and levodopa are being administered. However, the dosage of such other standard antiparkinsonian drugs may require adjustment. ### Interruption of Therapy Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and withdrawal of carbidopa-levodopa) or carbidopa-levodopa Extended Release. Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or carbidopa-levodopa Extended-Release is required, especially if the patient is receiving neuroleptics. If general anesthesia is required, therapy may be continued as long as the patient is permitted to take fluids and medication by mouth. When therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual daily dosage may be resumed as soon as the patient is able to take medication orally. Carbidopa is for use with carbidopa-levodopa in patients for whom the dosage of carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of carbidopa. Carbidopa is for use with levodopa in the occasional patient whose dosage requirement of carbidopa and levodopa necessitates separate titration of each medication Carbidopa is used with carbidopa-levodopa or with levodopa to permit the administration of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration, and with a somewhat smoother response. However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from the addition of carbidopa. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and levodopa concomitantly or as carbidopa-levodopa. Although the administration of Carbidopa permits control of parkinsonism and Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa. Certain patients who responded poorly to levodopa alone have improved when carbidopa and levodopa were given concurrently. This was most likely due to decreased peripheral decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa. In deciding whether to give Carbidopa with carbidopa-levodopa or with levodopa to patients who have nausea and/orvomiting, the physician should be aware that, while many patients may be expected to improve, some may not. Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy. It should be further noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about half the patients with nausea and/or vomiting on levodopa alone improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbidopa in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbidopa in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carbidopa in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carbidopa in pediatric patients. # Contraindications - Carbidopa is contraindicated in patients with known hypersensitivity to any component of this drug. - Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with levodopa or carbidopa-levodopa combination products with or without Carbidopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa. Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl). - Levodopa or carbidopa-levodopa products, with or without Carbidopa, are contraindicated in patients with narrow-angle glaucoma. # Warnings Carbidopa has no antiparkinsonian effect when given alone. It is indicated for use with carbidopa-levodopa or levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa. When Carbidopa is to be given to carbidopa-naive patients who are being treated with levodopa alone, the two drugs should be given at the same time. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with Carbidopa and levodopa in combination. Start with no more than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when given without Carbidopa. The addition of Carbidopa with levodopa or carbidopa-levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, Carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because Carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with levodopa in combination with Carbidopa than with levodopa alone. ### Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on dopaminergic medications, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with Carbidopa when taking it with other carbidopa-levodopa products. Before initiating treatment with Carbidopa, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with Carbidopa such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing Carbidopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with Carbidopa continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. ### Hyperpyrexia and Confusion Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release. Therefore, patients should be observed carefully when the dosage of levodopa or arbidopalevodopa 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. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation,leukocytosis, myoglobinuria, and increased serum myoglobin, have been reported. 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. # Precautions ### General As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended concomitant therapy with Carbidopa and levodopa, or with Carbidopa and carbidopa-levodopa or any combination of these drugs. ### Impulse Control/Compulsive Behaviors Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including Carbidopa taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Carbidopa. Physicians should consider dose reduction or stopping Carbidopa or levodopa if a patient develops such urges while taking Carbidopa with carbidopa/levodopa. ### Hallucinations/Psychotic-Like Behavior Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. Carbidopa when taken with carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Ordinarily, patients with a major psychotic disorder should not be treated with Carbidopa and carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of Carbidopa. ### Dyskinesia Carbidopa may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. ### Depression Patients treated with Carbidopa and carbidopa-levodopa should be observed carefully for the development of depression with concomitant suicidal tendencies. ### Melanoma 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 observed increased risk 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 Carbidopa tablets for Parkinson’s disease. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). ### Laboratory Tests Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during concomitant administration of carbidopa and levodopa than with levodopa alone. Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis There were no significant differences between treated and control rats with respect to mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135 mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia was seen when compared to concurrent controls. - Mutagenesis Mutagenicity studies have not been performed with either carbidopa or the combination of carbidopa and levodopa. - Fertility Carbidopa had no effect on the mating performance, fertility, or survival of the young when administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a moderate decrease in body weight gain in males. The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100 mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive performance, or the growth and survival of the young. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Carbidopa Clinical Trials Experience in the drug label. ## Postmarketing Experience Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. The only adverse reactions that have been observed have been with concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa-levodopa combination products. When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa combination products, the most common adverse reactions have included dyskinesias such as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions reported with LODOSYN when administered concomitantly with levodopa alone or carbidopa-levodopa combination products were psychotic episodes including delusions, hallucinations, and paranoid ideation, depression with or without development of suicidal tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with concomitant use of LODOSYN and levodopa has not been established. The following other adverse reactions have been reported with levodopa and carbidopa-levodopa combination products. These same adverse reactions may also occur when LODOSYN is administered with these products. - Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue. - Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension including orthostatic hypotension, palpitation, phlebitis, syncope. - Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste alterations, vomiting. - Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia, agranulocytosis. - Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions (including pemphigus-like reactions). - Metabolic: edema, weight gain, weight loss. - Musculoskeletal: [back pain]], leg pain, muscle cramps, shoulder pain. - Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and paranoid ideation,neuroleptic malignant syndrome, bradykinetic episodes (“on-off”phenomenon),confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares,insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with LODOSYN and levodopa, has not been established. - Skin: flushing, increased sweating, malignant melanoma, rash, alopecia, dark sweat. - Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils. - Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention, urinary tract infection. - Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose; decreased hemoglobin and hematocrit; decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in the urine; protein and glucose in the urine. - Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise, neuroleptic malignant syndrome, sense of stimulation. # Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with Carbidopa given with levodopa or carbidopa-levodopa fixed-dose combination products. Symptomatic postural hypotension has occurred when Carbidopa, given with levodopa or carbidopa-levodopa combination products, was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with Carbidopa, given with or without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of the antihypertensive drug may be required. For patients receiving monoamine oxidase inhibitors (Type A or B). Concomitant therapy with selegiline and rasigiline and carbidopa and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with Carbidopa and levodopa or carbidopa-levodopa combination products should be carefully observed for loss of therapeutic response. Carbidopa and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa. Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies with Carbidopa in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Carbidopa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by the concomitant administration of carbidopa. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carbidopa in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carbidopa during labor and delivery. ### Nursing Mothers t is not known whether carbidopa is excreted in human milk. Because many drugs are excreted in human milk, and because of their potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended. ### Geriatic Use Clinical studies of Carbidopa did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other 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 concomitant disease and other drug therapy. ### Gender There is no FDA guidance on the use of Carbidopa with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carbidopa with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carbidopa in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carbidopa in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carbidopa in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carbidopa in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Carbidopa tablets for Parkinson’s disease. - In the event of overdosage, electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias. - Because both therapeutic and adverse responses occur more rapidly with combined therapy than when only levodopa is given, patients should be monitored closely during the dose adjustment period. # IV Compatibility There is limited information regarding the compatibility of Carbidopa and IV administrations. # Overdosage No reports of overdose with Carbidopa have been received. Management of overdosage with carbidopa is the same as that with levodopa or carbidopa-levodopa preparations. In the event of overdosage, general supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously, and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Carbidopa should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not effective in reversing the actions of Carbidopa. Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg. # Pharmacology ## Mechanism of Action Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease. ## Structure Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4•H2O, and its structural formula is: Chemical Structure Carbidopa tablets contain 25 mg of carbidopa. Inactive ingredients are cellulose, FD&C Yellow 6, magnesium stearate and starch. Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3. ## Pharmacodynamics When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues. The incidence of levodopa-induced nausea and vomiting is less when Carbidopa is used with levodopa than when levodopa is used without Carbidopa. In many patients this reduction in nausea and vomiting will permit more rapid dosage titration. Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does not appear to cross the blood-brain barrier readily and does not affect the metabolism of levodopa within the central nervous system at doses of carbidopa that are recommended for maximum effective inhibition of peripheral decarboxylation of levodopa. Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. However, since levodopa and carbidopa compete with certain amino acids for transport across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients on a high protein diet. ## Pharmacokinetics Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. In clinical pharmacologic studies, simultaneous administration of separate tablets of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine when compared to the two drugs administered at separate times. Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving carbidopa and levodopa concomitantly or the fixed combination carbidopa-levodopa or carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that high doses of vitamin B6 should not be taken by patients on levodopa therapy alone because exogenously administered pyridoxine would enhance the metabolism of levodopa to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of pyridoxine. Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa extended release tablets. ## Nonclinical Toxicology There is limited information regarding Carbidopa Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Carbidopa Clinical Studies in the drug label. # How Supplied carbidopa Tablets, 25 mg, are orange, round, compressed tablets that are scored and coded 711 on one side and LODOSYN on the other. They are supplied as follows: NDC 68682-200-25 bottles of 100. ## Storage Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Information for Patients It is important that Carbidopa with levodopa be taken at regular intervals according to the schedule outlined by the health care provider. Caution patients not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa-levodopa preparations without first consulting a physician. Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing Interval. Tell patients to notify the prescriber if such response poses a problem to lifestyle. Patients should be advised that occasionally dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of Carbidopa and levodopa. Although the color appears to be clinically insignificant, garments may become discolored. The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available in the body. The above factors may reduce the clinical effectiveness of the Carbidopa and levodopa therapy. Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Advise patients to exercise caution while driving or operating machinery and that if they have experience somnolence and/or sudden sleep onset, they must refrain from these activities. 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 Carbidopa and levodopa. 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 intense urges while taking Carbidopa and levodopa. Physicians should consider dose reduction or stopping Carbidopa and levodopa if a patient develops such urges while taking Carbidopa with carbidopa/levodopa. # Precautions with Alcohol Alcohol-Carbidopa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Lodosyn # Look-Alike Drug Names There is limited information regarding Carbidopa Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carbidopa
906f8c50d76bc02f387d5890f25b3b1cef0beb03	wikidoc	Carbon-12	Carbon-12 Carbon-12 is the most abundant of the two stable isotopes of the element carbon, accounting for 98.89% of carbon; it contains 6 protons, 6 neutrons and 6 electrons. Carbon-12 is of particular importance as it is used as the standard from which atomic masses of all nuclides are measured: its mass number is by definition 12. # History Prior to 1959 both the IUPAP and IUPAC tended to use oxygen to define the mole, the chemists defining the mole as the number of atoms of oxygen which had mass 16 g, the physicists using a similar definition but with the oxygen-16 isotope only. The two organizations agreed in 1959/1960 to define the mole as: This was adopted by the CIPM (International Committee for Weights and Measures) in 1967, and in 1971 it was adopted by the 14th CGPM (General Conference on Weights and Measures). In 1980 the CIPM clarified the above definition, defining that the carbon-12 atoms are unbound and in their ground state.	Carbon-12 Template:Infobox isotope Carbon-12 is the most abundant of the two stable isotopes of the element carbon, accounting for 98.89% of carbon; it contains 6 protons, 6 neutrons and 6 electrons. Carbon-12 is of particular importance as it is used as the standard from which atomic masses of all nuclides are measured: its mass number is by definition 12. # History Prior to 1959 both the IUPAP and IUPAC tended to use oxygen to define the mole, the chemists defining the mole as the number of atoms of oxygen which had mass 16 g, the physicists using a similar definition but with the oxygen-16 isotope only. The two organizations agreed in 1959/1960 to define the mole as: This was adopted by the CIPM (International Committee for Weights and Measures) in 1967, and in 1971 it was adopted by the 14th CGPM (General Conference on Weights and Measures). In 1980 the CIPM clarified the above definition, defining that the carbon-12 atoms are unbound and in their ground state.	https://www.wikidoc.org/index.php/Carbon-12
18db42377b27e9622b40377387f53b79f15f6801	wikidoc	Carbon-13	Carbon-13 # Detection by NMR spectroscopy Because of its nuclear spin properties, this isotope responds to a resonant radio frequency (RF) signal. The absorption and emission of the RF signal by the nuclei can be monitored and detected using nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy. This is a technique that gives information on the identity and number of atoms adjacent to other atoms in said molecule, thereby giving clues to the structure of an organic molecule. Since 12C has zero spin, it does not give an NMR signal, and since only 1% of the atoms in a molecule are 13C, it is unlikely that carbon-carbon coupling is seen. Acquiring a 13C NMR spectrum can take from a couple of minutes to hours because many scans have to be summed together in order to have results distinguishable from background noise. In biological NMR proteins can be deliberately labelled with 13C (and usually nitrogen-15) to facilitate structure determination. This is achieved by growing microorganisms genetically engineered to express the protein on a growth medium with 13C labeled glucose as the only carbon source. In this way proteins with a 13C content of almost 100% can be produced. # Detection by mass spectroscopy A mass spectrogram of an organic compound will usually contain a small peak of one mass unit greater than the apparent molecular ion peak (M). This is known as the M+1 peak and originates due to the presence of 13C atoms. A molecule containing one carbon atom will be expected to have an M+1 peak of approximately 1.1% of the size of the M peak as 1.1% of the carbon atoms will be 13C rather than 12C. Similarly a molecule containing two carbon atoms will be expected to have an M+1 peak of approximately 2.2% of the size of the M peak, as there is double the previous likelihood that a molecule will contain a 13C atom. In the above the mathematics and chemistry have been simplified, however it can be used effectively to give the number of carbon atoms for small to medium sized organic molecules. In the following formula the result should be rounded to the nearest integer: C = \frac{100Y}{1.1X} C = number of C atoms X = amplitude of the M ion peak Y = amplitude of the M+1 ion peak 13C-enriched compounds are used in the research of metabolic processes by means of mass spectroscopy. Such compounds are safe because they are non-radioactive. In addition, 13C is used to quantitate proteins (quantitative proteomics). One important application is `stable isotope labeling with amino acids in cell culture´ (SILAC).	Carbon-13 Template:Infobox isotopeCarbon-13 (13C) is a natural, stable isotope of carbon and one of the environmental isotopes. It makes up about 1.1% of all natural carbon on Earth. Pure carbon-13 costs about 700 USD per gram.[1] # Detection by NMR spectroscopy Because of its nuclear spin properties, this isotope responds to a resonant radio frequency (RF) signal. The absorption and emission of the RF signal by the nuclei can be monitored and detected using nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy. This is a technique that gives information on the identity and number of atoms adjacent to other atoms in said molecule, thereby giving clues to the structure of an organic molecule. Since 12C has zero spin, it does not give an NMR signal, and since only 1% of the atoms in a molecule are 13C, it is unlikely that carbon-carbon coupling is seen. Acquiring a 13C NMR spectrum can take from a couple of minutes to hours because many scans have to be summed together in order to have results distinguishable from background noise. In biological NMR proteins can be deliberately labelled with 13C (and usually nitrogen-15) to facilitate structure determination. This is achieved by growing microorganisms genetically engineered to express the protein on a growth medium with 13C labeled glucose as the only carbon source. In this way proteins with a 13C content of almost 100% can be produced. # Detection by mass spectroscopy A mass spectrogram of an organic compound will usually contain a small peak of one mass unit greater than the apparent molecular ion peak (M). This is known as the M+1 peak and originates due to the presence of 13C atoms. A molecule containing one carbon atom will be expected to have an M+1 peak of approximately 1.1% of the size of the M peak as 1.1% of the carbon atoms will be 13C rather than 12C. Similarly a molecule containing two carbon atoms will be expected to have an M+1 peak of approximately 2.2% of the size of the M peak, as there is double the previous likelihood that a molecule will contain a 13C atom. In the above the mathematics and chemistry have been simplified, however it can be used effectively to give the number of carbon atoms for small to medium sized organic molecules. In the following formula the result should be rounded to the nearest integer: <math>C = \frac{100Y}{1.1X}</math> C = number of C atoms X = amplitude of the M ion peak Y = amplitude of the M+1 ion peak 13C-enriched compounds are used in the research of metabolic processes by means of mass spectroscopy. Such compounds are safe because they are non-radioactive. In addition, 13C is used to quantitate proteins (quantitative proteomics). One important application is `stable isotope labeling with amino acids in cell culture´ (SILAC).	https://www.wikidoc.org/index.php/Carbon-13
ceceb84fe26ecead9c12d4c491e1d50435923542	wikidoc	Carbon-14	Carbon-14 Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon discovered on February 27, 1940, by Martin Kamen and Sam Ruben at the University of California Radiation Laboratory in Berkeley. Its nucleus contains 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method to date archaeological, geological, and hydrogeological samples. There are three naturally occurring isotopes of carbon on Earth: 99% of the carbon is carbon-12, 1% is carbon-13, and carbon-14 occurs in trace amounts, making up as much as 1 part per trillion (0.0000000001%) of the carbon on the Earth. The half-life of carbon-14 is 5,730±40 years. It decays into nitrogen-14 through beta-decay. The activity of the modern radiocarbon standardis about 14 disintegrations per minute (dpm) per gram carbon . The atomic mass of carbon-14 is about 14.003241 amu. The different isotopes of carbon do not differ appreciably in their chemical properties. This is used in chemical research in a technique called carbon labeling: some carbon-12 atoms of a given compound are replaced with carbon-14 atoms (or some carbon-13 atoms) in order to trace them along chemical reactions involving the given compound. # Origin and radioactive decay of carbon-14 Carbon-14 is produced in the upper layers of the troposphere and the stratosphere by thermal neutrons absorbed by nitrogen atoms. When cosmic rays enter the atmosphere, they undergo various transformations, including the production of neutrons. The resulting neutrons (1n) participate in the following reaction: The highest rate of carbon-14 production takes place at altitudes of 9 to 15 km (30,000 to 50,000 feet) and at high geomagnetic latitudes, but the carbon-14 readily mixes and becomes evenly distributed throughout the atmosphere and reacts with oxygen to form radioactive carbon dioxide. Carbon dioxide also dissolves in water and thus permeates the oceans. Carbon-14 can also be produced in ice by fast neutrons causing spallation reactions in oxygen. Carbon-14 then goes through radioactive beta decay. By emitting an electron and an anti-neutrino, carbon-14 (half life of 5730 years) decays into the stable, non-radioactive isotope nitrogen-14. The inventory of carbon-14 in Earth's biosphere is about 300 million Curies, of which most is in the oceans. # Radiocarbon dating Radiocarbon dating is a radiometric dating method that uses (14C) to determine the age of carbonaceous materials up to about 60,000 years old. The technique was developed by Willard Libby and his colleagues in 1949 during his tenure as a professor at the University of Chicago. Libby estimated that the steady state radioactivity concentration of exchangeable carbon-14 would be about 14 disintegrations per minute (dpm) per gram. In 1960, he was awarded the Nobel Prize in chemistry for this work. One of the frequent uses of the technique is to date organic remains from archaeological sites. Plants fix atmospheric carbon during photosynthesis, so the level of 14C in plants at the time wood is laid down, or in animals at the time they die, equals the level of 14C in the atmosphere at that time. However, it decreases thereafter from radioactive decay, allowing the date of death or fixation to be estimated. The initial 14C level for the calculation can either be estimated, or else directly compared with known year-by-year data from tree-ring data (dendrochronology) to 10,000 years ago, or from cave deposits (speleothems), to about 45,000 years of age. A calculation or (more accurately) a direct comparison with tree ring or cave-deposit carbon-14 levels, gives the wood or animal sample age-from-formation. The technique has limitations within the modern industrial era, due to fossil fuel carbon (which has little carbon-14) being released into the atmosphere in large quantities, in the past several centuries. # Carbon-14 and fossil fuels Most man-made chemicals are made of fossil fuels, such as petroleum or coal, in which the carbon-14 has long since decayed. However, oil deposits often contain trace amounts of carbon-14 (varying significantly, but ranging from 1% the ratio found in living organisms to amounts comparable to an apparent age of 40,000 years for oils with the highest levels of carbon-14). This may indicate possible contamination by small amounts of bacteria, underground sources of radiation (such as uranium decay, although reported measured amounts of 14C/U in uranium-bearing ores imply an unlikely (improbably large) quantity of uranium involved, roughly half as much as the carbon in the deposits, to match the 10-15 14C/C measured), or other unknown secondary sources of carbon-14 production. Presence of carbon-14 in the isotopic signature of a sample of carbonaceous material indicates its possible contamination by biogenic sources or the decay of radioactive material in surrounding geologic strata. # Carbon-14 and nuclear tests The above-ground nuclear tests that occurred in several countries between 1955 and 1963 dramatically increased the amount of carbon-14 in the atmosphere and subsequently in the biosphere; after the tests ended the atmospheric concentration of the isotope began to decrease. One side effect of the change in atmospheric carbon-14 is that this enables the determination of the birth year of a deceased individual: the amount of carbon-14 in tooth enamel is measured with accelerator mass spectrometry and compared to records of past atmospheric carbon-14 concentrations. Since teeth are formed at a specific age and do not exchange carbon thereafter, this method allows age to be determined to within 1.6 years. This method only works for individuals born after 1943, and it must be known whether the individual was born in the Northern or the Southern Hemisphere. An alternative dating method relies on the lens of the eye; transparent proteins called "lens crystallines" produced during the first year of life are unchanged afterward, so measuring carbon-14 concentrations there can provide a record of the time of birth. The primary restrictions on the technology are that the person has to have been born after 1950, the lens must be removed within three days after death before it decays too much, and the individual cannot have subsisted primarily on seafood. # Carbon-14 in the human body Since essentially all sources of human food are derived from plants, the carbon that comprises our bodies contains carbon-14 at the same concentration as the atmosphere. The beta-decays from this internal radiocarbon contribute approx 1 mrem/year (.01 mSv /year) to each person's dose of ionizing radiation. This is small compared to the doses from potassium-40 (0.39 mSv/year) and radon (which vary). Carbon-14 can be used as a radioactive tracer in medicine. In the urea breath test, a diagnostic test for Helicobacter pylori, urea labeled with approx 1 μCi (37kBq) carbon-14 is fed to a patient. In the event of a H. pylori infection, the bacterial urease enzyme breaks down the urea into ammonia and radioactively-labeled carbon dioxide, which can be detected by low-level counting of the patient's breath.	Carbon-14 Template:Infobox isotope Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon discovered on February 27, 1940, by Martin Kamen and Sam Ruben at the University of California Radiation Laboratory in Berkeley. Its nucleus contains 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method to date archaeological, geological, and hydrogeological samples. There are three naturally occurring isotopes of carbon on Earth: 99% of the carbon is carbon-12, 1% is carbon-13, and carbon-14 occurs in trace amounts, making up as much as 1 part per trillion (0.0000000001%) of the carbon on the Earth. The half-life of carbon-14 is 5,730±40 years. It decays into nitrogen-14 through beta-decay.[1] The activity of the modern radiocarbon standard[2]is about 14 disintegrations per minute (dpm) per gram carbon [3]. The atomic mass of carbon-14 is about 14.003241 amu. The different isotopes of carbon do not differ appreciably in their chemical properties. This is used in chemical research in a technique called carbon labeling: some carbon-12 atoms of a given compound are replaced with carbon-14 atoms (or some carbon-13 atoms) in order to trace them along chemical reactions involving the given compound. # Origin and radioactive decay of carbon-14 Carbon-14 is produced in the upper layers of the troposphere and the stratosphere by thermal neutrons absorbed by nitrogen atoms. When cosmic rays enter the atmosphere, they undergo various transformations, including the production of neutrons. The resulting neutrons (1n) participate in the following reaction: The highest rate of carbon-14 production takes place at altitudes of 9 to 15 km (30,000 to 50,000 feet) and at high geomagnetic latitudes, but the carbon-14 readily mixes and becomes evenly distributed throughout the atmosphere and reacts with oxygen to form radioactive carbon dioxide. Carbon dioxide also dissolves in water and thus permeates the oceans. Carbon-14 can also be produced in ice by fast neutrons causing spallation reactions in oxygen. Carbon-14 then goes through radioactive beta decay. By emitting an electron and an anti-neutrino, carbon-14 (half life of 5730 years) decays into the stable, non-radioactive isotope nitrogen-14. The inventory of carbon-14 in Earth's biosphere is about 300 million Curies, of which most is in the oceans.[4] # Radiocarbon dating Template:See main Radiocarbon dating is a radiometric dating method that uses (14C) to determine the age of carbonaceous materials up to about 60,000 years old. The technique was developed by Willard Libby and his colleagues in 1949[5] during his tenure as a professor at the University of Chicago. Libby estimated that the steady state radioactivity concentration of exchangeable carbon-14 would be about 14 disintegrations per minute (dpm) per gram. In 1960, he was awarded the Nobel Prize in chemistry for this work. One of the frequent uses of the technique is to date organic remains from archaeological sites. Plants fix atmospheric carbon during photosynthesis, so the level of 14C in plants at the time wood is laid down, or in animals at the time they die, equals the level of 14C in the atmosphere at that time. However, it decreases thereafter from radioactive decay, allowing the date of death or fixation to be estimated. The initial 14C level for the calculation can either be estimated, or else directly compared with known year-by-year data from tree-ring data (dendrochronology) to 10,000 years ago, or from cave deposits (speleothems), to about 45,000 years of age. A calculation or (more accurately) a direct comparison with tree ring or cave-deposit carbon-14 levels, gives the wood or animal sample age-from-formation. The technique has limitations within the modern industrial era, due to fossil fuel carbon (which has little carbon-14) being released into the atmosphere in large quantities, in the past several centuries. # Carbon-14 and fossil fuels Most man-made chemicals are made of fossil fuels, such as petroleum or coal, in which the carbon-14 has long since decayed. However, oil deposits often contain trace amounts of carbon-14 (varying significantly, but ranging from 1% the ratio found in living organisms to amounts comparable to an apparent age of 40,000 years for oils with the highest levels of carbon-14).[citation needed] This may indicate possible contamination by small amounts of bacteria, underground sources of radiation (such as uranium decay, although reported measured amounts of 14C/U in uranium-bearing ores imply an unlikely (improbably large) quantity of uranium involved, roughly half as much as the carbon in the deposits, to match the 10-15 14C/C measured[6]), or other unknown secondary sources of carbon-14 production. Presence of carbon-14 in the isotopic signature of a sample of carbonaceous material indicates its possible contamination by biogenic sources or the decay of radioactive material in surrounding geologic strata. # Carbon-14 and nuclear tests The above-ground nuclear tests that occurred in several countries between 1955 and 1963 dramatically increased the amount of carbon-14 in the atmosphere and subsequently in the biosphere; after the tests ended the atmospheric concentration of the isotope began to decrease. One side effect of the change in atmospheric carbon-14 is that this enables the determination of the birth year of a deceased individual: the amount of carbon-14 in tooth enamel is measured with accelerator mass spectrometry and compared to records of past atmospheric carbon-14 concentrations. Since teeth are formed at a specific age and do not exchange carbon thereafter, this method allows age to be determined to within 1.6 years. This method only works for individuals born after 1943,[10][11] and it must be known whether the individual was born in the Northern or the Southern Hemisphere. An alternative dating method relies on the lens of the eye; transparent proteins called "lens crystallines" produced during the first year of life are unchanged afterward, so measuring carbon-14 concentrations there can provide a record of the time of birth. The primary restrictions on the technology are that the person has to have been born after 1950, the lens must be removed within three days after death before it decays too much, and the individual cannot have subsisted primarily on seafood[12]. # Carbon-14 in the human body Since essentially all sources of human food are derived from plants, the carbon that comprises our bodies contains carbon-14 at the same concentration as the atmosphere. The beta-decays from this internal radiocarbon contribute approx 1 mrem/year (.01 mSv /year) to each person's dose of ionizing radiation.[13] This is small compared to the doses from potassium-40 (0.39 mSv/year) and radon (which vary). Carbon-14 can be used as a radioactive tracer in medicine. In the urea breath test, a diagnostic test for Helicobacter pylori, urea labeled with approx 1 μCi (37kBq) carbon-14 is fed to a patient. In the event of a H. pylori infection, the bacterial urease enzyme breaks down the urea into ammonia and radioactively-labeled carbon dioxide, which can be detected by low-level counting of the patient's breath.[14]	https://www.wikidoc.org/index.php/Carbon-14
75724746a233c1238ed25381738196c9c57a44c5	wikidoc	Carbonate	Carbonate In chemistry, a carbonate is a salt or ester of carbonic acid. # Applications Soda water (also known as Seltzer water) is water with CO2 dissolved under pressure. The taste of soda water was discovered by the 18th century chemist Joseph Priestley. To test for the presence of the carbonate anion in a salt, the addition of dilute mineral acid (e.g. hydrochloric acid) will yield carbon dioxide gas. Carbonate-containing salts are industrially and mineralogically ubiquitous. The term "carbonate" is also commonly used to refer to one of these salts or carbonate minerals. Most common is calcite, or calcium carbonate, the chief constituent of limestone. The process of removing carbon dioxide from these salts by heating is called calcination. The term is also used as a verb, to describe the process of raising carbonate and bicarbonate concentrations in water, see also carbonated water, either by the introduction under pressure of carbon dioxide gas into the water, or by dissolving carbonate or bicarbonate salts into the water. # Chemical properties The carbonate ion is a polyatomic anion with the empirical formula CO32− and a molecular mass of 60.01 daltons; it consists of one central carbon atom surrounded by three identical oxygen atoms in a trigonal planar arrangement. The carbonate ion carries a negative two formal charge and is the conjugate base of the hydrogen carbonate ion, HCO3−, which is the conjugate base of H2CO3, carbonic acid. A carbonate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Most carbonate salts are insoluble in water at standard temperature and pressure, with solubility constants of less than 1×10−8. Exceptions include sodium, potassium and ammonium carbonates. In aqueous solution, carbonate, bicarbonate, carbon dioxide, and carbonic acid exist together in a dynamic equilibrium. In strongly basic conditions, the carbonate ion predominates, while in weakly basic conditions, the bicarbonate ion is prevalent. In more acid conditions, aqueous carbon dioxide, CO2(aq), is the main form, which, with water, H2O, is in equilibrium with carbonic acid - the equilibrium lies strongly towards carbon dioxide. Thus sodium carbonate is basic, sodium bicarbonate is weakly basic, while carbon dioxide itself is a weak acid. Carbonated water is formed by dissolving CO2 in water under pressure. When the partial pressure of CO2 is reduced, for example when a can of soda is opened, the equilibrium for each of the forms of carbonate (carbonate, bicarbonate, carbon dioxide, and carbonic acid) shifts until the concentration of CO2 in the solution is equal to the solubility of CO2 at that temperature and pressure. In living systems an enzyme, carbonic anhydrase, speeds the interconversion of CO2 and carbonic acid. In organic chemistry a carbonate can also refer to a functional group within a larger molecule that contains a carbon atom bound to three oxygen atoms, one which is double bonded. The VSEPR shape of the carbonate ion is trigonal planar or triplanar # Acid-base chemistry The carbonate ion (CO32−) is a strong base. It is a conjugate base of the weakly acidic bicarbonate (IUPAC name hydrogen carbonate HCO3−), itself a strong conjugate base of the still weakly acidic carbonic acid. As such in aqueous solution, the carbonate ion seeks to reclaim hydrogen atoms. It works as a buffer in the blood as follows: when pH is too low, the concentration of hydrogen ions is too high, so you exhale CO2. This cause the equation to shift left, essentially decreasing the concentration of H+ ions, causing a more basic pH. When pH is too high, the concentration of hydrogen ions in the blood is too low, so the kidneys excrete bicarbonate (HCO3−). This causes the equation to shift right, essentially increasing the concentration of hydrogen ions, causing a more acidic pH. # Carbonate salts - Carbonate overview: # History It is generally thought that the presence of carbonates in rock is unequivocal evidence for the presence of liquid water. Recent observations of the Planetary nebula NGC 6302 shows evidence for carbonates in space , where aqueous alteration similar to that on Earth is unlikely. Other minerals have been proposed which would fit the observations. Significant carbonate deposits have not been found on Mars via remote sensing or in situ missions, even though Martian meteorites contain small amounts and groundwater may have existed at both Gusev and Meridiani Planum.	Carbonate In chemistry, a carbonate is a salt or ester of carbonic acid. # Applications Soda water (also known as Seltzer water) is water with CO2 dissolved under pressure. The taste of soda water was discovered by the 18th century chemist Joseph Priestley. To test for the presence of the carbonate anion in a salt, the addition of dilute mineral acid (e.g. hydrochloric acid) will yield carbon dioxide gas. Carbonate-containing salts are industrially and mineralogically ubiquitous. The term "carbonate" is also commonly used to refer to one of these salts or carbonate minerals. Most common is calcite, or calcium carbonate, the chief constituent of limestone. The process of removing carbon dioxide from these salts by heating is called calcination. The term is also used as a verb, to describe the process of raising carbonate and bicarbonate concentrations in water, see also carbonated water, either by the introduction under pressure of carbon dioxide gas into the water, or by dissolving carbonate or bicarbonate salts into the water. # Chemical properties The carbonate ion is a polyatomic anion with the empirical formula CO32− and a molecular mass of 60.01 daltons; it consists of one central carbon atom surrounded by three identical oxygen atoms in a trigonal planar arrangement. The carbonate ion carries a negative two formal charge and is the conjugate base of the hydrogen carbonate ion, HCO3−, which is the conjugate base of H2CO3, carbonic acid. A carbonate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Most carbonate salts are insoluble in water at standard temperature and pressure, with solubility constants of less than 1×10−8. Exceptions include sodium, potassium and ammonium carbonates. In aqueous solution, carbonate, bicarbonate, carbon dioxide, and carbonic acid exist together in a dynamic equilibrium. In strongly basic conditions, the carbonate ion predominates, while in weakly basic conditions, the bicarbonate ion is prevalent. In more acid conditions, aqueous carbon dioxide, CO2(aq), is the main form, which, with water, H2O, is in equilibrium with carbonic acid - the equilibrium lies strongly towards carbon dioxide. Thus sodium carbonate is basic, sodium bicarbonate is weakly basic, while carbon dioxide itself is a weak acid. Carbonated water is formed by dissolving CO2 in water under pressure. When the partial pressure of CO2 is reduced, for example when a can of soda is opened, the equilibrium for each of the forms of carbonate (carbonate, bicarbonate, carbon dioxide, and carbonic acid) shifts until the concentration of CO2 in the solution is equal to the solubility of CO2 at that temperature and pressure. In living systems an enzyme, carbonic anhydrase, speeds the interconversion of CO2 and carbonic acid. In organic chemistry a carbonate can also refer to a functional group within a larger molecule that contains a carbon atom bound to three oxygen atoms, one which is double bonded. The VSEPR shape of the carbonate ion is trigonal planar or triplanar # Acid-base chemistry The carbonate ion (CO32−) is a strong base. It is a conjugate base of the weakly acidic bicarbonate (IUPAC name hydrogen carbonate HCO3−), itself a strong conjugate base of the still weakly acidic carbonic acid. As such in aqueous solution, the carbonate ion seeks to reclaim hydrogen atoms. It works as a buffer in the blood as follows: when pH is too low, the concentration of hydrogen ions is too high, so you exhale CO2. This cause the equation to shift left, essentially decreasing the concentration of H+ ions, causing a more basic pH. When pH is too high, the concentration of hydrogen ions in the blood is too low, so the kidneys excrete bicarbonate (HCO3−). This causes the equation to shift right, essentially increasing the concentration of hydrogen ions, causing a more acidic pH. # Carbonate salts Template:Seealso - Carbonate overview: Template:Carbonates # History It is generally thought that the presence of carbonates in rock is unequivocal evidence for the presence of liquid water. Recent observations of the Planetary nebula NGC 6302 shows evidence for carbonates in space [1], where aqueous alteration similar to that on Earth is unlikely. Other minerals have been proposed which would fit the observations. Significant carbonate deposits have not been found on Mars via remote sensing or in situ missions, even though Martian meteorites contain small amounts and groundwater may have existed at both Gusev[2] and Meridiani Planum[3].	https://www.wikidoc.org/index.php/Carbonate
8c092c7fec20d79f74d2ca65d2f7b0d3302c3d23	wikidoc	Carbuncle	Carbuncle # Overview A carbuncle is an abscess, larger than a boil, usually with one or more openings draining pus onto the skin. It is usually caused by bacterial infection. # Pathophysiology Carbuncles may develop anywhere, but they are most common on the back and the nape of the neck. Men get carbuncles more often than women. Because the condition is contagious, family members may develop carbuncles at the same time. Often, the direct cause of a carbuncle cannot be determined. Things that make carbuncle infections more likely include friction from clothing or shaving, generally poor hygiene and weakening of immunity. For example, persons with diabetes and immune system diseases are more likely to develop staphylococcal infections. # Causes Most carbuncles are caused by the bacteria staphylococcus aureus. The infection is contagious and may spread to other areas of the body or other people. # Natural History, Complications and Prognosis Carbuncles may heal on their own. Others usually respond well to treatment. However, a carbuncle can return again and again for months or years following the first infection. Call a doctor if a carbuncle does not heal with home treatment within 2 weeks or is located on the face, neck or spine. The same if you have a fever or a lot of swelling around the carbuncle, or pain that gets worse. Also consult a professional if carbuncles come back often. # Diagnosis ## Physical Examination A carbuncle is made up of several skin boils. The infected mass is filled with fluid, pus, and dead tissue. Fluid may drain out of the carbuncle, but sometimes the mass is so deep that it cannot drain on its own. The carbuncle may be the size of a pea or as large as a golf ball. It may be red and irritated and might hurt when you touch it. It may also grow very fast and have a white or yellow center. It may crust or spread to other skin areas. Sometimes, other symptoms may occur. These may include fatigue, fever and general discomfort or a sick feeling. Sometimes an itchy sensation occurs before the carbuncle develops. # Treatment Carbuncles usually must drain before they will heal. This most often occurs on its own in less than 2 weeks. Placing a warm moist cloth on the carbuncle helps it to drain, which speeds healing. The affected area should be soaked with a warm, moist cloth several times each day. The carbuncle should not be squeezed, or cut open without medical supervision, as this can spread and worsen the infection. Treatment is needed if the carbuncle lasts longer than 2 weeks, returns frequently, is located on the spine or the middle of the face, or occurs along with a fever or other symptoms. Treatment helps reduce complications related to an infection. A doctor may prescribe antibacterial soaps and antibiotics applied to the skin or taken by mouth. Deep or large lesions may need to be drained by a health professional. Proper hygiene is very important to prevent the spread of infection. Hands should always be washed thoroughly after touching a carbuncle. Washcloths and towels should not be shared or reused. Clothing, washcloths, towels, and sheets or other items that contact infected areas should be washed in very hot (preferably boiling) water. Bandages should be changed frequently and thrown away in a tightly-closed bag. ## Medical Therapy - Carbuncle - Mild - Preferred treatment: Incision and Drainage - Moderate - Empiric treatment: TMP-SMX OR Doxycycline - Culture directed treatment - MSSA: TMP-SMX - MRSA: Dicloxacillin OR Cephalexin - Severe - Empiric treatment: Vancomycin OR Daptomycin OR Linezolid OR Televancin OR Ceftaroline - Culture directed treatment - MSSA: Nafcillin OR Cefazolin OR Clindamycin - MRSA: Vancomycin OR Daptomycin OR Linezolid OR Televancin OR Ceftaroline	Carbuncle Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: # Overview A carbuncle is an abscess, larger than a boil, usually with one or more openings draining pus onto the skin. It is usually caused by bacterial infection. # Pathophysiology Carbuncles may develop anywhere, but they are most common on the back and the nape of the neck. Men get carbuncles more often than women. Because the condition is contagious, family members may develop carbuncles at the same time. Often, the direct cause of a carbuncle cannot be determined. Things that make carbuncle infections more likely include friction from clothing or shaving, generally poor hygiene and weakening of immunity. For example, persons with diabetes and immune system diseases are more likely to develop staphylococcal infections. # Causes Most carbuncles are caused by the bacteria staphylococcus aureus. The infection is contagious and may spread to other areas of the body or other people. # Natural History, Complications and Prognosis Carbuncles may heal on their own. Others usually respond well to treatment. However, a carbuncle can return again and again for months or years following the first infection. Call a doctor if a carbuncle does not heal with home treatment within 2 weeks or is located on the face, neck or spine. The same if you have a fever or a lot of swelling around the carbuncle, or pain that gets worse. Also consult a professional if carbuncles come back often. # Diagnosis ## Physical Examination A carbuncle is made up of several skin boils. The infected mass is filled with fluid, pus, and dead tissue. Fluid may drain out of the carbuncle, but sometimes the mass is so deep that it cannot drain on its own. The carbuncle may be the size of a pea or as large as a golf ball. It may be red and irritated and might hurt when you touch it. It may also grow very fast and have a white or yellow center. It may crust or spread to other skin areas. Sometimes, other symptoms may occur. These may include fatigue, fever and general discomfort or a sick feeling. Sometimes an itchy sensation occurs before the carbuncle develops. # Treatment Carbuncles usually must drain before they will heal. This most often occurs on its own in less than 2 weeks. Placing a warm moist cloth on the carbuncle helps it to drain, which speeds healing. The affected area should be soaked with a warm, moist cloth several times each day. The carbuncle should not be squeezed, or cut open without medical supervision, as this can spread and worsen the infection. Treatment is needed if the carbuncle lasts longer than 2 weeks, returns frequently, is located on the spine or the middle of the face, or occurs along with a fever or other symptoms. Treatment helps reduce complications related to an infection. A doctor may prescribe antibacterial soaps and antibiotics applied to the skin or taken by mouth. Deep or large lesions may need to be drained by a health professional. Proper hygiene is very important to prevent the spread of infection. Hands should always be washed thoroughly after touching a carbuncle. Washcloths and towels should not be shared or reused. Clothing, washcloths, towels, and sheets or other items that contact infected areas should be washed in very hot (preferably boiling) water. Bandages should be changed frequently and thrown away in a tightly-closed bag. ## Medical Therapy - Carbuncle[1] - Mild - Preferred treatment: Incision and Drainage - Moderate - Empiric treatment: TMP-SMX OR Doxycycline - Culture directed treatment - MSSA: TMP-SMX - MRSA: Dicloxacillin OR Cephalexin - Severe - Empiric treatment: Vancomycin OR Daptomycin OR Linezolid OR Televancin OR Ceftaroline - Culture directed treatment - MSSA: Nafcillin OR Cefazolin OR Clindamycin - MRSA: Vancomycin OR Daptomycin OR Linezolid OR Televancin OR Ceftaroline	https://www.wikidoc.org/index.php/Carbuncle
e33a4ed3f00587131b1b49b0c54142883bb5c70b	wikidoc	Carcinoma	Carcinoma # Overview In medicine, carcinoma is any cancer that arises from epithelial cells. It is malignant by definition: carcinomas invade surrounding tissues and organs, and may spread to lymph nodes and distal sites (metastasis). Carcinoma in situ (CIS) is a pre-malignant condition, in which cytological signs of malignancy are present, but there is no histological evidence of invasion through the epithelial basement membrane. # Classification of carcinoma Carcinoma, like all neoplasia, is classified by its histopathological appearance. Adenocarcinoma and squamous cell carcinoma, two common descriptive terms for tumours, reflect the fact that these cells may have glandular or squamous cell appearances respectively. Severely anaplastic tumours might be so undifferentiated that they do not have a distinct histological appearance (undifferentiated carcinoma). Sometimes a tumour is referred to by the presumptive organ of the primary (eg carcinoma of the prostate) or the putative cell of origin (hepatocellular carcinoma, renal cell carcinoma). # Types of carcinoma by ICD-O Code (8010-8790) Epithelial - (8010-8040) Epithelial neoplasms, NOS - (8050-8080) Squamous cell neoplasms (Template:ICDO) Squamous cell carcinoma, NOS - (Template:ICDO) Squamous cell carcinoma, NOS - (8090-8110) Basal cell neoplasms (Template:ICDO) Basal cell carcinoma, NOS - (Template:ICDO) Basal cell carcinoma, NOS - (8120-8130) Transitional cell papillomas and carcinomas - (8140-8380) Adenomas and Adenocarcinomas (glands) (Template:ICDO) Adenoma, NOS (Template:ICDO) Adenocarcinoma, NOS (Template:ICDO) Linitis plastica (Template:ICDO) Insulinoma, NOS (Template:ICDO) Glucagonoma, NOS (Template:ICDO) Gastrinoma, NOS (Template:ICDO) Vipoma (Template:ICDO) Cholangiocarcinoma (Template:ICDO) Hepatocellular carcinoma, NOS (Template:ICDO) Adenoid cystic carcinoma (Template:ICDO) Carcinoid tumor, NOS, of appendix (Template:ICDO) Prolactinoma (Template:ICDO) Oncocytoma (Template:ICDO) Hurthle cell adenoma (Template:ICDO) Renal cell carcinoma (Template:ICDO) Grawitz tumor (Template:ICDO) Multiple endocrine adenomas (Template:ICDO) Endometrioid adenoma, NOS - (Template:ICDO) Adenoma, NOS - (Template:ICDO) Adenocarcinoma, NOS - (Template:ICDO) Linitis plastica - (Template:ICDO) Insulinoma, NOS - (Template:ICDO) Glucagonoma, NOS - (Template:ICDO) Gastrinoma, NOS - (Template:ICDO) Vipoma - (Template:ICDO) Cholangiocarcinoma - (Template:ICDO) Hepatocellular carcinoma, NOS - (Template:ICDO) Adenoid cystic carcinoma - (Template:ICDO) Carcinoid tumor, NOS, of appendix - (Template:ICDO) Prolactinoma - (Template:ICDO) Oncocytoma - (Template:ICDO) Hurthle cell adenoma - (Template:ICDO) Renal cell carcinoma - (Template:ICDO) Grawitz tumor - (Template:ICDO) Multiple endocrine adenomas - (Template:ICDO) Endometrioid adenoma, NOS - (8390-8420) Adnexal and Skin appendage Neoplasms - (8430-8439) Mucoepidermoid Neoplasms - (8440-8490) Cystic, Mucinous and Serous Neoplasms (Template:ICDO) Cystadenoma, NOS (Template:ICDO) Pseudomyxoma peritonei - (Template:ICDO) Cystadenoma, NOS - (Template:ICDO) Pseudomyxoma peritonei - (8500-8540) Ductal, Lobular and Medullary Neoplasms - (8550-8559) Acinar cell neoplasms - (8560-8580) Complex epithelial neoplasms (Template:ICDO) Warthin's tumor (Template:ICDO) Thymoma, NOS - (Template:ICDO) Warthin's tumor - (Template:ICDO) Thymoma, NOS - (8590-8670) Specialized gonadal neoplasms (Template:ICDO) Sex cord-stromal tumor (Template:ICDO) Thecoma, NOS (Template:ICDO) Granulosa cell tumor, NOS (Template:ICDO) Arrhenoblastoma, NOS (Template:ICDO) Sertoli-Leydig cell tumor - (Template:ICDO) Sex cord-stromal tumor - (Template:ICDO) Thecoma, NOS - (Template:ICDO) Granulosa cell tumor, NOS - (Template:ICDO) Arrhenoblastoma, NOS - (Template:ICDO) Sertoli-Leydig cell tumor - (8680-8710) Paragangliomas and Glomus tumors (Template:ICDO) Paraganglioma, NOS (Template:ICDO) Pheochromocytoma, NOS (Template:ICDO) Glomus tumor - (Template:ICDO) Paraganglioma, NOS - (Template:ICDO) Pheochromocytoma, NOS - (Template:ICDO) Glomus tumor - (8720-8790) Nevi and Melanomas (Template:ICDO) Melanocytic nevus (Template:ICDO) Melanoma, NOS (Template:ICDO) Nodular melanoma (Template:ICDO) Dysplastic nevus (Template:ICDO) Lentigo maligna melanoma (Template:ICDO) Superficial spreading melanoma (Template:ICDO) Acral lentiginous melanoma, malignant - (Template:ICDO) Melanocytic nevus - (Template:ICDO) Melanoma, NOS - (Template:ICDO) Nodular melanoma - (Template:ICDO) Dysplastic nevus - (Template:ICDO) Lentigo maligna melanoma - (Template:ICDO) Superficial spreading melanoma - (Template:ICDO) Acral lentiginous melanoma, malignant # Types of lung carcinoma - Adenocarcinoma is a malignant tumor originating in the epithelial cells of glandular tissue and forming glandular structures. This is common in the lung (forming 30-40% of all lung carcinomas). It is found peripherally, arising from goblet cells or type II pneumocytes. - Squamous cell carcinoma due to squamous metaplasia. This accounts for 20-30% of lung tumors and is usually hilar in origin. - Small cell carcinoma is almost certainly due to smoking. These metastasise early, and may secrete ADH (lowering patient sodium concentration). - Large cell undifferentiated carcinomas account for 10-15% of lung neoplasms. These are aggressive and difficult to recognise due to the undifferentiated nature. These are most commonly central in the lung. - Sinonasal undifferentiated carcinoma # Staging and grading The staging of cancers is the extent of spread of the neoplasm. Grading is the system used to record the tumors degree of differentiation from the parent tissue. High grade shows little differentiation and the prognosis is therefore poor. Carcinomas, like all cancers, are staged according to the extent of disease. The UICC/AJCC TNM system is often used, however for some common tumors, classic staging methods (such as the Dukes classification for colon cancer) are still used. # Related chapters - Cancer - Sarcoma - Hematological malignancy - Basal cell carcinoma	Carcinoma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In medicine, carcinoma is any cancer that arises from epithelial cells. It is malignant by definition: carcinomas invade surrounding tissues and organs, and may spread to lymph nodes and distal sites (metastasis). Carcinoma in situ (CIS) is a pre-malignant condition, in which cytological signs of malignancy are present, but there is no histological evidence of invasion through the epithelial basement membrane. # Classification of carcinoma Carcinoma, like all neoplasia, is classified by its histopathological appearance. Adenocarcinoma and squamous cell carcinoma, two common descriptive terms for tumours, reflect the fact that these cells may have glandular or squamous cell appearances respectively. Severely anaplastic tumours might be so undifferentiated that they do not have a distinct histological appearance (undifferentiated carcinoma). Sometimes a tumour is referred to by the presumptive organ of the primary (eg carcinoma of the prostate) or the putative cell of origin (hepatocellular carcinoma, renal cell carcinoma). # Types of carcinoma by ICD-O Code (8010-8790) Epithelial - (8010-8040) Epithelial neoplasms, NOS - (8050-8080) Squamous cell neoplasms (Template:ICDO) Squamous cell carcinoma, NOS - (Template:ICDO) Squamous cell carcinoma, NOS - (8090-8110) Basal cell neoplasms (Template:ICDO) Basal cell carcinoma, NOS - (Template:ICDO) Basal cell carcinoma, NOS - (8120-8130) Transitional cell papillomas and carcinomas - (8140-8380) Adenomas and Adenocarcinomas (glands) (Template:ICDO) Adenoma, NOS (Template:ICDO) Adenocarcinoma, NOS (Template:ICDO) Linitis plastica (Template:ICDO) Insulinoma, NOS (Template:ICDO) Glucagonoma, NOS (Template:ICDO) Gastrinoma, NOS (Template:ICDO) Vipoma (Template:ICDO) Cholangiocarcinoma (Template:ICDO) Hepatocellular carcinoma, NOS (Template:ICDO) Adenoid cystic carcinoma (Template:ICDO) Carcinoid tumor, NOS, of appendix (Template:ICDO) Prolactinoma (Template:ICDO) Oncocytoma (Template:ICDO) Hurthle cell adenoma (Template:ICDO) Renal cell carcinoma (Template:ICDO) Grawitz tumor (Template:ICDO) Multiple endocrine adenomas (Template:ICDO) Endometrioid adenoma, NOS - (Template:ICDO) Adenoma, NOS - (Template:ICDO) Adenocarcinoma, NOS - (Template:ICDO) Linitis plastica - (Template:ICDO) Insulinoma, NOS - (Template:ICDO) Glucagonoma, NOS - (Template:ICDO) Gastrinoma, NOS - (Template:ICDO) Vipoma - (Template:ICDO) Cholangiocarcinoma - (Template:ICDO) Hepatocellular carcinoma, NOS - (Template:ICDO) Adenoid cystic carcinoma - (Template:ICDO) Carcinoid tumor, NOS, of appendix - (Template:ICDO) Prolactinoma - (Template:ICDO) Oncocytoma - (Template:ICDO) Hurthle cell adenoma - (Template:ICDO) Renal cell carcinoma - (Template:ICDO) Grawitz tumor - (Template:ICDO) Multiple endocrine adenomas - (Template:ICDO) Endometrioid adenoma, NOS - (8390-8420) Adnexal and Skin appendage Neoplasms - (8430-8439) Mucoepidermoid Neoplasms - (8440-8490) Cystic, Mucinous and Serous Neoplasms (Template:ICDO) Cystadenoma, NOS (Template:ICDO) Pseudomyxoma peritonei - (Template:ICDO) Cystadenoma, NOS - (Template:ICDO) Pseudomyxoma peritonei - (8500-8540) Ductal, Lobular and Medullary Neoplasms - (8550-8559) Acinar cell neoplasms - (8560-8580) Complex epithelial neoplasms (Template:ICDO) Warthin's tumor (Template:ICDO) Thymoma, NOS - (Template:ICDO) Warthin's tumor - (Template:ICDO) Thymoma, NOS - (8590-8670) Specialized gonadal neoplasms (Template:ICDO) Sex cord-stromal tumor (Template:ICDO) Thecoma, NOS (Template:ICDO) Granulosa cell tumor, NOS (Template:ICDO) Arrhenoblastoma, NOS (Template:ICDO) Sertoli-Leydig cell tumor - (Template:ICDO) Sex cord-stromal tumor - (Template:ICDO) Thecoma, NOS - (Template:ICDO) Granulosa cell tumor, NOS - (Template:ICDO) Arrhenoblastoma, NOS - (Template:ICDO) Sertoli-Leydig cell tumor - (8680-8710) Paragangliomas and Glomus tumors (Template:ICDO) Paraganglioma, NOS (Template:ICDO) Pheochromocytoma, NOS (Template:ICDO) Glomus tumor - (Template:ICDO) Paraganglioma, NOS - (Template:ICDO) Pheochromocytoma, NOS - (Template:ICDO) Glomus tumor - (8720-8790) Nevi and Melanomas (Template:ICDO) Melanocytic nevus (Template:ICDO) Melanoma, NOS (Template:ICDO) Nodular melanoma (Template:ICDO) Dysplastic nevus (Template:ICDO) Lentigo maligna melanoma (Template:ICDO) Superficial spreading melanoma (Template:ICDO) Acral lentiginous melanoma, malignant - (Template:ICDO) Melanocytic nevus - (Template:ICDO) Melanoma, NOS - (Template:ICDO) Nodular melanoma - (Template:ICDO) Dysplastic nevus - (Template:ICDO) Lentigo maligna melanoma - (Template:ICDO) Superficial spreading melanoma - (Template:ICDO) Acral lentiginous melanoma, malignant # Types of lung carcinoma - Adenocarcinoma is a malignant tumor originating in the epithelial cells of glandular tissue and forming glandular structures. This is common in the lung (forming 30-40% of all lung carcinomas). It is found peripherally, arising from goblet cells or type II pneumocytes. - Squamous cell carcinoma due to squamous metaplasia. This accounts for 20-30% of lung tumors and is usually hilar in origin. - Small cell carcinoma is almost certainly due to smoking. These metastasise early, and may secrete ADH (lowering patient sodium concentration). - Large cell undifferentiated carcinomas account for 10-15% of lung neoplasms. These are aggressive and difficult to recognise due to the undifferentiated nature. These are most commonly central in the lung. - Sinonasal undifferentiated carcinoma # Staging and grading The staging of cancers is the extent of spread of the neoplasm. Grading is the system used to record the tumors degree of differentiation from the parent tissue. High grade shows little differentiation and the prognosis is therefore poor. Carcinomas, like all cancers, are staged according to the extent of disease. The UICC/AJCC TNM system is often used, however for some common tumors, classic staging methods (such as the Dukes classification for colon cancer) are still used. # Related chapters - Cancer - Sarcoma - Hematological malignancy - Basal cell carcinoma	https://www.wikidoc.org/index.php/Carcinoma
c9d7a56dab6fc0751c9c5d2040bbbd15fa95c6c8	wikidoc	Sestamibi	Sestamibi # Overview Sestamibi is a radiopharmaceutical used in nuclear medicine imaging. It is also known as methoxyisobutylisonitrile or MIBI. The radioisotope attached to the sestamibi molecule is technetium-99m, forming 99Tcm-sestamibi (or Tc99m MIBI). # Uses Its main use is for imaging the myocardium (heart muscle). It is also used in the work-up of primary hyperparathyroidism to identify parathyroid adenomas, for radioguided surgery of the parathyroid and in the work-up of possible breast malignancies. ## Cardiac imaging Technetium-99m sestamibi is a lipophilic cation which, when injected intravenously into a patient, distributes in the myocardium proportionally to the myocardial blood flow. As opposed to Thallium-201, MIBI does not undergo significant redistribution. Single photon emission computed tomography (SPECT) imaging of the heart is performed using a gamma camera to detect the gamma rays emitted by the technetium-99m sestamibi as it decays. Two sets of images are acquired. For one set, the Tc99m MIBI is injected whilst the patient is at rest and then the myocardium is imaged. In the second set, the patient is stressed either by exercising on a treadmill or pharmacologically. The Tc99m MIBI is injected at peak stress and then imaging is performed . The resulting two sets of images are compared with each other to distinguish ischaemic from infarcted areas of the myocardium. This imaging technique is also known as myocardial perfusion imaging (MPI). ## Parathyroid imaging In hyperparathyroidism, one or more of the four parathyroid glands have developed a benign tumor called an adenoma. The affected gland takes up Tc99m MIBI following an intravenous injection. The patient's neck is imaged with a gamma camera to show the tumor. ## Breast imaging Tc99m MIBI is also used in the evaluation of breast nodules. Malignant breast tissues concentrate MIBI to a much greater extent and more frequently than benign disease. As such, limited characterization of breast anomalies is possible. Scintimammography has the highest specificity for breast cancer of any imaging test, but its sensitivity is too low to allow for routine use. ## Radioguided surgery of the parathyroids Following the administration of Tc99m MIBI it collects in overactive parathyroid glands. During surgery, the surgeon can use a probe sensitive to gamma rays to locate the overactive parathyroid before removing it.	Sestamibi # Overview Sestamibi is a radiopharmaceutical used in nuclear medicine imaging. It is also known as methoxyisobutylisonitrile or MIBI. The radioisotope attached to the sestamibi molecule is technetium-99m, forming 99Tcm-sestamibi (or Tc99m MIBI). # Uses Its main use is for imaging the myocardium (heart muscle). It is also used in the work-up of primary hyperparathyroidism to identify parathyroid adenomas, for radioguided surgery of the parathyroid and in the work-up of possible breast malignancies. ## Cardiac imaging Technetium-99m sestamibi is a lipophilic cation which, when injected intravenously into a patient, distributes in the myocardium proportionally to the myocardial blood flow. As opposed to Thallium-201, MIBI does not undergo significant redistribution. Single photon emission computed tomography (SPECT) imaging of the heart is performed using a gamma camera to detect the gamma rays emitted by the technetium-99m sestamibi as it decays. Two sets of images are acquired. For one set, the Tc99m MIBI is injected whilst the patient is at rest and then the myocardium is imaged. In the second set, the patient is stressed either by exercising on a treadmill or pharmacologically. The Tc99m MIBI is injected at peak stress and then imaging is performed . The resulting two sets of images are compared with each other to distinguish ischaemic from infarcted areas of the myocardium. This imaging technique is also known as myocardial perfusion imaging (MPI). ## Parathyroid imaging In hyperparathyroidism, one or more of the four parathyroid glands have developed a benign tumor called an adenoma. The affected gland takes up Tc99m MIBI following an intravenous injection. The patient's neck is imaged with a gamma camera to show the tumor. ## Breast imaging Tc99m MIBI is also used in the evaluation of breast nodules. Malignant breast tissues concentrate MIBI to a much greater extent and more frequently than benign disease. As such, limited characterization of breast anomalies is possible. Scintimammography has the highest specificity for breast cancer of any imaging test, but its sensitivity is too low to allow for routine use. ## Radioguided surgery of the parathyroids Following the administration of Tc99m MIBI it collects in overactive parathyroid glands. During surgery, the surgeon can use a probe sensitive to gamma rays to locate the overactive parathyroid before removing it.	https://www.wikidoc.org/index.php/Cardiolite
a6802c3985dedc3202d6ce35bffae4d3a7097629	wikidoc	Doxazosin	Doxazosin # 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 Doxazosin is a alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of benign prostatic hyperplasia (BPH) and hypertension. Common adverse reactions include edema, hypotension, nausea, dizziness, headache, somnolence, vertigo and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Initial dose: - 1 mg once a day - Depending on the patient's urodynamics and BPH symptomatology, dosage may be increased, with a recommended titration interval of 1-2 weeks, to: - 2 mg once a day, followed by 4 mg once a day until the maximum dosage of 8 mg once a day. - Initial dose: - 1 mg once a day - Depending on the patient's standing blood pressure response (based on measurements taken at 2-6 hours post-dose and 24 hours post-dose), dosage may then be increased to: - 2 mg once a day, followed by 4 mg once a day, than 8 mg once a day until the maximum dosage of 16 mg once a day to achieve the desired reduction in blood pressure. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Doxazonin in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 2 mg at bedtime, twice daily - Dosing Information - 4 mg daily - Dosing Information - 2—16 mg daily - Dosing Information - 4 mg daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial: 1 mg/day PO until the maximum dosage of 4 mg/day ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Doxazosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Doxazosin in pediatric patients. # Contraindications - Doxazosin tablets are contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients. # Warnings - Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. - To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2 mg, 4 mg, and 8 mg tablets are not for initial therapy. - Dosage should then be adjusted slowly with evaluations and increases in dose every two weeks to the recommended dose. - Additional antihypertensive agents should be added with caution. - Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night. - If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. - Rarely (probably less frequently than once in every several thousand patients), alpha-1 antagonists including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). - Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition. # Adverse Reactions ## Clinical Trials Experience - The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below are based on combined data from seven placebo-controlled trials involving once daily administration of doxazosin in doses of 1 mg to 16 mg in hypertensives and 0.5 mg to 8 mg in normotensives. The adverse events when the incidence in the doxazosin group was at least 1% are summarized in the table below. - No significant difference in the incidence of adverse events compared to placebo was seen except for dizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related. - In these placebo-controlled studies of 665 doxazosin patients, treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. - Adverse reactions with an incidence of less than 1% but of clinical interest are (doxazosin vs. placebo): - Cardiovascular System: angina pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0%), tachycardia (0.9% vs. 0%) - Urogenital System: dysuria (0.5% vs. 1.3%) - Psychiatric Disorders: libido decreased (0.8% vs. 0.3%). - The safety profile in patients treated for up to three years was similar to that in the placebo-controlled studies. - The majority of adverse experiences with doxazosin were mild. - Doxazosin mesylate has been administered to approximately 4,000 hypertensive patients, of whom 1,679 were included in the hypertension clinical development program. - In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. - In placebo-controlled studies adverse effects occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuation were: - Postural effects (2%) - Edema, about 0.7%. - Malaise/fatigue, about 0.7%. - Heart rate disturbance, about 0.7%. - In controlled hypertension clinical trials directly comparing doxazosin to placebo there was no significant difference in the incidence of side effects, except for: - Dizziness (including postural) - Weight gain - Malaise/fatigue. - Postural effects and edema appeared to be dose related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once daily administration of doxazosin at doses ranging from 1 mg to 16 mg. - The table below summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction is of particular interest. - Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. - The following adverse reactions occurred with a frequency of between 0.5% and 1%: - Syncope - Hypoesthesia - Increased sweating - Agitation - Increased weight. - The following additional adverse reactions were reported by < 0.5% of 3,960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including international studies. - Cardiovascular System: - Angina pectoris - Myocardial infarction - Cerebrovascular accident - Autonomic Nervous System: - Pallor - Metabolic: - Thirst - Gout - Hypokalemia - Hematopoietic: - Lymphadenopathy - Purpura - Reproductive System: - Breast pain - Skin Disorders: - Alopecia - Dry skin - Eczema - Central Nervous System: - Paresis - Tremor - Twitching - Confusion - Migraine - Impaired concentration - Psychiatric - Paroniria - Amnesia - Emotional lability - Abnormal thinking - Depersonalization - Special Senses: - Parosmia - Earache - Taste perversion - Photophobia - Abnormal lacrimation - Gastrointestinal System: - Increased appetite - Anorexia - Fecal incontinence - Gastroenteritis - Respiratory System: - Bronchospasm - Sinusitis - Coughing - Pharyngitis - Urinary System: - Renal calculus - General Body System: - Hot flushes - Back pain - Infection - Fever/rigors - Decreased weight - Influenza-like symptoms. - Doxazosin has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin has been associated with decreases in white blood cell counts. ## Postmarketing Experience - In post-marketing experience the following additional adverse reactions have been reported: - Priapism - Hypoesthesia - Gynecomastia - Vomiting - Allergic reaction - Bradycardia - Leukopenia - Thrombocytopenia - Hepatitis - Hepatitis cholestatic - Bronchospasm aggravated - Urticaria - Intraoperative Floppy Iris Syndrome - Hematuria - Micturition disorder - Nocturia # Drug Interactions - Protein-bound drugs: - Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. - There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding. - Thiazide diuretics, Beta-blockers and NSAIDS: - Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. - Cimetidine: - In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a 4-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown. - In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the following drugs or drug classes: - Analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin) - Antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin) - Antihistamines (e.g., chlorpheniramine) - Cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol) - Corticosteroids - Gastrointestinal agents (e.g., antacids) - Hypoglycemics and endocrine drugs - Sedatives and tranquilizers (e.g., diazepam) - Cold and flu remedies. - Phosphodiesterase-5 (PDE-5): - Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, doxazosin should be used during pregnancy only if clearly needed. Radioactivity was found to cross the placenta following oral administration of labeled doxazosin to pregnant rats. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of doxazosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Doxazosin during labor and delivery. ### Nursing Mothers Studies in lactating rats given a single oral dose of 1 mg/kg of -doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxazosin is administered to a nursing mother. ### Pediatric Use The safety and effectiveness of doxazosin as an antihypertensive agent have not been established in children. ### Geriatic Use The safety and effectiveness profile of doxazosin in BPH was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients. - For hypertension: - Clinical studies of doxazosin 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 Doxazosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Doxazosin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Doxazosin in patients with renal impairment. ### Hepatic Impairment Doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism ### Females of Reproductive Potential and Males Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day. Mutagenicity studies revealed no drug or metabolite-related effects at either chromosomal or subchromosomal levels. Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans. ### Immunocompromised Patients There is no FDA guidance one the use of Doxazosin in patients who are immunocompromised. ### Precautions in certain conditions - Prostate Cancer: - Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin. - Cataract surgery: - Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery. - Orthostatic Hypotension: - While syncope is the most severe orthostatic effect of doxazosin, other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases. - Hypertension: - These symptoms were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and causing discontinuation of therapy in about 2%. - In placebo-controlled titration trials in hypertension, orthostatic effects were minimized by beginning therapy at 1 mg per day and titrating every two weeks to 2, 4, or 8 mg per day. There was an increased frequency of orthostatic effects in patients given 8 mg or more, 10%, compared to 5% at 1 mg to 4 mg and 3% in the placebo group. - Benign Prostatic Hyperplasia: - In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin was 0.3% and did not increase with increasing dosage (to 8 mg/day). - The incidence of discontinuations due to hypotensive or orthostatic symptoms was 3.3% with doxazosin and 1% with placebo. The titration interval in these studies was one to two weeks. - Patients in occupations in which orthostatic hypotension could be dangerous should be treated with particular caution. As alpha-1 antagonists can cause orthostatic effects, it is important to evaluate standing blood pressure two minutes after standing and patients should be advised to exercise care when arising from a supine or sitting position. - If hypotension occurs, the patient should be placed in the supine position and, if this measure is inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Drug Monitoring of doxazosin in the drug label. # IV Compatibility There is limited information regarding the compatibility of Doxazosin and IV administrations. # Overdosage - Experience with doxazosin overdosage is limited. - Two adolescents who each intentionally ingested 40 mg doxazosin with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. - A two-year-old child who accidentally ingested 4 mg doxazosin was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. - A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin and was reported to have been drowsy. - A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg doxazosin (blood level 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. - A 39-year-old female who ingested 70 mg doxazosin, alcohol and flurazepam developed hypotension which responded to fluid therapy. - The oral LD50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated. # Pharmacology ## Mechanism of Action - The mechanism of action of doxazosin mesylate is selective blockade of the alpha-1 (postjunctional) subtype of adrenergic receptors. - Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha-1 agonist) and the systolic pressor effect of norepinephrine. - Doxazosin and prazosin have similar abilities to antagonize phenylephrine. - The antihypertensive effect of doxazosin results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 mcM, in vitro. - Administration of doxazosin results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position. - In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 mg to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1 to 6 hours) were larger by about 50% to 75% (i.e., trough values were about 55% to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of caucasians and blacks or of patients above and below age 65. In these predominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2% to 3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the same patient population, patients receiving doxazosin gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients. ## Structure Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha-1 subtype of alpha adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The molecular formula for doxazosin mesylate is C23H25N5O5 - CH4O3S and the molecular weight is 547.6. It has the following structure: ## Pharmacodynamics - Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. - The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. - The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha-1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. - Blockade of the alpha-1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. - In the human prostate, doxazosin antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1c adrenoceptor. The receptor subtype is thought to be the predominant functional type in the prostate. Doxazosin acts within 1 to 2 weeks to decrease the severity of BPH symptoms and improve urinary flow rate. Since alpha1 adrenoceptors are of low density in the urinary bladder (apart from the bladder neck), doxazosin should maintain bladder contractility. - The efficacy of doxazosin was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin treatment was superior to placebo in improving patient symptoms and urinary flow rate. - Significant relief with doxazosin was seen as early as one week into the treatment regimen, with doxazosin treated patients (N = 173) showing a significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41). In long-term studies improvement was maintained for up to 2 years of treatment. In 66% to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate. - In three placebo-controlled studies of 14 to 16 weeks duration obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin. - The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in Table 1. In all three studies, doxazosin resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin in Studies 1 and 2, compared to 0.1 to 0.7 mL/sec with placebo. - In one fixed dose study, doxazosin therapy (4 mg to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 to 3.3 mL/sec compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin vs. placebo was seen after one week. - The proportion of patients who responded with a maximum flow rate improvement of ≥ 3 mL/sec was significantly larger with doxazosin (34% to 42%) than placebo (13% to 17%). A significantly greater improvement was also seen in average flow rate with doxazosin (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated in figure below. - In BPH patients (N = 450) treated for up to 2 years in open-label studies, doxazosin therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin were maintained over the entire treatment period. - Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect. The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic blood pressure less than 60 mmHg at any time during treatment with doxazosin 1 mg to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%). ## Pharmacokinetics - After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate occur at about 2 to 3 hours. - Bioavailability is approximately 65%, reflecting first pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin was examined in a crossover study with 12 hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin was administered with food. Neither of these differences was statistically or clinically significant. - Doxazosin is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses approximately 98% of the circulating drug is bound to plasma proteins. - Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2 mg to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations. - In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs. 3.5 hr). - The pharmacokinetics of doxazosin in young (< 65 years) and elderly (≥ 65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution. - In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin were similar in the two populations. Linear kinetics and dose proportionality were observed. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of doxazosin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of doxazosin in the drug label. # How Supplied - Doxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate, USP equivalent to 1 mg, 2 mg or 4 mg of doxazosin. - The 1 mg are available as white to off-white, round tablets debossed with M over D9 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-957-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). - The 2 mg are available as pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-958-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). The 4 mg are available as blue, round tablets debossed with M over D11 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-959-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). - PHARMACIST: Dispense a Patient Information Leaflet with each prescription. ## Storage - Store at 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this leaflet: - Before you start taking doxazosin tablets. - Each time you get a new prescription. - You and your doctor should discuss this treatment and your BPH symptoms before you start taking doxazosin tablets and at your regular checkups. This leaflet does NOT take the place of discussions with your doctor. - Doxazosin tablets are used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describes doxazosin tablets as treatment for BPH (although you may be taking doxazosin tablets for both your BPH and high blood pressure). - What is BHP: - BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. This can lead to such symptoms as: - Weak or start-and-stop stream when urinating. - Feeling that the bladder is not completely emptied after urination. - Delay or difficulty in the beginning of urination. - Need to urinate often during the day and especially at night. - Feeling that you must urinate immediately. - Treatment options for: - The four main treatment options for BPH are: - If you are not bothered by your symptoms, you and your doctor may decide on a program of "watchful waiting". It is not an active treatment like taking medication or surgery but involves having regular checkups to see if your condition is getting worse or causing problems. - Treatment with doxazosin tablets or other similar drugs. Doxazosin tablets is the medication your doctor has prescribed for you. See "What Doxazosin Tablets Do", below. - Treatment with the medication class of 5-alpha reductase inhibitors (e.g., finasteride). It can cause the prostate to shrink. It may take 6 months or more for the full benefit of finasteride to be seen. - Various surgical procedures. Your doctor can describe these procedures to you. The best procedure for you depends on your BPH symptoms and medical condition. - What Doxazosin tablets do: - Doxazosin tablets work on a specific type of muscle found in the prostate, causing it to relax. This in turn decreases the pressure within the prostate, thus improving the flow of urine and your symptoms. - Doxazosin tablets help relieve the symptoms of BPH (weak stream, start-and-stop stream, a feeling that your bladder is not completely empty, delay in beginning of urination, need to urinate often during the day and especially at night, and feeling that you must urinate immediately). It does not change the size of the prostate. The prostate may continue to grow; however a larger prostate is not necessarily related to more symptoms or to worse symptoms. Doxazosin tablets can decrease your symptoms and improve urinary flow, without decreasing the size of the prostate. - If doxazosin tablets are helping you, you should notice an affect within 1 to 2 weeks after you start your medication. Doxazosin tablets have been studied in over 900 patients for up to 2 years and the drug has been shown to continue to work during long-term treatment. Even though you take doxazosin tablets and it may help you, doxazosin tablets may not prevent the need for surgery in the future. - Doxazosin tablets do not affect PSA levels. PSA is the abbreviation for Prostate Specific Antigen. Your doctor may have done a blood test called PSA. You may want to ask your doctor more about this if you have had a PSA test done. - Other important facts: - You should see an improvement of your symptoms within 1 to 2 weeks. In addition to your other regular checkups you will need to continue seeing your doctor regularly to check your progress regarding your BPH and to monitor your blood pressure. - Doxazosin Mesylate is not a treatment for prostate cancer. Your doctor has prescribed doxazosin tablets for your BPH and not for prostate cancer; however, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). A higher incidence of prostate cancer has been noted in men of African-American descent. These checks should continue even if you are taking doxazosin tablets. - How to take Doxazosin tablets and what you should know while taking Doxazosin tablets for BPH: - Doxazosin Tablets Can Cause a Sudden Drop in Blood Pressure After the very first dose. You may feel dizzy, faint or "light-headed", especially after you stand up from a lying or sitting position. This is more likely to occur after you've taken the first few doses or if you increase your dose, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then restart treatment. If you feel very dizzy, faint or "light-headed" you should contact your doctor. Your doctor will discuss with you how often you need to visit and how often your blood pressure should be checked. - Your blood pressure should be checked when you start taking doxazosin tablets even if you do not have high blood pressure (hypertension). Your doctor will discuss with you the details of how blood pressure is measured. - Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to be measured in the following way: measure your blood pressure after lying quietly on your back for five minutes. Then, after standing for two minutes measure your blood pressure again. Your doctor will discuss with you what other times during the day your blood pressure should be taken, such as two to six hours after a dose, before bedtime or after waking up in the morning. Note that moderate to high-intensity exercise can, over a period of time, lower your average blood pressure. - You can take doxazosin tablets either in the morning or at bedtime and it will be equally effective. If you take doxazosin tablets at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It is important to get up slowly from a chair or bed at any time until you learn how you react to doxazosin tablets. - You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. - You will start with a 1 mg dose of doxazosin tablets once daily. Then the once daily dose will be increased as your body gets used to the effects of the medication. Follow your doctor's instructions about how to take doxazosin tablets. You must take it every day at the dose prescribed. - Talk with your doctor if you don't take it for a few days for some reason; you may then need to restart the medication at a 1 mg dose. Increase your dose gradually and again be cautious about possible dizziness. Do not share doxazosin tablets with anyone else; it was prescribed only for you. - Other side effects you could have while taking doxazosin tablets, in addition to lowering of the blood pressure, include dizziness, fatigue (tiredness), swelling of the feet and shortness of breath. Most side effects are mild. However, you should discuss any unexpected effects you notice with your doctor. - Warning: Extremely rarely, doxazosin tablets and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. - Tell your surgeon if you take or have taken doxazosin tablets if you plan to have surgery for cataracts (clouding of the eye). During cataract surgery, a condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen if you take or have taken doxazosin tablets. - If you use doxazosin tablets with an oral erectile dysfunction medicine (phosphodiesterase-5 (PDE-5) inhibitor), it can cause a sudden drop in your blood pressure and you can become dizzy or faint. Talk with your healthcare provider before using PDE-5 inhibitors. - Keep doxazosin tablets and all medicines out of the reach of children. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. FOR MORE INFORMATION ABOUT DOXAZOSIN TABLETS AND BPH TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER. # Precautions with Alcohol Alcohol-Doxazosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cardura - Cardura XL # Look-Alike Drug Names - Cardura - Coumadin # Drug Shortage Status # Price	Doxazosin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, 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 Doxazosin is a alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of benign prostatic hyperplasia (BPH) and hypertension. Common adverse reactions include edema, hypotension, nausea, dizziness, headache, somnolence, vertigo and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Initial dose:[1] - 1 mg once a day - Depending on the patient's urodynamics and BPH symptomatology, dosage may be increased, with a recommended titration interval of 1-2 weeks, to: - 2 mg once a day, followed by 4 mg once a day until the maximum dosage of 8 mg once a day. - Initial dose:[1] - 1 mg once a day - Depending on the patient's standing blood pressure response (based on measurements taken at 2-6 hours post-dose and 24 hours post-dose), dosage may then be increased to:[1] - 2 mg once a day, followed by 4 mg once a day, than 8 mg once a day until the maximum dosage of 16 mg once a day to achieve the desired reduction in blood pressure. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Doxazonin in adult patients.[1] ### Non–Guideline-Supported Use - Dosing Information[1] - 2 mg at bedtime, twice daily - Dosing Information[1] - 4 mg daily - Dosing Information[1] - 2—16 mg daily - Dosing Information[1] - 4 mg daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial: 1 mg/day PO until the maximum dosage of 4 mg/day ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Doxazosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Doxazosin in pediatric patients. # Contraindications - Doxazosin tablets are contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients. # Warnings - Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. - To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2 mg, 4 mg, and 8 mg tablets are not for initial therapy. - Dosage should then be adjusted slowly with evaluations and increases in dose every two weeks to the recommended dose. - Additional antihypertensive agents should be added with caution. - Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night. - If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. - Rarely (probably less frequently than once in every several thousand patients), alpha-1 antagonists including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). - Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition. # Adverse Reactions ## Clinical Trials Experience - The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below are based on combined data from seven placebo-controlled trials involving once daily administration of doxazosin in doses of 1 mg to 16 mg in hypertensives and 0.5 mg to 8 mg in normotensives. The adverse events when the incidence in the doxazosin group was at least 1% are summarized in the table below. - No significant difference in the incidence of adverse events compared to placebo was seen except for dizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related. - In these placebo-controlled studies of 665 doxazosin patients, treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. - Adverse reactions with an incidence of less than 1% but of clinical interest are (doxazosin vs. placebo): - Cardiovascular System: angina pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0%), tachycardia (0.9% vs. 0%) - Urogenital System: dysuria (0.5% vs. 1.3%) - Psychiatric Disorders: libido decreased (0.8% vs. 0.3%). - The safety profile in patients treated for up to three years was similar to that in the placebo-controlled studies. - The majority of adverse experiences with doxazosin were mild. - Doxazosin mesylate has been administered to approximately 4,000 hypertensive patients, of whom 1,679 were included in the hypertension clinical development program. - In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. - In placebo-controlled studies adverse effects occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuation were: - Postural effects (2%) - Edema, about 0.7%. - Malaise/fatigue, about 0.7%. - Heart rate disturbance, about 0.7%. - In controlled hypertension clinical trials directly comparing doxazosin to placebo there was no significant difference in the incidence of side effects, except for: - Dizziness (including postural) - Weight gain - Malaise/fatigue. - Postural effects and edema appeared to be dose related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once daily administration of doxazosin at doses ranging from 1 mg to 16 mg. - The table below summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction is of particular interest. - Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. - The following adverse reactions occurred with a frequency of between 0.5% and 1%: - Syncope - Hypoesthesia - Increased sweating - Agitation - Increased weight. - The following additional adverse reactions were reported by < 0.5% of 3,960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including international studies. - Cardiovascular System: - Angina pectoris - Myocardial infarction - Cerebrovascular accident - Autonomic Nervous System: - Pallor - Metabolic: - Thirst - Gout - Hypokalemia - Hematopoietic: - Lymphadenopathy - Purpura - Reproductive System: - Breast pain - Skin Disorders: - Alopecia - Dry skin - Eczema - Central Nervous System: - Paresis - Tremor - Twitching - Confusion - Migraine - Impaired concentration - Psychiatric - Paroniria - Amnesia - Emotional lability - Abnormal thinking - Depersonalization - Special Senses: - Parosmia - Earache - Taste perversion - Photophobia - Abnormal lacrimation - Gastrointestinal System: - Increased appetite - Anorexia - Fecal incontinence - Gastroenteritis - Respiratory System: - Bronchospasm - Sinusitis - Coughing - Pharyngitis - Urinary System: - Renal calculus - General Body System: - Hot flushes - Back pain - Infection - Fever/rigors - Decreased weight - Influenza-like symptoms. - Doxazosin has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin has been associated with decreases in white blood cell counts. ## Postmarketing Experience - In post-marketing experience the following additional adverse reactions have been reported: - Priapism - Hypoesthesia - Gynecomastia - Vomiting - Allergic reaction - Bradycardia - Leukopenia - Thrombocytopenia - Hepatitis - Hepatitis cholestatic - Bronchospasm aggravated - Urticaria - Intraoperative Floppy Iris Syndrome - Hematuria - Micturition disorder - Nocturia # Drug Interactions - Protein-bound drugs: - Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. - There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding. - Thiazide diuretics, Beta-blockers and NSAIDS: - Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. - Cimetidine: - In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a 4-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown. - In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the following drugs or drug classes: - Analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin) - Antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin) - Antihistamines (e.g., chlorpheniramine) - Cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol) - Corticosteroids - Gastrointestinal agents (e.g., antacids) - Hypoglycemics and endocrine drugs - Sedatives and tranquilizers (e.g., diazepam) - Cold and flu remedies. - Phosphodiesterase-5 (PDE-5): - Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, doxazosin should be used during pregnancy only if clearly needed. Radioactivity was found to cross the placenta following oral administration of labeled doxazosin to pregnant rats. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of doxazosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Doxazosin during labor and delivery. ### Nursing Mothers Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxazosin is administered to a nursing mother. ### Pediatric Use The safety and effectiveness of doxazosin as an antihypertensive agent have not been established in children. ### Geriatic Use The safety and effectiveness profile of doxazosin in BPH was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients. - For hypertension: - Clinical studies of doxazosin 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 Doxazosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Doxazosin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Doxazosin in patients with renal impairment. ### Hepatic Impairment Doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism ### Females of Reproductive Potential and Males Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day. Mutagenicity studies revealed no drug or metabolite-related effects at either chromosomal or subchromosomal levels. Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans. ### Immunocompromised Patients There is no FDA guidance one the use of Doxazosin in patients who are immunocompromised. ### Precautions in certain conditions - Prostate Cancer: - Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin. - Cataract surgery: - Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery. - Orthostatic Hypotension: - While syncope is the most severe orthostatic effect of doxazosin, other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases. - Hypertension: - These symptoms were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and causing discontinuation of therapy in about 2%. - In placebo-controlled titration trials in hypertension, orthostatic effects were minimized by beginning therapy at 1 mg per day and titrating every two weeks to 2, 4, or 8 mg per day. There was an increased frequency of orthostatic effects in patients given 8 mg or more, 10%, compared to 5% at 1 mg to 4 mg and 3% in the placebo group. - Benign Prostatic Hyperplasia: - In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin was 0.3% and did not increase with increasing dosage (to 8 mg/day). - The incidence of discontinuations due to hypotensive or orthostatic symptoms was 3.3% with doxazosin and 1% with placebo. The titration interval in these studies was one to two weeks. - Patients in occupations in which orthostatic hypotension could be dangerous should be treated with particular caution. As alpha-1 antagonists can cause orthostatic effects, it is important to evaluate standing blood pressure two minutes after standing and patients should be advised to exercise care when arising from a supine or sitting position. - If hypotension occurs, the patient should be placed in the supine position and, if this measure is inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Drug Monitoring of doxazosin in the drug label. # IV Compatibility There is limited information regarding the compatibility of Doxazosin and IV administrations. # Overdosage - Experience with doxazosin overdosage is limited. - Two adolescents who each intentionally ingested 40 mg doxazosin with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. - A two-year-old child who accidentally ingested 4 mg doxazosin was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. - A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin and was reported to have been drowsy. - A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg doxazosin (blood level 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. - A 39-year-old female who ingested 70 mg doxazosin, alcohol and flurazepam developed hypotension which responded to fluid therapy. - The oral LD50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated. # Pharmacology ## Mechanism of Action - The mechanism of action of doxazosin mesylate is selective blockade of the alpha-1 (postjunctional) subtype of adrenergic receptors. - Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha-1 agonist) and the systolic pressor effect of norepinephrine. - Doxazosin and prazosin have similar abilities to antagonize phenylephrine. - The antihypertensive effect of doxazosin results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 mcM, in vitro. - Administration of doxazosin results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position. - In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 mg to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1 to 6 hours) were larger by about 50% to 75% (i.e., trough values were about 55% to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of caucasians and blacks or of patients above and below age 65. In these predominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2% to 3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the same patient population, patients receiving doxazosin gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients. ## Structure Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha-1 subtype of alpha adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The molecular formula for doxazosin mesylate is C23H25N5O5 • CH4O3S and the molecular weight is 547.6. It has the following structure: ## Pharmacodynamics - Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. - The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. - The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha-1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. - Blockade of the alpha-1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. - In the human prostate, doxazosin antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1c adrenoceptor. The receptor subtype is thought to be the predominant functional type in the prostate. Doxazosin acts within 1 to 2 weeks to decrease the severity of BPH symptoms and improve urinary flow rate. Since alpha1 adrenoceptors are of low density in the urinary bladder (apart from the bladder neck), doxazosin should maintain bladder contractility. - The efficacy of doxazosin was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin treatment was superior to placebo in improving patient symptoms and urinary flow rate. - Significant relief with doxazosin was seen as early as one week into the treatment regimen, with doxazosin treated patients (N = 173) showing a significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41). In long-term studies improvement was maintained for up to 2 years of treatment. In 66% to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate. - In three placebo-controlled studies of 14 to 16 weeks duration obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin. - The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in Table 1. In all three studies, doxazosin resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin in Studies 1 and 2, compared to 0.1 to 0.7 mL/sec with placebo. - In one fixed dose study, doxazosin therapy (4 mg to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 to 3.3 mL/sec compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin vs. placebo was seen after one week. - The proportion of patients who responded with a maximum flow rate improvement of ≥ 3 mL/sec was significantly larger with doxazosin (34% to 42%) than placebo (13% to 17%). A significantly greater improvement was also seen in average flow rate with doxazosin (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated in figure below. - In BPH patients (N = 450) treated for up to 2 years in open-label studies, doxazosin therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin were maintained over the entire treatment period. - Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect. The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic blood pressure less than 60 mmHg at any time during treatment with doxazosin 1 mg to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%). ## Pharmacokinetics - After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate occur at about 2 to 3 hours. - Bioavailability is approximately 65%, reflecting first pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin was examined in a crossover study with 12 hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin was administered with food. Neither of these differences was statistically or clinically significant. - Doxazosin is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses approximately 98% of the circulating drug is bound to plasma proteins. - Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2 mg to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations. - In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs. 3.5 hr). - The pharmacokinetics of doxazosin in young (< 65 years) and elderly (≥ 65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution. - In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin were similar in the two populations. Linear kinetics and dose proportionality were observed. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of doxazosin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of doxazosin in the drug label. # How Supplied - Doxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate, USP equivalent to 1 mg, 2 mg or 4 mg of doxazosin. - The 1 mg are available as white to off-white, round tablets debossed with M over D9 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-957-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). - The 2 mg are available as pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-958-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). The 4 mg are available as blue, round tablets debossed with M over D11 on one side of the tablet and scored on the other side. They are available as follows: - NDC 51079-959-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). - PHARMACIST: Dispense a Patient Information Leaflet with each prescription. ## Storage - Store at 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this leaflet: - Before you start taking doxazosin tablets. - Each time you get a new prescription. - You and your doctor should discuss this treatment and your BPH symptoms before you start taking doxazosin tablets and at your regular checkups. This leaflet does NOT take the place of discussions with your doctor. - Doxazosin tablets are used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describes doxazosin tablets as treatment for BPH (although you may be taking doxazosin tablets for both your BPH and high blood pressure). - What is BHP: - BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. This can lead to such symptoms as: - Weak or start-and-stop stream when urinating. - Feeling that the bladder is not completely emptied after urination. - Delay or difficulty in the beginning of urination. - Need to urinate often during the day and especially at night. - Feeling that you must urinate immediately. - Treatment options for: - The four main treatment options for BPH are: - If you are not bothered by your symptoms, you and your doctor may decide on a program of "watchful waiting". It is not an active treatment like taking medication or surgery but involves having regular checkups to see if your condition is getting worse or causing problems. - Treatment with doxazosin tablets or other similar drugs. Doxazosin tablets is the medication your doctor has prescribed for you. See "What Doxazosin Tablets Do", below. - Treatment with the medication class of 5-alpha reductase inhibitors (e.g., finasteride). It can cause the prostate to shrink. It may take 6 months or more for the full benefit of finasteride to be seen. - Various surgical procedures. Your doctor can describe these procedures to you. The best procedure for you depends on your BPH symptoms and medical condition. - What Doxazosin tablets do: - Doxazosin tablets work on a specific type of muscle found in the prostate, causing it to relax. This in turn decreases the pressure within the prostate, thus improving the flow of urine and your symptoms. - Doxazosin tablets help relieve the symptoms of BPH (weak stream, start-and-stop stream, a feeling that your bladder is not completely empty, delay in beginning of urination, need to urinate often during the day and especially at night, and feeling that you must urinate immediately). It does not change the size of the prostate. The prostate may continue to grow; however a larger prostate is not necessarily related to more symptoms or to worse symptoms. Doxazosin tablets can decrease your symptoms and improve urinary flow, without decreasing the size of the prostate. - If doxazosin tablets are helping you, you should notice an affect within 1 to 2 weeks after you start your medication. Doxazosin tablets have been studied in over 900 patients for up to 2 years and the drug has been shown to continue to work during long-term treatment. Even though you take doxazosin tablets and it may help you, doxazosin tablets may not prevent the need for surgery in the future. - Doxazosin tablets do not affect PSA levels. PSA is the abbreviation for Prostate Specific Antigen. Your doctor may have done a blood test called PSA. You may want to ask your doctor more about this if you have had a PSA test done. - Other important facts: - You should see an improvement of your symptoms within 1 to 2 weeks. In addition to your other regular checkups you will need to continue seeing your doctor regularly to check your progress regarding your BPH and to monitor your blood pressure. - Doxazosin Mesylate is not a treatment for prostate cancer. Your doctor has prescribed doxazosin tablets for your BPH and not for prostate cancer; however, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). A higher incidence of prostate cancer has been noted in men of African-American descent. These checks should continue even if you are taking doxazosin tablets. - How to take Doxazosin tablets and what you should know while taking Doxazosin tablets for BPH: - Doxazosin Tablets Can Cause a Sudden Drop in Blood Pressure After the very first dose. You may feel dizzy, faint or "light-headed", especially after you stand up from a lying or sitting position. This is more likely to occur after you've taken the first few doses or if you increase your dose, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then restart treatment. If you feel very dizzy, faint or "light-headed" you should contact your doctor. Your doctor will discuss with you how often you need to visit and how often your blood pressure should be checked. - Your blood pressure should be checked when you start taking doxazosin tablets even if you do not have high blood pressure (hypertension). Your doctor will discuss with you the details of how blood pressure is measured. - Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to be measured in the following way: measure your blood pressure after lying quietly on your back for five minutes. Then, after standing for two minutes measure your blood pressure again. Your doctor will discuss with you what other times during the day your blood pressure should be taken, such as two to six hours after a dose, before bedtime or after waking up in the morning. Note that moderate to high-intensity exercise can, over a period of time, lower your average blood pressure. - You can take doxazosin tablets either in the morning or at bedtime and it will be equally effective. If you take doxazosin tablets at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It is important to get up slowly from a chair or bed at any time until you learn how you react to doxazosin tablets. - You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. - You will start with a 1 mg dose of doxazosin tablets once daily. Then the once daily dose will be increased as your body gets used to the effects of the medication. Follow your doctor's instructions about how to take doxazosin tablets. You must take it every day at the dose prescribed. - Talk with your doctor if you don't take it for a few days for some reason; you may then need to restart the medication at a 1 mg dose. Increase your dose gradually and again be cautious about possible dizziness. Do not share doxazosin tablets with anyone else; it was prescribed only for you. - Other side effects you could have while taking doxazosin tablets, in addition to lowering of the blood pressure, include dizziness, fatigue (tiredness), swelling of the feet and shortness of breath. Most side effects are mild. However, you should discuss any unexpected effects you notice with your doctor. - Warning: Extremely rarely, doxazosin tablets and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. - Tell your surgeon if you take or have taken doxazosin tablets if you plan to have surgery for cataracts (clouding of the eye). During cataract surgery, a condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen if you take or have taken doxazosin tablets. - If you use doxazosin tablets with an oral erectile dysfunction medicine (phosphodiesterase-5 (PDE-5) inhibitor), it can cause a sudden drop in your blood pressure and you can become dizzy or faint. Talk with your healthcare provider before using PDE-5 inhibitors. - Keep doxazosin tablets and all medicines out of the reach of children. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. FOR MORE INFORMATION ABOUT DOXAZOSIN TABLETS AND BPH TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER. # Precautions with Alcohol Alcohol-Doxazosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cardura - Cardura XL # Look-Alike Drug Names - Cardura - Coumadin # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cardura
4112a01db1bc49e13ae799933bdaa58d672e87a5	wikidoc	Carnitine	Carnitine # Overview Carnitine, also known as L-carnitine or levocarnitine, is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. It helps in the consumption and disposal of fat in the body because it is responsible for the transport of fatty acids from the cytosol into the mitochondria. It is often sold as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin Bt. Natural carnitine is the L-stereoisomer. # Production Carnitine is biosynthesized within the body from the amino acids lysine or methionine primarily in the liver and kidneys. Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. It has been speculated that during growth or pregnancy the requirement of carnitine could exceed its natural production. # Role in fatty acid metabolism Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through beta-oxidation to acetate to obtain usable energy via the citric acid cycle. In some organisms such as fungi, the acetate is used in the glyoxylate cycle for gluconeogenesis and formation of carbohydrates. Fatty acids must be activated before binding to the carnitine molecule to form acyl-carnitine. The free fatty acid in the cytosol is attached with a thioester bond to coenzyme A (CoA). This reaction is catalyzed by the enzyme fatty acyl-CoA synthetase and driven to completion by inorganic pyrophosphatase. The acyl group on CoA can now be transferred to carnitine and the resulting acyl-carnitine transported into the mitochondrial matrix. This occurs via a series of similar steps: - Acyl-CoA is conjugated to carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane - Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase - Acyl-carnitine is converted to acyl-CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol. Dysfunction of this process leads to the genetic disorders primary carnitine deficiency, carnitine palmitoyltransferase I deficiency, carnitine palmitoyltransferase II deficiency and carnitine-acylcarnitine translocase deficiency. Carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl-CoA, an intermediate in fatty acid biosynthesis, in order to prevent futile cycling between beta-oxidation and fatty acid synthesis. # Natural sources The highest concentrations of carnitine are found in red meat and dairy products. Other natural sources of carnitine include nuts and seeds (e.g. pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens, broccoli, brussels sprouts, collard greens, garlic, mustard greens, okra, parsley), fruits (apricots, bananas), cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other 'health' foods (bee pollen, brewer's yeast, carob, and kale). # Other sources Other sources may be found in over the counter vitamins, energy drinks and various other products. Products containing L-carnitine cannot be marketed as "natural health products" in Canada. L-Carnitine products and supplements are not allowed to be imported into Canada(Health Canada). # Effects on diabetes L-Carnitine improved glucose disposal among 15 patients with type II diabetes and 20 healthy volunteers. Glucose storage increased between both groups, but glucose oxidation increased only in the diabetic group. Finally, glucose uptake increased about 8% for both.	Carnitine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Carnitine, also known as L-carnitine or levocarnitine, is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine.[1] It helps in the consumption and disposal of fat in the body because it is responsible for the transport of fatty acids from the cytosol into the mitochondria. It is often sold as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin Bt. Natural carnitine is the L-stereoisomer. # Production Carnitine is biosynthesized within the body from the amino acids lysine or methionine primarily in the liver and kidneys.[2] Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. It has been speculated that during growth or pregnancy the requirement of carnitine could exceed its natural production. # Role in fatty acid metabolism Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through beta-oxidation to acetate to obtain usable energy via the citric acid cycle. In some organisms such as fungi, the acetate is used in the glyoxylate cycle for gluconeogenesis and formation of carbohydrates. Fatty acids must be activated before binding to the carnitine molecule to form acyl-carnitine. The free fatty acid in the cytosol is attached with a thioester bond to coenzyme A (CoA). This reaction is catalyzed by the enzyme fatty acyl-CoA synthetase and driven to completion by inorganic pyrophosphatase. The acyl group on CoA can now be transferred to carnitine and the resulting acyl-carnitine transported into the mitochondrial matrix. This occurs via a series of similar steps: - Acyl-CoA is conjugated to carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane - Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase - Acyl-carnitine is converted to acyl-CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol. Dysfunction of this process leads to the genetic disorders primary carnitine deficiency, carnitine palmitoyltransferase I deficiency, carnitine palmitoyltransferase II deficiency and carnitine-acylcarnitine translocase deficiency.[3] Carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl-CoA, an intermediate in fatty acid biosynthesis, in order to prevent futile cycling between beta-oxidation and fatty acid synthesis. # Natural sources The highest concentrations of carnitine are found in red meat and dairy products. Other natural sources of carnitine include nuts and seeds (e.g. pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens, broccoli, brussels sprouts, collard greens, garlic, mustard greens, okra, parsley), fruits (apricots, bananas), cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other 'health' foods (bee pollen, brewer's yeast, carob, and kale). # Other sources Other sources may be found in over the counter vitamins, energy drinks and various other products. Products containing L-carnitine cannot be marketed as "natural health products" in Canada. L-Carnitine products and supplements are not allowed to be imported into Canada(Health Canada).[4] # Effects on diabetes L-Carnitine improved glucose disposal among 15 patients with type II diabetes and 20 healthy volunteers.[5] Glucose storage increased between both groups, but glucose oxidation increased only in the diabetic group. Finally, glucose uptake increased about 8% for both.	https://www.wikidoc.org/index.php/Carnitine
ca3be316f5bda1fc2fc603fb96bb648cf6a068c3	wikidoc	Carnivora	Carnivora The diverse order Carnivora (Template:IPAEng or sometimes Template:IPA; from Latin carō (stem carn-) "flesh", + vorāre "to devour") includes over 260 species of placental mammals. Its members are formally referred to as carnivorans, while the word "carnivore" (often popularly applied to members of this group) can refer to any meat-eating animal. Carnivorans are the most diverse in size of any mammalian order, ranging from the Least Weasel (Mustela nivalis), at as little as 25 grams and 11 cm (4.3 in), to the Polar Bear (Ursus maritimus) which can weigh up to 1000 kg (2200 lb) and the Brown Bear at up to 1140 kg (2500 lb), to the Southern Elephant Seal (Mirounga leonina) whose adult males weigh up to 5000 kg (11,000 lb) and measure up to 6.9 m (22.5 ft) in length. The first carnivoran was a carnivore, and nearly all carnivorans today primarily eat meat. Some, such as cats, pinnipeds, and weasels, are almost completely carnivorous. Others, such as bears, are more omnivorous, although the Polar Bear is predominantly carnivorous, with 90% of its diet consisting of seals. The Giant Panda is almost exclusively an herbivore but occasionally eats fish, eggs and insects. Carnivorans have teeth and claws adapted for catching and eating other animals. Their eyes point forward. Many carnivorans hunt in packs and are social animals. Carnivorans apparently evolved in North America out of members of the family Miacidae (miacids) c 42 million years ago. They soon split into cat-like and dog-like forms (feliformia and caniformia). # Distinguishing features Carnivorans are primarily terrestrial and usually have strong sharp claws, with never less than four toes to each foot, and well-developed prominent canine teeth and cheek teeth (premolars and molars) that generally have cutting edges. The last premolar of the upper jaw and first molar of the lower are termed the carnassials or sectorial teeth. These are blade-like teeth that occlude (close) with a scissor-like action for shearing and shredding meat. Carnassials are most highly developed in the Felidae and the least developed in the Ursidae. Carnivorans have six incisors and two conical canines in each jaw. The only two exceptions to this are the Sea Otter (Enhydra lutris), which has four incisors in the lower jaw, and the Sloth Bear (Melursus ursinus), which has four incisors in the upper jaw. The number of molars and premolars is variable between carnivoran species, but all teeth are deeply rooted and are diphyodont. Incisors are retained by carnivorans and the third incisor is commonly large and sharp (canine-like). Carnivorans have either four or five digits on each foot, with the first digit on the forepaws, also known as the dew claw, being vestigial in most species and absent in some. The Canoidea superfamily – Canidae (dogs), Mephitidae (skunks and stink badgers) Mustelidae (weasels), Procyonidae (raccoons), Ursidae (bears), Otariidae (eared seals), Odobenidae (Walrus), and Phocidae (earless seals) (the last three families formally classified in the suborder Pinnipedia) and the extinct family Amphicyonidae (bear-dogs) - are characterized by having a non-chambered or partially chambered auditory bullae, non-retractable claws, and well-developed baculum. Most species are rather simply colored, lacking the flashy spotted or rosetted coats of like many species of felids and viverrids have. This is because Canoidea tend to range in the temperate and subarctic biomes, although Mustelidae and Procyonidae have a few tropical species. Most are terrestrial, although a few species, like procyonids, are arboreal. All families except the Canidae and a few species of Mustelidae are plantigrade. Diet is varied and most tend to be omnivorous to some degree and thus the carnassial teeth are less specialized. Canoidea have more premolars and molars in an elongated skull. The Feloidea superfamily – Felidae (cats), Herpestidae (mongooses), Hyaenidae (hyenas), Viverridae (civets), and Eupleridae (Malagasy carnivores), as well as the extinct family Nimravidae (paleofelids) – often have spotted, rosetted or striped coats, and tend to be more brilliantly colored than their Canoidean counterparts. This is due to the fact that these species tend to range in tropical habitats, although a few species do inhabit temperate and subarctic habitats. Many are arboreal or semi-arboreal, and the majority are digitigrade. Diet tends to be more strictly carnivorous, especially in the Felidae family. They have fewer teeth and shorter skulls, with much more specialized carnassials meant for shearing meat. Felidae claws are retractile. The terminal phalange with the claw attached folds back in the fore-foot into a sheath by the outer side of the middle phalange of the digit, and is retained in this position when at rest by a strong elastic ligament. In the hind-foot the terminal joint or phalange is retracted on to the top, and not the side of the middle phalange. Deep flexor muscles straighten the terminal phalanges so that the claws protrude from their sheath, and the soft "velvety" paw becomes suddenly converted into a formidable weapon of offence. The habitual retraction of the claws preserves their points from wear. The Pinnipedia superfamily (walruses, seals, and sea lions) are medium to large (to 6.5 m) aquatic mammals. Pinnipeds are marine Carnivora and therefore need to have a relatively large body to retain heat. They need a low surface area to body mass ratio to minimize heat loss due to conduction because water conducts heat well. The body is usually insulated with a thick layer of fat called blubber and usually covered with hair. The digits are not separate, but connected by a thick web that forms flippers for swimming; thus the forelimbs and hindlimbs are transformed into paddles. This enables them to dive at extreme depths (600 meters for the Weddell Seal) and they can remain underwater for long periods of time, sometimes over an hour or more, but most dives are usually short. The facial region of skull is relatively small, with pinnae very small or lacking and the vibrissae is well developed. The molariform teeth are mostly homodont and the canines are well developed. The tail is very short or absent, the ears are small or absent as well, and the external genitalia are hidden in slits or depressions in the body. ## Skull structure Members of Carnivora have a characteristic skull shape with relatively large brains encased in a heavy skull. The skull has a highly developed zygomatic arch just behind the maxilla (common to all mammals and their cynodont forebears), and they have ossified external auditory bullae. Feloidea have a two-chambered auditory bullae. In addition to allowing extra room for the passage of muscles to work the lower jaw, the zygomatic arch also allows for differentiation of separate muscle groups to be involved in biting and chewing. Masseters attach from the dentary (specifically, the masseteric fossa) to the zygomatic arch and onto the maxilla in front of the arch, providing crushing force. The temporalis attaches from the dentary (specifically, the coronoid process) to the side of the braincase, providing torque about the axis of jaw articulation. In comparing the skulls of carnivores and herbivores, it can be seen that the shearing force of the temporalis is somewhat more important to carnivores, which have more room on the braincase (this is not unrelated to carnivoran intelligence) and commonly develop a sagittal crest (running from posterior to anterior on the skull) providing yet additional room for temporalis attachment. Carnivoran jaws can only move on a vertical axis, in an up-and-down motion, and cannot move from side-to-side. The jaw joint in carnivores tends to lie within the plane of tooth occlusion; an arrangement that further emphasizes shearing (as in a pair of scissors). In herbivores, the crushing force of the masseters is relatively more important than is shearing. The jaw joint is generally well above the plane of tooth occlusion, allowing extra room for masseteric attachment on the dentary and causing the rotation of the lower jaw to be translated into straight-ahead crushing force between the teeth of the upper and lower jaws. ## Physiology Carnivora have a simple stomach designed to digest primarily meat, as compared to the elaborate digestive systems of herbivorous animals which are necessary to break down tough, complex plant fibers. The caecum is either absent or short and simple, and the colon is not sacculated or much wider than the small intestine. Most species of Carnivora are, to some degree, omnivorous, except the Felidae, which are obligate carnivores. Most have highly-developed senses, especially vision and hearing, and often a highly acute sense of smell in many species, such as in the Canoidea. They are excellent runners: some long-distance runners, but more commonly sprinters. Even bears and raccoons, although seemingly slow and clumsy, are capable of remarkable bursts of speed. ## Diet specializations Carnivorans include carnivores, omnivores, and even a few primarily herbivorous species, such as the Giant Panda. Important teeth for carnivorans are the large, slightly recurved canines, used to dispatch prey, and the carnassial complex, used to rend meat from bone and slice it into digestible pieces. Dogs have molar teeth behind the carnassials for crushing bones, but cats have only a greatly reduced, functionless molar behind the carnassial in the upper jaw. Cats will strip bones clean but will not crush them to get the marrow inside. Omnivores, such as bears and raccoons, have developed blunt, molar-like carnassials. Carnassials are a key adaptation for terrestrial vertebrate predation; all other placental orders are primarily herbivores, insectivores, or aquatic. ## Reproductive system Carnivora tend to produce a single litter annually, but some produce multiple litters a year, and larger carnivores like bears have gaps of 2-3 years between litters. The average gestation period lies between 50-115 days, although the ursids and mustelids have delayed implantation, thus extending the gestation period 6-9 months beyond the normal period. Litter sizes are usually small, ranging from 1-13 young, which are born with underdeveloped eyes and ears. In most species, the mother has exclusive or at least primary care of the offspring. Many species of carnivores are solitary, but a few are gregarious. # Phylogeny Carnivorans evolved out of members of the family Miacidae (miacids). The transition from Miacidae to Carnivora was a general trend in the middle and late Eocene with taxa from both North America and Eurasia involved. The divergence of carnivorans from other miacids, as well as the divergence of the two clades within Carnivora, Caniformia and Feliformia, is now inferred to have happened in the middle Eocene (ca. 42 million years ago). Traditionally the Viverravidae (viverravids) had been thought to be the earliest carnivorans with fossil records first appearing in the Paleocene of North America about 60 million years ago, but recently described evidence from cranial morphology now places them outside the order Carnivora. Traditionally, some paleontologists considered the viverravids to be ancestral to the aeluroid carnivorans (felids, hyaenids, herpestids and viverrids), but this is now doubted. The Miacidae is not a monophyletic group, but a paraphyletic array of stem taxa. Traditionally, the Miacidae and the Viverravidae had been classified in a third, extinct paraphyletic superfamily, the Miacoidea, from which the direct ancestors of both Carnivora and Creodonta were thought to have arisen. Today Carnivora is restricted to the crown group, and Carnivora and miacoids are grouped together in the clade Carnivoramorpha, and the miacoids are regarded as basal carnivoramorphs. Based on dental features and braincase sizes, it is now known that Carnivora must have evolved from a form even more primitive than Creodonta and thus these two orders may not even be sister groups. The Carnivora, Creodonta, Pholidota, and a few other extinct orders are informally grouped together in the clade Ferae. Older classification schemes divided the order into two suborders: Fissipedia (which included the families of primarily land Carnivora) and Pinnipedia (which included the true seals, eared seals, and Walrus). However, it is now recognized that the Fissipedia is a paraphyletic group and that the pinnipeds were not the sister group to the fissipeds but rather had arisen from among them. Carnivora are generally divided into the suborders Feliformia (cat-like) and Caniformia (dog-like), the latter of which includes the pinnipeds. The pinnipeds are part of a clade, known as the Arctoidea, which also includes the Ursidae (bears) and the superfamily Musteloidea. The Musteloidea in turn consists of the Mustelidae (mustelids: weasels), Procyonidae (procyonids: raccoons), Mephitidae (skunks) and Ailurus. The oldest caniforms are the Miacis species Miacis cognitus, the Amphicyonidae (Bear-dogs) such as Daphoenus, and Hesperocyon (of the family Canidae, subfamily Hesperocyoninae). Hesperocyonine canids first appeared in North America and the earliest species is currently dated at 39.74 Ma, but they were not represented in Europe until well into the Miocene, and not into Asia and Africa until the Pliocene. Miacis and Amphicyonidae were the first of the caniforms to split from the others and are sometimes considered to be sister groups to Ursidae, but the exact closeness of Amphicyonidae and Ursidae, as well as Arctoidae to Ursidae, is still uncertain. The Canidae (wolves, coyotes, jackals, foxes and dogs) are generally considered to be the sister group to Arctoidea. The Ursidae first occur in North America in the Late Eocene (ca. 38 million years ago) as the very small and graceful Parictis that had a skull only 7 cm long. Like the canids, this family does not appear in Eurasia and Africa until the Miocene. The other caniform families Amphicyonidae, Mustelidae and Procyonidae occur in both the Old World and the New World by the Late Eocene and Early Oligocene. The ancestor of all Feliformia evolved from the Caniformia-Feliformia split but the exact position of the Felidae, especially some extinct Felidae, in relation to the other families is somewhat disputed. Nandinia, the African Palm Civet, seems to be the most primitive of all the feliforms and the very first to split from the others. The Asiatic linsangs of the genus Prionodon (traditionally placed in the Viverridae) might form a family of their own as well, as some recent studies indicate that Prionodon is actually the closest living relative to the cats. The Nimravidae are sometimes seen as the most basal of all feliforms and the first to split from the others, but there is a possibility that Nimravidae might not even be Carnivora. Its position as a Carnivora is currently unstable. Other studies indicate that Barbourofelids forms a separate family, which is closely related to the true felids instead of being related to the Nimravids. Recognizable Nimravid fossils date from the late Eocene (37 mya), from the Chadronian White River Carnivora Formation at Flagstaff Rim, Wyoming. Nimravid diversity appears to have peaked about 28 mya. The hypercarnivorous (strictly meat-eating) nimravid feliforms were extinct in North America after 26 mya and felids did not arrive in North America until the early middle Miocene (16 mya). It has been suggested that canids evolved hypercarnivorous morphologies because feliforms were absent during this period (the "cat-gap," 26-16 mya), however recent data does not support this hypothesis. Hypercarnivore feliforms (felids and nimravids) occupied an area that canids did not and where felids, nimravids, and hypercarnivorous creodonts are found. Hypercarnivorous canids were present before the disappearance of the nimravids, and all went extinct before the appearance of felids. Following the extinction of nimravids, only three taxa originated, two of which were relatively small in body size. Disparity increased during the "cat-gap" even with the extinction of the hypercarnivorous extremes. This was due to the extinction of morphological intermediates, and because carnivorans began to occupy hypocarnivorous (non-meat-specialist) morphospace for the first time in North America. Procyonids did not arrive in North America until the early Miocene, and "modern" ursids (e.g., Ursinae), did not arrive until the late Miocene. Extinct lineages of Ursidae were present in North America from the late Eocene through the Miocene and Amphicyonid (bear-dogs) were present during this period as well but occupied a morphospace generally shared with canids and not in close proximity to ursids. A large question remains as to why there was a progressive decline in hypercarnivorous carnivoramorphans during the late Oligocene/early Miocene. During this period all hypercarnivorous forms disappeared from the fossil record, including hypercarnivorous feliforms, canids, and mustelids. One possible explanation is climate change. Earth was gradually cooling after the late Paleocene, and over a period spanning the Eocene/Oligocene boundary there was a dramatic climatic cooling event occurred. A recent study finally resolves the exact position of Ailurus: the Red Panda is neither a procyonid nor an ursid, but forms a monotypic family with the other musteloids as its closest living relatives. The same study also shows that the mustelids are not a primitive family, as was once thought. Their small body size is a secondary trait — the primitive body form of the arctoids was large, not small. Recent molecular studies also suggest that the endemic Carnivora of Madagascar, including three genera usually classed with the civets and four genera of mongooses classed with the Herpestidae, are all descended from a single ancestor. They form a single sister taxon to the Herpestidae. The hyenas are also closely related to this clade. # Classification - ORDER CARNIVORA Suborder Feliformia ("cat-like") Family †Stenoplesictidae Family †Percrocutidae Family †Nimravidae: false sabre-tooth cats (5–36 Ma) Family Nandiniidae: African Palm Civet; 1 species in 1 genus Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera Suborder Caniformia ("dog-like") Family †Amphicyonidae: bear-dogs (9–37 Ma) Family Canidae: dogs and allies; 37 species in 10 genera Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Suborder Feliformia ("cat-like") Family †Stenoplesictidae Family †Percrocutidae Family †Nimravidae: false sabre-tooth cats (5–36 Ma) Family Nandiniidae: African Palm Civet; 1 species in 1 genus Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family †Stenoplesictidae - Family †Percrocutidae - Family †Nimravidae: false sabre-tooth cats (5–36 Ma) - Family Nandiniidae: African Palm Civet; 1 species in 1 genus - Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera - Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus - Family †Barbourofelidae (6–18 Ma) - Family Felidae: cats; 40 species in 14 genera - Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family Viverridae: civets and allies; 35 species in 15 genera - Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera - Family Eupleridae : Malagasy carnivores; 8 species in 7 genera - Family Herpestidae: mongooses and allies; 33 species in 14 genera - Suborder Caniformia ("dog-like") Family †Amphicyonidae: bear-dogs (9–37 Ma) Family Canidae: dogs and allies; 37 species in 10 genera Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Family †Amphicyonidae: bear-dogs (9–37 Ma) - Family Canidae: dogs and allies; 37 species in 10 genera - Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera - Family †Hemicyonidae: (2-22 Ma) - Family Ursidae: bears; 8 species in 5 genera - Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera - Family Ailuridae: Red Panda; 1 species in 1 genus. - Family Mephitidae: skunks and stink badgers; 10 species in 4 genera - Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera - Family Procyonidae: raccoons and allies; 19 species in 6 genera - Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Family †Enaliarctidae: (23–20 Ma?) - Family Odobenidae: Walrus; 1 species in 1 genus - Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera - Family Phocidae: true seals; 19 species in 9 genera ## Phylogenetic Tree	Carnivora The diverse order Carnivora (Template:IPAEng or sometimes Template:IPA; from Latin carō (stem carn-) "flesh", + vorāre "to devour") includes over 260 species of placental mammals. Its members are formally referred to as carnivorans, while the word "carnivore" (often popularly applied to members of this group) can refer to any meat-eating animal. Carnivorans are the most diverse in size of any mammalian order, ranging from the Least Weasel (Mustela nivalis), at as little as 25 grams and 11 cm (4.3 in), to the Polar Bear (Ursus maritimus) which can weigh up to 1000 kg (2200 lb) and the Brown Bear at up to 1140 kg (2500 lb), to the Southern Elephant Seal (Mirounga leonina) whose adult males weigh up to 5000 kg (11,000 lb) and measure up to 6.9 m (22.5 ft) in length. The first carnivoran was a carnivore, and nearly all carnivorans today primarily eat meat. Some, such as cats, pinnipeds, and weasels, are almost completely carnivorous. Others, such as bears, are more omnivorous, although the Polar Bear is predominantly carnivorous, with 90% of its diet consisting of seals.[1][2] The Giant Panda is almost exclusively an herbivore but occasionally eats fish, eggs and insects. Carnivorans have teeth and claws adapted for catching and eating other animals. Their eyes point forward. Many carnivorans hunt in packs and are social animals. Carnivorans apparently evolved in North America out of members of the family Miacidae (miacids) c 42 million years ago. They soon split into cat-like and dog-like forms (feliformia and caniformia). # Distinguishing features Carnivorans are primarily terrestrial and usually have strong sharp claws, with never less than four toes to each foot, and well-developed prominent canine teeth and cheek teeth (premolars and molars) that generally have cutting edges. The last premolar of the upper jaw and first molar of the lower are termed the carnassials or sectorial teeth. These are blade-like teeth that occlude (close) with a scissor-like action for shearing and shredding meat. Carnassials are most highly developed in the Felidae and the least developed in the Ursidae. Carnivorans have six incisors and two conical canines in each jaw. The only two exceptions to this are the Sea Otter (Enhydra lutris), which has four incisors in the lower jaw, and the Sloth Bear (Melursus ursinus), which has four incisors in the upper jaw. The number of molars and premolars is variable between carnivoran species, but all teeth are deeply rooted and are diphyodont. Incisors are retained by carnivorans and the third incisor is commonly large and sharp (canine-like). Carnivorans have either four or five digits on each foot, with the first digit on the forepaws, also known as the dew claw, being vestigial in most species and absent in some. The Canoidea superfamily – Canidae (dogs), Mephitidae (skunks and stink badgers) Mustelidae (weasels), Procyonidae (raccoons), Ursidae (bears), Otariidae (eared seals), Odobenidae (Walrus), and Phocidae (earless seals) (the last three families formally classified in the suborder Pinnipedia) and the extinct family Amphicyonidae (bear-dogs) - are characterized by having a non-chambered or partially chambered auditory bullae, non-retractable claws, and well-developed baculum. Most species are rather simply colored, lacking the flashy spotted or rosetted coats of like many species of felids and viverrids have. This is because Canoidea tend to range in the temperate and subarctic biomes, although Mustelidae and Procyonidae have a few tropical species. Most are terrestrial, although a few species, like procyonids, are arboreal. All families except the Canidae and a few species of Mustelidae are plantigrade. Diet is varied and most tend to be omnivorous to some degree and thus the carnassial teeth are less specialized. Canoidea have more premolars and molars in an elongated skull. The Feloidea superfamily – Felidae (cats), Herpestidae (mongooses), Hyaenidae (hyenas), Viverridae (civets), and Eupleridae (Malagasy carnivores), as well as the extinct family Nimravidae (paleofelids) – often have spotted, rosetted or striped coats, and tend to be more brilliantly colored than their Canoidean counterparts. This is due to the fact that these species tend to range in tropical habitats, although a few species do inhabit temperate and subarctic habitats. Many are arboreal or semi-arboreal, and the majority are digitigrade. Diet tends to be more strictly carnivorous, especially in the Felidae family. They have fewer teeth and shorter skulls, with much more specialized carnassials meant for shearing meat. Felidae claws are retractile. The terminal phalange with the claw attached folds back in the fore-foot into a sheath by the outer side of the middle phalange of the digit, and is retained in this position when at rest by a strong elastic ligament. In the hind-foot the terminal joint or phalange is retracted on to the top, and not the side of the middle phalange. Deep flexor muscles straighten the terminal phalanges so that the claws protrude from their sheath, and the soft "velvety" paw becomes suddenly converted into a formidable weapon of offence. The habitual retraction of the claws preserves their points from wear. The Pinnipedia superfamily (walruses, seals, and sea lions) are medium to large (to 6.5 m) aquatic mammals. Pinnipeds are marine Carnivora and therefore need to have a relatively large body to retain heat. They need a low surface area to body mass ratio to minimize heat loss due to conduction because water conducts heat well. The body is usually insulated with a thick layer of fat called blubber and usually covered with hair. The digits are not separate, but connected by a thick web that forms flippers for swimming; thus the forelimbs and hindlimbs are transformed into paddles. This enables them to dive at extreme depths (600 meters for the Weddell Seal) and they can remain underwater for long periods of time, sometimes over an hour or more, but most dives are usually short. The facial region of skull is relatively small, with pinnae very small or lacking and the vibrissae is well developed. The molariform teeth are mostly homodont and the canines are well developed. The tail is very short or absent, the ears are small or absent as well, and the external genitalia are hidden in slits or depressions in the body. ## Skull structure Members of Carnivora have a characteristic skull shape with relatively large brains encased in a heavy skull. The skull has a highly developed zygomatic arch just behind the maxilla (common to all mammals and their cynodont forebears), and they have ossified external auditory bullae. Feloidea have a two-chambered auditory bullae. In addition to allowing extra room for the passage of muscles to work the lower jaw, the zygomatic arch also allows for differentiation of separate muscle groups to be involved in biting and chewing. Masseters attach from the dentary (specifically, the masseteric fossa) to the zygomatic arch and onto the maxilla in front of the arch, providing crushing force. The temporalis attaches from the dentary (specifically, the coronoid process) to the side of the braincase, providing torque about the axis of jaw articulation. In comparing the skulls of carnivores and herbivores, it can be seen that the shearing force of the temporalis is somewhat more important to carnivores, which have more room on the braincase (this is not unrelated to carnivoran intelligence) and commonly develop a sagittal crest (running from posterior to anterior on the skull) providing yet additional room for temporalis attachment. Carnivoran jaws can only move on a vertical axis, in an up-and-down motion, and cannot move from side-to-side. The jaw joint in carnivores tends to lie within the plane of tooth occlusion; an arrangement that further emphasizes shearing (as in a pair of scissors). In herbivores, the crushing force of the masseters is relatively more important than is shearing. The jaw joint is generally well above the plane of tooth occlusion, allowing extra room for masseteric attachment on the dentary and causing the rotation of the lower jaw to be translated into straight-ahead crushing force between the teeth of the upper and lower jaws. ## Physiology Carnivora have a simple stomach designed to digest primarily meat, as compared to the elaborate digestive systems of herbivorous animals which are necessary to break down tough, complex plant fibers. The caecum is either absent or short and simple, and the colon is not sacculated or much wider than the small intestine. Most species of Carnivora are, to some degree, omnivorous, except the Felidae, which are obligate carnivores. Most have highly-developed senses, especially vision and hearing, and often a highly acute sense of smell in many species, such as in the Canoidea. They are excellent runners: some long-distance runners, but more commonly sprinters. Even bears and raccoons, although seemingly slow and clumsy, are capable of remarkable bursts of speed. ## Diet specializations Carnivorans include carnivores, omnivores, and even a few primarily herbivorous species, such as the Giant Panda. Important teeth for carnivorans are the large, slightly recurved canines, used to dispatch prey, and the carnassial complex, used to rend meat from bone and slice it into digestible pieces. Dogs have molar teeth behind the carnassials for crushing bones, but cats have only a greatly reduced, functionless molar behind the carnassial in the upper jaw. Cats will strip bones clean but will not crush them to get the marrow inside. Omnivores, such as bears and raccoons, have developed blunt, molar-like carnassials. Carnassials are a key adaptation for terrestrial vertebrate predation; all other placental orders are primarily herbivores, insectivores, or aquatic. ## Reproductive system Carnivora tend to produce a single litter annually, but some produce multiple litters a year, and larger carnivores like bears have gaps of 2-3 years between litters. The average gestation period lies between 50-115 days, although the ursids and mustelids have delayed implantation, thus extending the gestation period 6-9 months beyond the normal period. Litter sizes are usually small, ranging from 1-13 young, which are born with underdeveloped eyes and ears. In most species, the mother has exclusive or at least primary care of the offspring. Many species of carnivores are solitary, but a few are gregarious. # Phylogeny Carnivorans evolved out of members of the family Miacidae (miacids). The transition from Miacidae to Carnivora was a general trend in the middle and late Eocene with taxa from both North America and Eurasia involved. The divergence of carnivorans from other miacids, as well as the divergence of the two clades within Carnivora, Caniformia and Feliformia, is now inferred to have happened in the middle Eocene (ca. 42 million years ago). Traditionally the Viverravidae (viverravids) had been thought to be the earliest carnivorans with fossil records first appearing in the Paleocene of North America about 60 million years ago, but recently described evidence from cranial morphology now places them outside the order Carnivora.[3] Traditionally, some paleontologists considered the viverravids to be ancestral to the aeluroid carnivorans (felids, hyaenids, herpestids and viverrids), but this is now doubted. The Miacidae is not a monophyletic group, but a paraphyletic array of stem taxa. Traditionally, the Miacidae and the Viverravidae had been classified in a third, extinct paraphyletic superfamily, the Miacoidea, from which the direct ancestors of both Carnivora and Creodonta were thought to have arisen. Today Carnivora is restricted to the crown group, and Carnivora and miacoids are grouped together in the clade Carnivoramorpha, and the miacoids are regarded as basal carnivoramorphs. Based on dental features and braincase sizes, it is now known that Carnivora must have evolved from a form even more primitive than Creodonta and thus these two orders may not even be sister groups.[4] The Carnivora, Creodonta, Pholidota, and a few other extinct orders are informally grouped together in the clade Ferae. Older classification schemes divided the order into two suborders: Fissipedia (which included the families of primarily land Carnivora) and Pinnipedia (which included the true seals, eared seals, and Walrus). However, it is now recognized that the Fissipedia is a paraphyletic group and that the pinnipeds were not the sister group to the fissipeds but rather had arisen from among them. Carnivora are generally divided into the suborders Feliformia (cat-like) and Caniformia (dog-like), the latter of which includes the pinnipeds. The pinnipeds are part of a clade, known as the Arctoidea, which also includes the Ursidae (bears) and the superfamily Musteloidea. The Musteloidea in turn consists of the Mustelidae (mustelids: weasels), Procyonidae (procyonids: raccoons), Mephitidae (skunks) and Ailurus. The oldest caniforms are the Miacis species Miacis cognitus, the Amphicyonidae (Bear-dogs) such as Daphoenus, and Hesperocyon (of the family Canidae, subfamily Hesperocyoninae). Hesperocyonine canids first appeared in North America and the earliest species is currently dated at 39.74 Ma, but they were not represented in Europe until well into the Miocene, and not into Asia and Africa until the Pliocene. Miacis and Amphicyonidae were the first of the caniforms to split from the others and are sometimes considered to be sister groups to Ursidae, but the exact closeness of Amphicyonidae and Ursidae, as well as Arctoidae to Ursidae, is still uncertain. The Canidae (wolves, coyotes, jackals, foxes and dogs) are generally considered to be the sister group to Arctoidea.[4][5][6] The Ursidae first occur in North America in the Late Eocene (ca. 38 million years ago) as the very small and graceful Parictis that had a skull only 7 cm long. Like the canids, this family does not appear in Eurasia and Africa until the Miocene. The other caniform families Amphicyonidae, Mustelidae and Procyonidae occur in both the Old World and the New World by the Late Eocene and Early Oligocene.[4] The ancestor of all Feliformia evolved from the Caniformia-Feliformia split but the exact position of the Felidae, especially some extinct Felidae, in relation to the other families is somewhat disputed. Nandinia, the African Palm Civet, seems to be the most primitive of all the feliforms and the very first to split from the others. The Asiatic linsangs of the genus Prionodon (traditionally placed in the Viverridae) might form a family of their own as well, as some recent studies indicate that Prionodon is actually the closest living relative to the cats. The Nimravidae are sometimes seen as the most basal of all feliforms and the first to split from the others, but there is a possibility that Nimravidae might not even be Carnivora.[6] Its position as a Carnivora is currently unstable. Other studies indicate that Barbourofelids forms a separate family, which is closely related to the true felids instead of being related to the Nimravids. Recognizable Nimravid fossils date from the late Eocene (37 mya), from the Chadronian White River Carnivora Formation at Flagstaff Rim, Wyoming. Nimravid diversity appears to have peaked about 28 mya. The hypercarnivorous (strictly meat-eating) nimravid feliforms were extinct in North America after 26 mya and felids did not arrive in North America until the early middle Miocene (16 mya). It has been suggested that canids evolved hypercarnivorous morphologies because feliforms were absent during this period (the "cat-gap," 26-16 mya), however recent data does not support this hypothesis. Hypercarnivore feliforms (felids and nimravids) occupied an area that canids did not and where felids, nimravids, and hypercarnivorous creodonts are found. Hypercarnivorous canids were present before the disappearance of the nimravids, and all went extinct before the appearance of felids. Following the extinction of nimravids, only three taxa originated, two of which were relatively small in body size. Disparity increased during the "cat-gap" even with the extinction of the hypercarnivorous extremes. This was due to the extinction of morphological intermediates, and because carnivorans began to occupy hypocarnivorous (non-meat-specialist) morphospace for the first time in North America. Procyonids did not arrive in North America until the early Miocene, and "modern" ursids (e.g., Ursinae), did not arrive until the late Miocene. Extinct lineages of Ursidae were present in North America from the late Eocene through the Miocene and Amphicyonid (bear-dogs) were present during this period as well but occupied a morphospace generally shared with canids and not in close proximity to ursids. A large question remains as to why there was a progressive decline in hypercarnivorous carnivoramorphans during the late Oligocene/early Miocene. During this period all hypercarnivorous forms disappeared from the fossil record, including hypercarnivorous feliforms, canids, and mustelids. One possible explanation is climate change. Earth was gradually cooling after the late Paleocene, and over a period spanning the Eocene/Oligocene boundary there was a dramatic climatic cooling event occurred.[7] A recent study finally resolves the exact position of Ailurus: the Red Panda is neither a procyonid nor an ursid, but forms a monotypic family with the other musteloids as its closest living relatives. The same study also shows that the mustelids are not a primitive family, as was once thought. Their small body size is a secondary trait — the primitive body form of the arctoids was large, not small.[5] Recent molecular studies also suggest that the endemic Carnivora of Madagascar, including three genera usually classed with the civets and four genera of mongooses classed with the Herpestidae, are all descended from a single ancestor. They form a single sister taxon to the Herpestidae. The hyenas are also closely related to this clade. # Classification - ORDER CARNIVORA Suborder Feliformia ("cat-like") Family †Stenoplesictidae Family †Percrocutidae Family †Nimravidae: false sabre-tooth cats (5–36 Ma) Family Nandiniidae: African Palm Civet; 1 species in 1 genus Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera Suborder Caniformia ("dog-like") Family †Amphicyonidae: bear-dogs (9–37 Ma) Family Canidae: dogs and allies; 37 species in 10 genera Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Suborder Feliformia ("cat-like") Family †Stenoplesictidae Family †Percrocutidae Family †Nimravidae: false sabre-tooth cats (5–36 Ma) Family Nandiniidae: African Palm Civet; 1 species in 1 genus Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family †Stenoplesictidae - Family †Percrocutidae - Family †Nimravidae: false sabre-tooth cats (5–36 Ma) - Family Nandiniidae: African Palm Civet; 1 species in 1 genus - Superfamily Feloidea Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus Family †Barbourofelidae (6–18 Ma) Family Felidae: cats; 40 species in 14 genera - Family Prinonodontidae: Asiatic linsangs; 2 species in 1 genus - Family †Barbourofelidae (6–18 Ma) - Family Felidae: cats; 40 species in 14 genera - Infraorder Viverroidea Family Viverridae: civets and allies; 35 species in 15 genera Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family Viverridae: civets and allies; 35 species in 15 genera - Superfamily Herpestoidea Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera Family Eupleridae : Malagasy carnivores; 8 species in 7 genera Family Herpestidae: mongooses and allies; 33 species in 14 genera - Family Hyaenidae: hyenas and Aardwolf; 4 species in 4 genera - Family Eupleridae : Malagasy carnivores; 8 species in 7 genera - Family Herpestidae: mongooses and allies; 33 species in 14 genera - Suborder Caniformia ("dog-like") Family †Amphicyonidae: bear-dogs (9–37 Ma) Family Canidae: dogs and allies; 37 species in 10 genera Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Family †Amphicyonidae: bear-dogs (9–37 Ma) - Family Canidae: dogs and allies; 37 species in 10 genera - Infraorder Arctoidea Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Superfamily Ursoidea Family †Hemicyonidae: (2-22 Ma) Family Ursidae: bears; 8 species in 5 genera - Family †Hemicyonidae: (2-22 Ma) - Family Ursidae: bears; 8 species in 5 genera - Superfamily Musteloidea Family Ailuridae: Red Panda; 1 species in 1 genus. Family Mephitidae: skunks and stink badgers; 10 species in 4 genera Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera Family Procyonidae: raccoons and allies; 19 species in 6 genera - Family Ailuridae: Red Panda; 1 species in 1 genus. - Family Mephitidae: skunks and stink badgers; 10 species in 4 genera - Family Mustelidae: weasels, martens, badgers, wolverines, minks, and otters; 55 species in 24 genera - Family Procyonidae: raccoons and allies; 19 species in 6 genera - Superfamily Pinnipedia Family †Enaliarctidae: (23–20 Ma?) Family Odobenidae: Walrus; 1 species in 1 genus Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera Family Phocidae: true seals; 19 species in 9 genera - Family †Enaliarctidae: (23–20 Ma?) - Family Odobenidae: Walrus; 1 species in 1 genus - Family Otariidae: sea lions, eared seals, fur seals; 14 species in 7 genera - Family Phocidae: true seals; 19 species in 9 genera ## Phylogenetic Tree Template:Clade	https://www.wikidoc.org/index.php/Carnivora
3141447e07d98047bc5caa89aeaab598686b4d61	wikidoc	Carnivore	Carnivore A carnivore (Template:IPAEng), meaning 'meat eater' (Latin carne meaning 'flesh' and vorare meaning 'to devour'), is an animal with a diet consisting mainly of meat, whether it comes from animals living (predation) or dead (scavenging). In a more general sense, animals are loosely considered carnivores if their feeding behaviour consists of preying on other animals rather than grazing on plants. There are many predatory invertebrates, for example arthropods such as spiders or mantises and various species of predatory land snails and sea snails. Animals that subsist on a diet consisting only of meat are referred to as obligate carnivores. Plants that capture and digest insects are called carnivorous plants. Similarly fungi that capture microscopic animals are often called carnivorous fungi. The designation "hypercarnivore" is used to describe animals that exclusively feed on animal tissue. Additionally, it is used in paleobiology to describe taxa of animals which have an increased slicing component of their dentition relative to the grinding component. # Classification Carnivores that eat insects and similar invertebrates primarily or exclusively are called insectivores, while those that eat fish primarily or exclusively are called piscivores. Carnivory that entails the consumption of members of an organism's own species is referred to as cannibalism. This includes sexual cannibalism and cannibalistic infanticide. The word "carnivore" sometimes refers to the mammalian Order Carnivora, but this is misleading. Although many Carnivora fit the first definition of being exclusively meat eaters, not all do. For example, bears are members of Carnivora that are not carnivores in the dietary sense, and pandas are almost exclusively herbivorous. Likewise, some full-time (dolphins, shrews) and part-time (humans, pigs) predatory species among mammals, let alone all carnivorous non-mammals, are not members of Carnivora. Outside of the animal kingdom, there are several genera containing carnivorous plants and several phyla containing carnivorous fungi. The former are predominantly insectivores, while the latter prey mostly on microscopic invertebrates such as nematodes, amoeba and springtails. Prehistoric mammals of the crown-clade Carnivoramorpha (Carnivora and Miacoidea without Creodonta), along with the early Order Creodonta, and some mammals of the even early Order Cimolesta, were true carnivores. The earliest carnivorous mammal is considered to be the Cimolestes that existed during the Late Cretaceous and Tertiary Periods in North America about 65 million years ago. Most species of Cimolestes were mouse to rat-sized, but the Late Cretaceous Cimolestes magnus reached the size of a marmot, making it one of the largest Mesozoic mammals known (20-60g). The cheek teeth combined the functions of piercing, shearing and grinding, and the molars of Palaeoryctes had extremely high and acute cusps that had little function other than piercing. The dentition of Cimolestes foreshadows the same cutting structures seen in all later carnivores. While the earlier smaller species were insectivores, the later marmot-sized Cimolestes magnus probably took larger prey and were definitely a carnivore to some degree. The cheek teeth of Hyracolestes ermineus (an ermine-like shrew - 40g) and Sarcodon pygmaeus ("pygmy flesh tooth" - 75g), were common in the Latest Paleocene of Mongolia and China and occupied the small predator niche. The cheek teeth show the same characteristic notches that serve in today's carnivores to hold flesh in place to shear apart with cutting ridges. The theropod dinosaurs such as Tyrannosaurus rex that existed during the late Cretaceous, although not mammals, were "obligate carnivores". ## Obligate carnivores An obligate or true carnivore is an animal that must eat meat in order to thrive. Hypercarnivores present specialized dentition for a meat-only diet. They may consume other products presented to them, especially animal products like eggs and bone marrow or sweet sugary substances like honey and syrup, but, as these items are not essential, they do not consume these on a regular basis. True carnivores lack the physiology required for the efficient digestion of vegetable matter, and, in fact, some carnivorous mammals eat vegetation specifically as an emetic. The domestic cat is a prime example of an obligate carnivore, as are all of the other felids. # Characteristics of carnivores Characteristics commonly 'associated' with carnivores include organs for capturing and disarticulating prey (teeth and claws serve these functions in many vertebrates) and status as a predator. In truth, these assumptions may be misleading, as some carnivores do not hunt and are scavengers (though most hunting carnivores will scavenge when the opportunity exists). Thus they do not have the characteristics associated with hunting carnivores. Carnivores have comparatively short digestive systems as they are not required to break down tough cellulose found in plants. # Plant material In most cases, some plant material is essential for adequate nutrition, particularly with regard to minerals, vitamins and fiber. Most wild carnivores consume this in the digestive system of their prey. Many carnivores also eat herbivore dung, presumably to obtain essential nutrients that they could not otherwise obtain, since their dentition and digestive system do not permit efficient processing of vegetable matter. # List of carnivores - Felines, ranging from domestic cats to lions, tigers, cheetahs and leopards. - Some Canines, such the Gray Wolf and coyote. Domestic dogs and red foxes are broadly considered carnivorous but are able to digest some vegetable matter making them somewhat omnivorous. The Smithsonian Institution has listed them as carnivores, because of their dental makeup and digestive tract.. - Hyenas - Some mustelids, including ferrets - Polar Bears - Pinnipeds (seals, sea lions, walruses, etc.) - Dolphins - Whales - Microbats - Carnivorous Marsupials, such as the Tasmanian Devil - Birds of prey, including hawks, eagles, falcons and owls - Scavenger birds, for example vultures - Several species of waterfowl including gulls, penguins, pelicans, storks, and herons - Anurans (frogs and toads) - Snakes - Some lizards, such as the Gila Monster and all monitor lizards. - Crocodilians - the Komodo dragon also known as the Komodo Monitor, Komodo Island Monitor - Some turtles, including the snapping turtle and most sea turtles - Sharks - Many bony fish, including tuna, marlin, salmon, and bass - Octopuses and squid - Cone shells - Spiders, scorpions, and many other arachnids - Mantises, Giant water bugs, and many other insects - Cnidarians - Sea stars	Carnivore A carnivore (Template:IPAEng), meaning 'meat eater' (Latin carne meaning 'flesh' and vorare meaning 'to devour'), is an animal with a diet consisting mainly of meat, whether it comes from animals living (predation) or dead (scavenging). In a more general sense, animals are loosely considered carnivores if their feeding behaviour consists of preying on other animals rather than grazing on plants. There are many predatory invertebrates, for example arthropods such as spiders or mantises and various species of predatory land snails and sea snails. Animals that subsist on a diet consisting only of meat are referred to as obligate carnivores. Plants that capture and digest insects are called carnivorous plants. Similarly fungi that capture microscopic animals are often called carnivorous fungi. The designation "hypercarnivore" is used to describe animals that exclusively feed on animal tissue. Additionally, it is used in paleobiology to describe taxa of animals which have an increased slicing component of their dentition relative to the grinding component.[1] # Classification Carnivores that eat insects and similar invertebrates primarily or exclusively are called insectivores, while those that eat fish primarily or exclusively are called piscivores. Carnivory that entails the consumption of members of an organism's own species is referred to as cannibalism. This includes sexual cannibalism and cannibalistic infanticide. The word "carnivore" sometimes refers to the mammalian Order Carnivora, but this is misleading. Although many Carnivora fit the first definition of being exclusively meat eaters, not all do. For example, bears are members of Carnivora that are not carnivores in the dietary sense, and pandas are almost exclusively herbivorous. Likewise, some full-time (dolphins, shrews) and part-time (humans, pigs) predatory species among mammals, let alone all carnivorous non-mammals, are not members of Carnivora. Outside of the animal kingdom, there are several genera containing carnivorous plants and several phyla containing carnivorous fungi. The former are predominantly insectivores, while the latter prey mostly on microscopic invertebrates such as nematodes, amoeba and springtails. Prehistoric mammals of the crown-clade Carnivoramorpha (Carnivora and Miacoidea without Creodonta), along with the early Order Creodonta, and some mammals of the even early Order Cimolesta, were true carnivores. The earliest carnivorous mammal is considered to be the Cimolestes that existed during the Late Cretaceous and Tertiary Periods in North America about 65 million years ago. Most species of Cimolestes were mouse to rat-sized, but the Late Cretaceous Cimolestes magnus reached the size of a marmot, making it one of the largest Mesozoic mammals known (20-60g). The cheek teeth combined the functions of piercing, shearing and grinding, and the molars of Palaeoryctes had extremely high and acute cusps that had little function other than piercing. The dentition of Cimolestes foreshadows the same cutting structures seen in all later carnivores. While the earlier smaller species were insectivores, the later marmot-sized Cimolestes magnus probably took larger prey and were definitely a carnivore to some degree. The cheek teeth of Hyracolestes ermineus (an ermine-like shrew - 40g) and Sarcodon pygmaeus ("pygmy flesh tooth" - 75g), were common in the Latest Paleocene of Mongolia and China and occupied the small predator niche. The cheek teeth show the same characteristic notches that serve in today's carnivores to hold flesh in place to shear apart with cutting ridges. The theropod dinosaurs such as Tyrannosaurus rex that existed during the late Cretaceous, although not mammals, were "obligate carnivores". ## Obligate carnivores An obligate or true carnivore is an animal that must eat meat in order to thrive.[2] Hypercarnivores present specialized dentition for a meat-only diet. They may consume other products presented to them, especially animal products like eggs and bone marrow or sweet sugary substances like honey and syrup, but, as these items are not essential, they do not consume these on a regular basis. True carnivores lack the physiology required for the efficient digestion of vegetable matter, and, in fact, some carnivorous mammals eat vegetation specifically as an emetic. The domestic cat is a prime example of an obligate carnivore, as are all of the other felids.[3] # Characteristics of carnivores Characteristics commonly 'associated' with carnivores include organs for capturing and disarticulating prey (teeth and claws serve these functions in many vertebrates) and status as a predator. In truth, these assumptions may be misleading, as some carnivores do not hunt and are scavengers (though most hunting carnivores will scavenge when the opportunity exists). Thus they do not have the characteristics associated with hunting carnivores. Carnivores have comparatively short digestive systems as they are not required to break down tough cellulose found in plants. # Plant material In most cases, some plant material is essential for adequate nutrition, particularly with regard to minerals, vitamins and fiber. Most wild carnivores consume this in the digestive system of their prey. Many carnivores also eat herbivore dung, presumably to obtain essential nutrients that they could not otherwise obtain, since their dentition and digestive system do not permit efficient processing of vegetable matter. # List of carnivores - Felines, ranging from domestic cats to lions, tigers, cheetahs and leopards. - Some Canines, such the Gray Wolf and coyote. Domestic dogs and red foxes are broadly considered carnivorous but are able to digest some vegetable matter making them somewhat omnivorous. The Smithsonian Institution has listed them as carnivores, because of their dental makeup and digestive tract.[citation needed]. - Hyenas - Some mustelids, including ferrets - Polar Bears - Pinnipeds (seals, sea lions, walruses, etc.) - Dolphins - Whales - Microbats - Carnivorous Marsupials, such as the Tasmanian Devil - Birds of prey, including hawks, eagles, falcons and owls - Scavenger birds, for example vultures - Several species of waterfowl including gulls, penguins, pelicans, storks, and herons - Anurans (frogs and toads) - Snakes - Some lizards, such as the Gila Monster and all monitor lizards. - Crocodilians - the Komodo dragon also known as the Komodo Monitor, Komodo Island Monitor - Some turtles, including the snapping turtle and most sea turtles - Sharks - Many bony fish, including tuna, marlin, salmon, and bass - Octopuses and squid - Cone shells - Spiders, scorpions, and many other arachnids - Mantises, Giant water bugs, and many other insects - Cnidarians - Sea stars	https://www.wikidoc.org/index.php/Carnivore
0b1d263e92525430f1e0bcd98d4a883b1a079d99	wikidoc	Carnosine	Carnosine Carnosine (beta-alanyl-L-histidine) is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues. A small 2002 study reported that carnosine improved on a measure of socialization and receptive vocabulary in children with autism. Improvement in this study could have been due to maturation, educational interventions, placebo effect, or other confounds that were not addressed in the study design. Supplemental carnosine may increase corticosterone levels, which can explain the hyperactivity sometimes seen in high doses. Researchers in Australia, Britain, and Russia have also shown that carnosine has a number of antioxidant properties that may be beneficial. Carnosine has been proven to scavenge ROS (radical oxygen species) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. It can oppose glycation and it can chelate divalent metal ions. While a small number of studies have produced evidence of beneficial effects of N-acetyl carnosine in treating cataracts of the eyes, these and other ophthamological benefits have not been proven. Britain's Royal College of Ophthamologists assert that neither safety nor efficacy have been sufficiently demonstrated to recommend its use as a topical treatment for cataracts. Typical vegetarian diets are thought to be lacking in carnosine, but whether this has a detrimental effect on vegetarians is controversial.	Carnosine Carnosine (beta-alanyl-L-histidine) is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues. A small 2002 study reported that carnosine improved on a measure of socialization and receptive vocabulary in children with autism.[1] Improvement in this study could have been due to maturation, educational interventions, placebo effect, or other confounds that were not addressed in the study design.[2] Supplemental carnosine may increase corticosterone levels, which can explain the hyperactivity sometimes seen in high doses.[citation needed] Researchers in Australia, Britain, and Russia have also shown that carnosine has a number of antioxidant properties that may be beneficial.[citation needed] Carnosine has been proven to scavenge ROS (radical oxygen species) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. It can oppose glycation and it can chelate divalent metal ions. While a small number of studies have produced evidence of beneficial effects of N-acetyl carnosine in treating cataracts of the eyes, these and other ophthamological benefits have not been proven. Britain's Royal College of Ophthamologists assert that neither safety nor efficacy have been sufficiently demonstrated to recommend its use as a topical treatment for cataracts. Typical vegetarian diets are thought to be lacking in carnosine, but whether this has a detrimental effect on vegetarians is controversial.	https://www.wikidoc.org/index.php/Carnosine
e16b1dee1d152d97c91a1de1caec2f6e4385d732	wikidoc	Carprofen	Carprofen # Overview Carprofen (marketed as Vetprofen, Rimadyl, Imadyl, Novox, Imafen and Rovera) is a non-steroidal anti-inflammatory drug that veterinarians prescribe as a supportive treatment for various conditions. It provides day-to-day treatment for pain and inflammation from arthritis in geriatric dogs, joint pain, osteoarthritis, hip dysplasia, and other forms of joint deterioration. It is also used to relieve short-term post-operative pain, inflammation, and swelling after spaying, neutering, and other procedures. Carprofen reduces inflammation by inhibition of COX-2 and other sources of inflammatory prostaglandins. This is targeted protection, in that it does not interfere with COX-1 activity. # Administration Carprofen is available in the USA in 25, 75 and 100 mg tablets (given with food or fed directly to the animal), and in injectable form. In the UK, it is available in 20, 50 and 100 mg tablets. The usual dosage is 4.4 mg per kilogram (2.0 mg/lb) daily. In Australia, carprofen is marketed as Norocarp or Tergive Injection. Norocarp is available in 20 mg and 50 mg tablets or Norophen in injectable liquid at 5.0% w/v, for cattle and canines. Carprofen is also marketed in many Latin-American (and some Asian and African countries) as Carprodyl in 25 mg and 100 mg tablets for canines and Carprobay in 20 mg and 50 mg tablets for dogs. Carprofen is sometimes divided between morning and evening doses. It is administered two hours before surgery for post-operative pain. # Health issues Most dogs respond well to carprofen use, but like all non-steroidal anti-inflammatory (NSAID) medications used in humans and animals, it is capable of causing gastrointestinal, liver and kidney problems in some patients. After introduction, significant anecdotal reports of sudden animal deaths from its use arose. To date, the FDA has received more than 6,000 adverse reaction reports about the drug (manufactured by Pfizer). As a result, the FDA requested that Pfizer advise consumers in their advertising that death is a possible side effect. Pfizer refused and pulled their advertising; however, they now include death as a possible side effect on the drug label. Plans call for a "Dear Doctor" letter to advise veterinarians, and a safety sheet attached to pill packages. Pfizer acknowledges a problem with some dog owners, especially a consumer group that mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects—which include loss of appetite, wobbling, vomiting, seizures, and severe liver malfunction. Reports say the drug company has contacted pet owners who told their stories on the Internet, offering to pay medical and diagnostic expenses for dogs that carprofen may have harmed. Symptoms to watch for include: - Loss of appetite - Vomiting - Diarrhea - Increase in thirst - Increase in urination - Fatigue and/or Lethargy - Loss of coordination - Seizures Other symptoms worth discussing with a vet include excessive drinking or urination, blood or dark tar-like material in urine or stools, jaundice (yellowing of eyes), and unusual lethargy. Other side effects of Rimadyl include: - Black, tarry stools or flecks of blood in the vomit - Drowsiness - Staggering, stumbling, weakness or partial paralysis, full paralysis, dizziness, loss of balance. - Change in urination habits (frequency, color, or smell) - Change in skin (redness, scabs, or scratching) - Change in behavior (such as decreased or increased activity level, seizure or aggression). Excess use of Rimadyl can lead to gastritis and ulcer formation. It is also believed that in some breeds of dogs it may induce kidney and liver damage. Carprofen should not be administered to animals that are also being given steroids (one of the primary risks of this combination being that it can cause ulcers in the stomach). In dogs, it is recommended that the dog be taken off carprofen for three full days before ingesting a steroid (such as prednisolone). According to the official Rimadyl website, the drug should not be given at the same time with other types of medications such as other NSAIDs (aspirin, etodolac, deracoxib, meloxicam, tepoxalin) or steroids such as dexamethasone, triamcinolone, cortisone or prednisone. However, dog owners whose pets have been administered Rimadyl and have experienced side effects are highly recommended to contact a veterinarian as soon as they appear and to stop the therapy. Also, Rimadyl must be used with caution and within the closely monitoring of a veterinarian in dogs with liver or kidney disease, dehydration, bleeding deficits, or other health problems. Rimadyl is not recommended for use in dogs with bleeding disorders (such as Von Willebrand's disease), as safety has not been established in dogs with these disorders. Also, it has been not yet established if Rimadyl can be safely used in pregnant dogs, dogs used for breeding purposes or in lactating female dogs. Several laboratory studies and clinical trials have been conducted to establish the safety of using Rimadyl. Clinical studies were conducted in nearly 300 dogs, coming from different breeds. These dogs have been treated with Rimadyl at the recommended dose for 2 weeks. According to these studies, the drug was clinically well tolerated and dogs treated with Rimadyl did not have a greater incidence of adverse reactions when compared to the placebo-treated animals. There are a number of factors that might however contribute to the high incidence of adverse drug experience reports received for Rimadyl by the Center for Veterinary Medicine in the late 1990s. These include: - The type of drug; - Wide use; - Duration of use. While the side effects from Rimadyl are known to occur within a short period of time after administration, it is believed that long-term use may actually result in a higher risk for adverse reactions; - Senior dog use. Older dogs are generally more prone to side effects caused by carprofen. # Human use Carprofen was used in humans for almost 10 years, starting in 1988. It was used for the same conditions as in dogs, viz., joint pain and inflammation. The human body accepted the drug well and side effects tended to be mild, usually consisting of nausea or gastro-intestinal pain and diarrhea. For human use, Rimadyl was available only by prescription in 150 to 600 mg doses. Dosage over 250 mg was only for relieving pain after severe trauma, such as post-surgery inflammation. 150 mg doses were commonly used to relieve the pain of arthritis, while 200 mg doses were commonly prescribed in cases of severe arthritis or severe inflammation pain. The drug was taken orally. Pfizer voluntarily pulled it from the market for human use on commercial grounds. # Equine use Carprofen is given intravenously to horses at a dose of 0.7 mg/kg once daily. A single dose has been shown to reduce prostaglandin E2 production and inflammatory exudate for up to 15 hours, although there was less effect on eicosanoid production when compared to the effects produced by NSAIDs such as phenylbutazone or flunixin. Prostaglandin E2 and inflammatory exudate are better reduced at a dose of 4 mg/kg IV, with the added benefit of inhibition of leukotriene B4. Carprofen can also be given orally, but intramuscular use may produce muscle damage.	Carprofen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Carprofen (marketed as Vetprofen,[1] Rimadyl,[2] Imadyl, Novox, Imafen and Rovera) is a non-steroidal anti-inflammatory drug that veterinarians prescribe as a supportive treatment for various conditions. It provides day-to-day treatment for pain and inflammation from arthritis in geriatric dogs, joint pain, osteoarthritis, hip dysplasia, and other forms of joint deterioration. It is also used to relieve short-term post-operative pain, inflammation, and swelling after spaying, neutering, and other procedures. Carprofen reduces inflammation by inhibition of COX-2 and other sources of inflammatory prostaglandins. This is targeted protection, in that it does not interfere with COX-1 activity. # Administration Carprofen is available in the USA in 25, 75 and 100 mg tablets (given with food or fed directly to the animal), and in injectable form.[3] In the UK, it is available in 20, 50 and 100 mg tablets. The usual dosage is 4.4 mg per kilogram (2.0 mg/lb) daily.[4] In Australia, carprofen is marketed as Norocarp or Tergive Injection. Norocarp is available in 20 mg and 50 mg tablets or Norophen in injectable liquid at 5.0% w/v, for cattle and canines.[5] Carprofen is also marketed in many Latin-American (and some Asian and African countries) as Carprodyl in 25 mg and 100 mg tablets for canines and Carprobay in 20 mg and 50 mg tablets for dogs.[6] Carprofen is sometimes divided between morning and evening doses. It is administered two hours before surgery for post-operative pain. # Health issues Most dogs respond well to carprofen use, but like all non-steroidal anti-inflammatory (NSAID) medications used in humans and animals, it is capable of causing gastrointestinal, liver and kidney problems in some patients. After introduction, significant anecdotal reports of sudden animal deaths from its use arose. To date, the FDA has received more than 6,000 adverse reaction reports about the drug (manufactured by Pfizer). As a result, the FDA requested that Pfizer advise consumers in their advertising that death is a possible side effect.[7] Pfizer refused and pulled their advertising; however, they now include death as a possible side effect on the drug label. Plans call for a "Dear Doctor" letter to advise veterinarians, and a safety sheet attached to pill packages. Pfizer acknowledges a problem with some dog owners, especially a consumer group that mounted a campaign dubbed BARKS, for Be Aware of Rimadyl's Known Side-effects—which include loss of appetite, wobbling, vomiting, seizures, and severe liver malfunction. Reports say the drug company has contacted pet owners who told their stories on the Internet, offering to pay medical and diagnostic expenses for dogs that carprofen may have harmed.[citation needed] Symptoms to watch for include: - Loss of appetite - Vomiting - Diarrhea - Increase in thirst - Increase in urination - Fatigue and/or Lethargy - Loss of coordination - Seizures Other symptoms worth discussing with a vet include excessive drinking or urination, blood or dark tar-like material in urine or stools, jaundice (yellowing of eyes), and unusual lethargy. Other side effects of Rimadyl include: - Black, tarry stools or flecks of blood in the vomit - Drowsiness - Staggering, stumbling, weakness or partial paralysis, full paralysis, dizziness, loss of balance.[8] - Change in urination habits (frequency, color, or smell) - Change in skin (redness, scabs, or scratching) - Change in behavior (such as decreased or increased activity level, seizure or aggression).[9] Excess use of Rimadyl can lead to gastritis and ulcer formation.[10] It is also believed that in some breeds of dogs it may induce kidney and liver damage.[citation needed] Carprofen should not be administered to animals that are also being given steroids (one of the primary risks of this combination being that it can cause ulcers in the stomach). In dogs, it is recommended that the dog be taken off carprofen for three full days before ingesting a steroid (such as prednisolone). According to the official Rimadyl website, the drug should not be given at the same time with other types of medications such as other NSAIDs (aspirin, etodolac, deracoxib, meloxicam, tepoxalin) or steroids such as dexamethasone, triamcinolone, cortisone or prednisone. However, dog owners whose pets have been administered Rimadyl and have experienced side effects are highly recommended to contact a veterinarian as soon as they appear and to stop the therapy. Also, Rimadyl must be used with caution and within the closely monitoring of a veterinarian in dogs with liver or kidney disease, dehydration, bleeding deficits, or other health problems. Rimadyl is not recommended for use in dogs with bleeding disorders (such as Von Willebrand's disease), as safety has not been established in dogs with these disorders.[11] Also, it has been not yet established if Rimadyl can be safely used in pregnant dogs, dogs used for breeding purposes or in lactating female dogs. Several laboratory studies and clinical trials have been conducted to establish the safety of using Rimadyl. Clinical studies were conducted in nearly 300 dogs, coming from different breeds. These dogs have been treated with Rimadyl at the recommended dose for 2 weeks. According to these studies, the drug was clinically well tolerated and dogs treated with Rimadyl did not have a greater incidence of adverse reactions when compared to the placebo-treated animals.[12] There are a number of factors that might however contribute to the high incidence of adverse drug experience reports received for Rimadyl by the Center for Veterinary Medicine in the late 1990s. These include: - The type of drug; - Wide use; - Duration of use. While the side effects from Rimadyl are known to occur within a short period of time after administration, it is believed that long-term use may actually result in a higher risk for adverse reactions; - Senior dog use. Older dogs are generally more prone to side effects caused by carprofen. # Human use Carprofen was used in humans for almost 10 years, starting in 1988. It was used for the same conditions as in dogs, viz., joint pain and inflammation. The human body accepted the drug well and side effects tended to be mild, usually consisting of nausea or gastro-intestinal pain and diarrhea. For human use, Rimadyl was available only by prescription in 150 to 600 mg doses. Dosage over 250 mg was only for relieving pain after severe trauma, such as post-surgery inflammation.[citation needed] 150 mg doses were commonly used to relieve the pain of arthritis, while 200 mg doses were commonly prescribed in cases of severe arthritis or severe inflammation pain.[citation needed] The drug was taken orally. Pfizer voluntarily pulled it from the market for human use on commercial grounds.[13] # Equine use Carprofen is given intravenously to horses at a dose of 0.7 mg/kg once daily.[14] A single dose has been shown to reduce prostaglandin E2 production and inflammatory exudate for up to 15 hours,[15] although there was less effect on eicosanoid production when compared to the effects produced by NSAIDs such as phenylbutazone or flunixin.[16] Prostaglandin E2 and inflammatory exudate are better reduced at a dose of 4 mg/kg IV, with the added benefit of inhibition of leukotriene B4. Carprofen can also be given orally, but intramuscular use may produce muscle damage.[17]	https://www.wikidoc.org/index.php/Carprofen
c5c463631d85d286abcce6ba8859f1c9be682952	wikidoc	Safflower	Safflower Safflower (Carthamus tinctorius L. ) is a highly branched, herbaceous, thistle-like annual, usually with many long sharp spines on the leaves. Plants are 30 to 150 cm tall with globular flower heads (capitula) and commonly, brilliant yellow, orange or red flowers which bloom in July. Each branch will usually have from one to five flower heads containing 15 to 20 seeds per head. Safflower has a strong taproot which enables it to thrive in dry climates, but the plant is very susceptible to frost injury from stem elongation to maturity. # Uses Traditionally, the crop was grown for its seeds, and used for colouring and flavouring foods and making red (carthamin) and yellow dyes, especially before cheaper aniline dyes became available, and in medicines. For the last fifty years or so, the plant has been cultivated mainly for the vegetable oil extracted from its seeds. In April 2007 it was reported that genetically modified safflower has been bred to create insulin. Safflower oil is flavorless and colorless, and nutritionally similar to sunflower oil. It is used mainly as a cooking oil, in salad dressing, and for the production of margarine. It may also be taken as a nutritional supplement. INCI nomenclature is Carthamus tinctorius. Safflower flowers are occasionally used in cooking as a cheaper substitute for saffron, and are thus sometimes referred to as "bastard saffron." Safflower seed is also used quite commonly as an alternative to sunflower seed in birdfeeders, as squirrels do not like the taste of it. There are two types of safflower that produce different kinds of oil: one high in monounsaturated fatty acid (oleic acid) and the other high in polyunsaturated fatty acid (linoleic acid). Currently the predominant oil market is for the former, which is lower in saturates than olive oil, for example. Safflower oil is also used in painting in the place of linseed oil, particularly with white, as it does not have the yellow tint which linseed oil possesses. Lana is a strain of Safflower that grows in the southwestern United States, most notably Arizona and New Mexico. # History Safflower is one of humanity's oldest crops. Chemical analysis of ancient Egyptian textiles dated to the Twelfth dynasty identified dyes made from safflower, and garlands made from safflowers were found in the tomb of the pharaoh Tutankhamun. John Chadwick reports that the Greek name for safflower occurs many times in Linear B tablets, distinguished into two kinds: a white safflower, which is measured, and red which is weighed. "The explanation is that there are two parts of the plant which can be used; the pale seeds and the red florets." Safflower was also known as carthamine in the 19th century. It is a minor crop today, with about 600,000 tons being produced commercially in more than sixty countries worldwide. India, United States, and Mexico are the leading producers, with Ethiopia, Kazakhstan, China, Argentina and Australia accounting for most of the remainder. # Diseases	Safflower Safflower (Carthamus tinctorius L. [1]) is a highly branched, herbaceous, thistle-like annual, usually with many long sharp spines on the leaves. Plants are 30 to 150 cm tall with globular flower heads (capitula) and commonly, brilliant yellow, orange or red flowers which bloom in July. Each branch will usually have from one to five flower heads containing 15 to 20 seeds per head. Safflower has a strong taproot which enables it to thrive in dry climates, but the plant is very susceptible to frost injury from stem elongation to maturity. # Uses Traditionally, the crop was grown for its seeds, and used for colouring and flavouring foods and making red (carthamin) and yellow dyes, especially before cheaper aniline dyes became available, and in medicines.[2] For the last fifty years or so, the plant has been cultivated mainly for the vegetable oil extracted from its seeds. In April 2007 it was reported that genetically modified safflower has been bred to create insulin.[3] Safflower oil is flavorless and colorless, and nutritionally similar to sunflower oil. It is used mainly as a cooking oil, in salad dressing, and for the production of margarine. It may also be taken as a nutritional supplement. INCI nomenclature is Carthamus tinctorius. Safflower flowers are occasionally used in cooking as a cheaper substitute for saffron, and are thus sometimes referred to as "bastard saffron." Safflower seed is also used quite commonly as an alternative to sunflower seed in birdfeeders, as squirrels do not like the taste of it. There are two types of safflower that produce different kinds of oil: one high in monounsaturated fatty acid (oleic acid) and the other high in polyunsaturated fatty acid (linoleic acid). Currently the predominant oil market is for the former, which is lower in saturates than olive oil, for example. Safflower oil is also used in painting in the place of linseed oil, particularly with white, as it does not have the yellow tint which linseed oil possesses. Lana is a strain of Safflower that grows in the southwestern United States, most notably Arizona and New Mexico. # History Safflower is one of humanity's oldest crops. Chemical analysis of ancient Egyptian textiles dated to the Twelfth dynasty identified dyes made from safflower, and garlands made from safflowers were found in the tomb of the pharaoh Tutankhamun.[4] John Chadwick reports that the Greek name for safflower occurs many times in Linear B tablets, distinguished into two kinds: a white safflower, which is measured, and red which is weighed. "The explanation is that there are two parts of the plant which can be used; the pale seeds and the red florets."[5] Safflower was also known as carthamine in the 19th century.[6] It is a minor crop today, with about 600,000 tons being produced commercially in more than sixty countries worldwide. India, United States, and Mexico are the leading producers, with Ethiopia, Kazakhstan, China, Argentina and Australia accounting for most of the remainder. # Diseases	https://www.wikidoc.org/index.php/Carthamus_Tinctorius
59f29fd909dbd2802f6112b3da7de07cee235d75	wikidoc	Castoreum	Castoreum Castoreum is the name given to the exudate from the castor sacs of the mature North American Beaver Castor canadensis and the European Beaver, Castor fiber. Within the zoological realm, castoreum is the yellowish secretion of the castor sac in combination with the beaver's urine, used during scent marking of territory. Both male and female beavers possess a pair of castor sacs and a pair of anal glands located in two cavities under the skin between the pelvis and the base of the tail. The castor sacs are not true glands (endocrine or exocrine) on a cellular level, hence references to these structures as preputial glands or castor glands are misnomers. Today, it is used in trapping, as a tincture in some perfumes, or touted as an aphrodisiac. # Castoreum in Perfume In perfume-making, the term castoreum is more liberally applied to denote the resinoid extract resulting from the dried and alcohol tinctured beaver castor (www.hyraceum.com). The dried beaver castor sacs are generally aged for two or more years to mellow and for their raw harshness to dissipate. In perfumery, castoreum has largely been used as an animalic note suggesting leather, compounded with other ingredients including top, middle, and base notes as a composition. Some classic perfumes incorporating castor are Emeraude, Coty Chanel Cuir de Russie, Magie Noire, Lancôme Caractère, Hechter Madame, Carven, Givenchy III, Shalimar, and many "leather" themed compositions. Twenty four compounds known to be constituents of beaver castoreum were individually screened for pheremonal activity. These are the phenols 4-ethylphenol and 1,2-dihydroxybenzene and the ketones acetophenone and 3-hydroxyacetophenone. Five additional compounds noted are 4-methyl-1,2-dihydroxybenzene, 4-methoxyacetophenone, 5-methoxysalicylic acid, salicylaldehyde, and 3-hydroxybenzoic acid. # Medicinal Use of Castoreum Although modern medical use of castoreum is rare, the dried pair of scent glands (the "castors") may still be worth more than a beaver pelt itself. Castoreum appeared in the materia medica until the 1700s, used to treat many different ailments, including headache, fever, and hysteria. The Romans believed the fumes produced by burning castoreum could induce an abortion; Paracelsus thought it could be used in the treatment of epilepsy; and medieval beekeepers used it to increase honey production. Castoreum, an anal gland secretion, appears to be used by beavers to mark their territory. Castoreum is also used in small amounts to contribute to the flavor and odor of cigarettes.	Castoreum Castoreum is the name given to the exudate from the castor sacs of the mature North American Beaver Castor canadensis and the European Beaver, Castor fiber. Within the zoological realm, castoreum is the yellowish secretion of the castor sac in combination with the beaver's urine, used during scent marking of territory.[1] Both male and female beavers possess a pair of castor sacs and a pair of anal glands located in two cavities under the skin between the pelvis and the base of the tail. The castor sacs are not true glands (endocrine or exocrine) on a cellular level, hence references to these structures as preputial glands or castor glands are misnomers.[2] Today, it is used in trapping, as a tincture in some perfumes[3], or touted as an aphrodisiac. # Castoreum in Perfume In perfume-making, the term castoreum is more liberally applied to denote the resinoid extract resulting from the dried and alcohol tinctured beaver castor (www.hyraceum.com).[4] The dried beaver castor sacs are generally aged for two or more years to mellow and for their raw harshness to dissipate. In perfumery, castoreum has largely been used as an animalic note suggesting leather, compounded with other ingredients including top, middle, and base notes as a composition. Some classic perfumes incorporating castor are Emeraude, Coty Chanel Cuir de Russie, Magie Noire, Lancôme Caractère, Hechter Madame, Carven, Givenchy III, Shalimar, and many "leather" themed compositions[5]. Twenty four compounds known to be constituents of beaver castoreum were individually screened for pheremonal activity. These are the phenols 4-ethylphenol and 1,2-dihydroxybenzene and the ketones acetophenone and 3-hydroxyacetophenone. Five additional compounds noted are 4-methyl-1,2-dihydroxybenzene, 4-methoxyacetophenone, 5-methoxysalicylic acid, salicylaldehyde, and 3-hydroxybenzoic acid.[6] # Medicinal Use of Castoreum Although modern medical use of castoreum is rare, the dried pair of scent glands (the "castors") may still be worth more than a beaver pelt itself.[7] Castoreum appeared in the materia medica until the 1700s, used to treat many different ailments, including headache, fever, and hysteria.[8] The Romans believed the fumes produced by burning castoreum could induce an abortion; Paracelsus thought it could be used in the treatment of epilepsy[9]; and medieval beekeepers used it to increase honey production. Castoreum, an anal gland secretion,[10] appears to be used by beavers to mark their territory.[11] Castoreum is also used in small amounts to contribute to the flavor and odor of cigarettes. [12]	https://www.wikidoc.org/index.php/Castoreum
4075c9cb271625204de481ed2f9a128a310247da	wikidoc	Catalepsy	Catalepsy Catalepsy is a condition characterized by muscular rigidity, fixity of posture and decreased sensitivity to pain. Professionals once believed this disorder was the result of (controllable) mental states that had no basis in physiology. Researchers now know, however, that catalepsy does not appear of its own accord; instead, it often manifests as one in a constellation of symptoms caused by disorders that have physical causes. Catalepsy can be produced by conditions as varied as Parkinson's disease and epilepsy, for example. Catalepsy is also a characteristic symptom of cocaine withdrawal, and schizophrenia treatment with typical anti-psychotics. Symptoms include: rigid body, rigid limbs, limbs staying in same position when moved, no response, loss of muscle control, and slowing down of bodily functions, such as breathing. In some cases, isolated cataleptic instances can also be precipitated by extreme emotional shock. Catalepsy is also a term used by hypnotists to refer to the state of making a hypnotised subject's arm, leg or back rigid. "Arm catalepsy" is often a pre-hypnotic test performed prior to an induction into a full trance. # Literary depictions In Alexander Dumas' novel The Count of Monte Cristo, the Abbé Faria suffered from fits of Catalepsy from time to time. In George Eliot's novel Silas Marner, the main character Silas Marner frequently suffers from catalepsic fits and seizures. It is not mentioned if they are caused by any of the aforementioned factors. In Edgar Allan Poe's The Premature Burial, the narrator suffers from catalepsy. He fears being mistakenly declared dead and buried alive, and goes to great lengths to prevent this. In Edgar Allan Poe's Fall of the House of Usher, Madeline Usher suffers from catalepsy. She is buried alive by her unstable brother Rodderick. In Arthur Conan Doyle's The Resident Patient, a doctor attempts to treat catalepsy with amyl nitrite	Catalepsy Catalepsy is a condition characterized by muscular rigidity, fixity of posture and decreased sensitivity to pain. Professionals once believed this disorder was the result of (controllable) mental states that had no basis in physiology. Researchers now know, however, that catalepsy does not appear of its own accord; instead, it often manifests as one in a constellation of symptoms caused by disorders that have physical causes. Catalepsy can be produced by conditions as varied as Parkinson's disease and epilepsy, for example. Catalepsy is also a characteristic symptom of cocaine withdrawal, and schizophrenia treatment with typical anti-psychotics. Symptoms include: rigid body, rigid limbs, limbs staying in same position when moved, no response, loss of muscle control, and slowing down of bodily functions, such as breathing.[1] In some cases, isolated cataleptic instances can also be precipitated by extreme emotional shock. Catalepsy is also a term used by hypnotists to refer to the state of making a hypnotised subject's arm, leg or back rigid. "Arm catalepsy" is often a pre-hypnotic test performed prior to an induction into a full trance. # Literary depictions In Alexander Dumas' novel The Count of Monte Cristo, the Abbé Faria suffered from fits of Catalepsy from time to time. In George Eliot's novel Silas Marner, the main character Silas Marner frequently suffers from catalepsic fits and seizures. It is not mentioned if they are caused by any of the aforementioned factors. In Edgar Allan Poe's The Premature Burial, the narrator suffers from catalepsy. He fears being mistakenly declared dead and buried alive, and goes to great lengths to prevent this. In Edgar Allan Poe's Fall of the House of Usher, Madeline Usher suffers from catalepsy. She is buried alive by her unstable brother Rodderick. In Arthur Conan Doyle's The Resident Patient, a doctor attempts to treat catalepsy with amyl nitrite	https://www.wikidoc.org/index.php/Catalepsy
107573465d387fa395c2b578ac553b9ee9f97cbe	wikidoc	Catalysis	Catalysis In chemistry and biology, catalysis is the acceleration (increase in rate) of a chemical reaction by means of a substance called a catalyst, which is itself not consumed by the overall reaction. More generally, one may at times call anything that accelerates a process, a "catalyst" (f related to the verb καταλύειν, meaning to annul or to untie or to pick up. A catalyst provides an alternative route to products, the catalytic route being subject to lower activation energy than in the uncatalyzed reaction. A lowered activation energy increases the reaction rate. Catalysts change in the course of a reaction but are regenerated. A good example of a catalyst is in the disproportionation of hydrogen peroxide to give water and oxygen: This reaction is slow (hence one can buy solutions of hydrogen peroxide). Upon the addition of manganese dioxide to hydrogen peroxide, the reaction occurs rapidly as signaled by effervescence of oxygen. In demonstrations, the evolved oxygen is detectable by its effect on a glowing splint. The manganese dioxide may be recovered, and re-used indefinitely, thus it is a catalyst — it is not consumed by the reaction. (The H2O2 sold as a sterilizing agent in drugstores is too dilute for this to work dramatically.) A promoter chemically modifies a catalyst but is not itself a catalyst. An inhibitor reduces the effectiveness of (or slows down the effect of) a catalyst. # History The phrase catalysis was coined by Jöns Jakob Berzelius who in 1835 was the first to note that certain chemicals speed up a reaction. Other early chemists involved in catalysis were Alexander Mitscherlich who in 1831 referred to contact processes and Johann Wolfgang Döbereiner who spoke of contact action and whose lighter based on hydrogen and a platinum sponge became a huge commercial success in the 1820’s. In the 1880s, Wilhelm Ostwald at Leipzig University started a series of systematic investigations into reactions that were catylized by the presence of acids and bases, and found both that chemical reactions occur at finite rates, and that these rates can be used to determine the strengths of acids and bases. For this work, Ostwald was awarded the 1909 Nobel Prize in Chemistry. # Definitions Catalysts generally react with one or more reactants to form an intermediate that subsequently give the final reaction product, in the process regenerating the catalyst. The following is a typical reaction scheme, where C represents the catalyst, A and B are reactants, and D is the product of the reaction of A and B: Although the catalyst (C) is consumed by reaction 1, it is subsequently produced by reaction 4, so for the overall reaction: # Catalytic cycles A catalytic cycle is another term for mechanism. Catalytic cycles are central to any discussion of catalysis, be it in biochemistry, organometallic chemistry, or solid state chemistry. Often, a so-called sacrificial catalyst is also part of the reaction system with the purpose of regenerating the true catalyst in each cycle. As the name implies the sacrificial catalyst is not regenerated and is instead irreversibly consumed. This sacrificial compound is also known as a stoichiometric catalyst when added in stoichiometric quantities compared to the main reactant. Usually the true catalyst is an expensive and complex molecule and added in quantities as small as possible. The stoichiometric catalyst on the other hand should be cheap and abundant. # Catalysts and reaction energetics Catalysts work by providing an (alternative) mechanism involving a different transition state and lower activation energy. The effect of this is that more molecular collisions have the energy needed to reach the transition state. Hence, catalysts can perform reactions that, albeit thermodynamically feasible, would not run without the presence of a catalyst, or perform them much faster, more specific, or at lower temperatures. This can be observed on a Boltzmann distribution and energy profile diagram. This means that catalysts reduce the amount of energy needed to start a chemical reaction. Catalysts cannot make energetically unfavorable reactions possible — they have no effect on the chemical equilibrium of a reaction because the rate of both the forward and the reverse reaction are equally affected (see also thermodynamics). The net free energy change of a reaction is the same whether a catalyst is used or not; the catalyst just makes it easier to activate. The SI derived unit for measuring the catalytic activity of a catalyst is the katal, which is moles per second. The degree of activity of a catalyst can also be described by the turn over number (or TON) and the catalytic efficiency by the turn over frequency (TOF). The biochemical equivalent is the enzyme unit. For more information on the efficiency of enzymatic catalysis see the Enzyme#Kinetics section. ## Autocatalysis In autocatalysis, a reaction produces catalysts. # Types of catalysts Catalysts can be either heterogeneous or homogeneous. Biocatalysts are often seen as a separate group. Heterogeneous catalysts are present in different phases from the reactants (for example, a solid catalyst in a liquid reaction mixture), whereas homogeneous catalysts are in the same phase (for example, a dissolved catalyst in a liquid reaction mixture). ## Heterogeneous catalysts A simple model for heterogeneous catalysis involves the catalyst providing a surface on which the reactants (or substrates) temporarily become adsorbed. Bonds in the substrate become weakened sufficiently for new bonds to be created. The bonds between the products and the catalyst are weaker, so the products are released. Different possible mechanisms for reactions on surfaces are known, depending on how the adsorption takes place (Langmuir-Hinshelwood and Eley-Rideal). For example, in the Haber process to manufacture ammonia, finely divided iron acts as a heterogeneous catalyst. Active sites on the metal allow partial weak bonding to the reactant gases, which are adsorbed onto the metal surface. As a result, the bond within the molecule of a reactant is weakened and the reactant molecules are held in close proximity to each other. In this way the particularly strong triple bond in nitrogen is weakened and the hydrogen and nitrogen molecules are brought closer together than would be the case in the gas phase, so the rate of reaction increases. Other heterogeneous catalysts include vanadium(V) oxide in the contact process, nickel in the manufacture of margarine, alumina and silica in the cracking of alkanes and platinum rhodium palladium in catalytic converters. Mesoporous silicates have found utility in heterogeneous reaction catalysis because their large accessible surface area allows for high catalyst loading. In car engines, incomplete combustion of the fuel produces carbon monoxide, which is toxic. The electric spark and high temperatures also allow oxygen and nitrogen to react and form nitrogen monoxide and nitrogen dioxide, which are responsible for photochemical smog and acid rain. Catalytic converters reduce such emissions by adsorbing CO and NO onto catalytic surface, where the gases undergo a redox reaction. Carbon dioxide and nitrogen are desorbed from the surface and emitted as relatively harmless gases: Many catalysts used in refineries and in petrochemical applications are regenerated and reused multiple times to save costs and energy and to reduce environmental impact from recycling or disposal of spent catalysts. ## Homogeneous catalysts Homogeneous catalysts are in the same phase as the reactants. In homogeneous catalysis the catalyst is a molecule which facilitates the reaction. The reactant(s) coordinate to the catalyst (or vice versa), are transformed to product(s), which are then released from the catalyst. Examples of homogeneous catalysts are H+(aq) which acts as a catalyst in esterification, and chlorine free radicals in the break down of ozone. Chlorine free radicals are formed by the action of ultraviolet radiation on chlorofluorocarbons (CFCs). They react with ozone forming oxygen molecules and regenerating chlorine free radicals which then in turn destroys the thin layer that is the ozone. ## Biocatalysts In nature enzymes are catalysts in the metabolic pathway. In biochemistry catalysis is also observed with abzymes, ribozymes and deoxyribozymes. Biocatalysts can be thought of as a mixture of a homogenous and heterogeneous catalyst. This is because the enzyme is in solution itself, but the reaction takes place on the enzyme surface. ## Electrocatalysts In the context of electrochemistry, specifically in fuel cell engineering, various metal-rich catalysts are used to promote the efficiency of a half reaction that occurs within the fuel cell. One common type of fuel cell electrocatalyst is based upon tiny nanoparticles of platinum which adorn slightly larger carbon particles. When this type of platinum electrocatalyst is in contact with one of the electrodes in a fuel cell, it increases the rate of the redox half reaction in which oxygen gas is reduced to water (or hydroxide or hydrogen peroxide). # Significance Catalysis is of paramount importance in the chemical industry. The production of most industrially important chemicals involves catalysis. The earliest commercial processes are the Haber process for ammonia synthesis and the Fischer-Tropsch synthesis. Research into catalysis is a major field in applied science, and involves many fields of chemistry, notably in organometallic chemistry, and physics. Catalysis is important in many aspects of environmental science, from the catalytic converter in automobiles to the causes of the ozone hole. Catalytic, rather than stoichiometric reactions are preferred in environmentally friendly green chemistry due to the reduced amount of waste generated. # Notable examples Estimates are that 90% of all commercially produced chemical products involve catalysts at some stage in the process of their manufacture. Manganese dioxide is used in the laboratory to prepare oxygen by the decomposition of hydrogen peroxide to oxygen and water. Well-known applications of synthetic catalysts are: - Catalytic converters made from platinum and manganese break down some of the more harmful byproducts of automobile exhaust. There is a honey comb affect and the surface area is as big as a football pitch. - the Haber process for the synthesis of ammonia from nitrogen and hydrogen, where iron is the catalyst. Examples of catalysts that perform specific transformations on functional groups: - Transformations of olefinic groups: the Ziegler-Natta catalyst used to mass produce polyethylene and polypropylene. the Grubbs' catalyst for olefin metathesis. the Monsanto process the Wacker process the Heck reaction. - the Ziegler-Natta catalyst used to mass produce polyethylene and polypropylene. - the Grubbs' catalyst for olefin metathesis. - the Monsanto process - the Wacker process - the Heck reaction. These given examples show that different catalysts perform other transformations on the same functional groups, where the reaction would not proceed, proceed very slowly, or proceed in an unselective manner without the presence of the catalyst. The most common catalyst is the proton. Many transition metals and transition metal complexes are used in catalysis as well. # New directions - organocatalysis While transition metal catalysts are well established, a new trend is toward organocatalysis which use comparatively simple organic molecules as catalysts. While typically, catalyst loading is much higher than transition metal-based catalysts, the catalysts are usually commercially available in bulk, helping to reduce costs drastically. Organocatalysts of the "new generation" are competitive to traditional metal-containing catalysts and are owing to low product inhibition applicable in substoichiometric quantities. The chemical character of organocatalysts offers new and attractive perspectives and advantages to synthetically working chemists. # Catalytic processes - Acid-base catalysis - Catalytic converters made from platinum and rhodium break down some of the more harmful byproducts of automobile exhaust. - Fuel cells - Fischer-Tropsch synthesis. - Haber process (synthesis of ammonia from nitrogen and hydrogen, where ordinary iron is used as a catalyst) - Hydrogenation - Methanol synthesis - Nitric acid production - Petroleum refining and processing Alkylation Catalytic cracking - breaking long-chain hydrocarbons into smaller pieces Naphtha reforming - Alkylation - Catalytic cracking - breaking long-chain hydrocarbons into smaller pieces - Naphtha reforming - Steam reforming of hydrocarbons to produce synthesis gas - Sulfuric acid production - Transesterification - Olefin polymerisation	Catalysis In chemistry and biology, catalysis is the acceleration (increase in rate) of a chemical reaction by means of a substance called a catalyst, which is itself not consumed by the overall reaction. More generally, one may at times call anything that accelerates a process, a "catalyst" (f related to the verb καταλύειν, meaning to annul or to untie or to pick up. A catalyst provides an alternative route to products, the catalytic route being subject to lower activation energy than in the uncatalyzed reaction. A lowered activation energy increases the reaction rate. Catalysts change in the course of a reaction but are regenerated. A good example of a catalyst is in the disproportionation of hydrogen peroxide to give water and oxygen: This reaction is slow (hence one can buy solutions of hydrogen peroxide). Upon the addition of manganese dioxide to hydrogen peroxide, the reaction occurs rapidly as signaled by effervescence of oxygen. In demonstrations, the evolved oxygen is detectable by its effect on a glowing splint. The manganese dioxide may be recovered, and re-used indefinitely, thus it is a catalyst — it is not consumed by the reaction. (The H2O2 sold as a sterilizing agent in drugstores is too dilute for this to work dramatically.) A promoter chemically modifies a catalyst but is not itself a catalyst. An inhibitor reduces the effectiveness of (or slows down the effect of) a catalyst. # History The phrase catalysis was coined by Jöns Jakob Berzelius who in 1835 was the first to note that certain chemicals speed up a reaction. Other early chemists involved in catalysis were Alexander Mitscherlich who in 1831[citation needed] referred to contact processes and Johann Wolfgang Döbereiner who spoke of contact action and whose lighter based on hydrogen and a platinum sponge became a huge commercial success in the 1820’s. In the 1880s, Wilhelm Ostwald at Leipzig University started a series of systematic investigations into reactions that were catylized by the presence of acids and bases, and found both that chemical reactions occur at finite rates, and that these rates can be used to determine the strengths of acids and bases. For this work, Ostwald was awarded the 1909 Nobel Prize in Chemistry. # Definitions Catalysts generally react with one or more reactants to form an intermediate that subsequently give the final reaction product, in the process regenerating the catalyst. The following is a typical reaction scheme, where C represents the catalyst, A and B are reactants, and D is the product of the reaction of A and B: Although the catalyst (C) is consumed by reaction 1, it is subsequently produced by reaction 4, so for the overall reaction: # Catalytic cycles A catalytic cycle is another term for mechanism. Catalytic cycles are central to any discussion of catalysis, be it in biochemistry, organometallic chemistry, or solid state chemistry. Often, a so-called sacrificial catalyst is also part of the reaction system with the purpose of regenerating the true catalyst in each cycle. As the name implies the sacrificial catalyst is not regenerated and is instead irreversibly consumed. This sacrificial compound is also known as a stoichiometric catalyst when added in stoichiometric quantities compared to the main reactant. Usually the true catalyst is an expensive and complex molecule and added in quantities as small as possible. The stoichiometric catalyst on the other hand should be cheap and abundant. # Catalysts and reaction energetics Catalysts work by providing an (alternative) mechanism involving a different transition state and lower activation energy. The effect of this is that more molecular collisions have the energy needed to reach the transition state. Hence, catalysts can perform reactions that, albeit thermodynamically feasible, would not run without the presence of a catalyst, or perform them much faster, more specific, or at lower temperatures. This can be observed on a Boltzmann distribution and energy profile diagram. This means that catalysts reduce the amount of energy needed to start a chemical reaction. Catalysts cannot make energetically unfavorable reactions possible — they have no effect on the chemical equilibrium of a reaction because the rate of both the forward and the reverse reaction are equally affected (see also thermodynamics). The net free energy change of a reaction is the same whether a catalyst is used or not; the catalyst just makes it easier to activate. The SI derived unit for measuring the catalytic activity of a catalyst is the katal, which is moles per second. The degree of activity of a catalyst can also be described by the turn over number (or TON) and the catalytic efficiency by the turn over frequency (TOF). The biochemical equivalent is the enzyme unit. For more information on the efficiency of enzymatic catalysis see the Enzyme#Kinetics section. ## Autocatalysis In autocatalysis, a reaction produces catalysts. # Types of catalysts Catalysts can be either heterogeneous or homogeneous. Biocatalysts are often seen as a separate group. Heterogeneous catalysts are present in different phases from the reactants (for example, a solid catalyst in a liquid reaction mixture), whereas homogeneous catalysts are in the same phase (for example, a dissolved catalyst in a liquid reaction mixture). ## Heterogeneous catalysts A simple model for heterogeneous catalysis involves the catalyst providing a surface on which the reactants (or substrates) temporarily become adsorbed. Bonds in the substrate become weakened sufficiently for new bonds to be created. The bonds between the products and the catalyst are weaker, so the products are released. Different possible mechanisms for reactions on surfaces are known, depending on how the adsorption takes place (Langmuir-Hinshelwood and Eley-Rideal). For example, in the Haber process to manufacture ammonia, finely divided iron acts as a heterogeneous catalyst. Active sites on the metal allow partial weak bonding to the reactant gases, which are adsorbed onto the metal surface. As a result, the bond within the molecule of a reactant is weakened and the reactant molecules are held in close proximity to each other. In this way the particularly strong triple bond in nitrogen is weakened and the hydrogen and nitrogen molecules are brought closer together than would be the case in the gas phase, so the rate of reaction increases. Other heterogeneous catalysts include vanadium(V) oxide in the contact process, nickel in the manufacture of margarine, alumina and silica in the cracking of alkanes and platinum rhodium palladium in catalytic converters. Mesoporous silicates have found utility in heterogeneous reaction catalysis because their large accessible surface area allows for high catalyst loading. In car engines, incomplete combustion of the fuel produces carbon monoxide, which is toxic. The electric spark and high temperatures also allow oxygen and nitrogen to react and form nitrogen monoxide and nitrogen dioxide, which are responsible for photochemical smog and acid rain. Catalytic converters reduce such emissions by adsorbing CO and NO onto catalytic surface, where the gases undergo a redox reaction. Carbon dioxide and nitrogen are desorbed from the surface and emitted as relatively harmless gases: Many catalysts used in refineries and in petrochemical applications are regenerated and reused multiple times to save costs and energy and to reduce environmental impact from recycling or disposal of spent catalysts. ## Homogeneous catalysts Homogeneous catalysts are in the same phase as the reactants. In homogeneous catalysis the catalyst is a molecule which facilitates the reaction. The reactant(s) coordinate to the catalyst (or vice versa), are transformed to product(s), which are then released from the catalyst. Examples of homogeneous catalysts are H+(aq) which acts as a catalyst in esterification, and chlorine free radicals in the break down of ozone. Chlorine free radicals are formed by the action of ultraviolet radiation on chlorofluorocarbons (CFCs). They react with ozone forming oxygen molecules and regenerating chlorine free radicals which then in turn destroys the thin layer that is the ozone. ## Biocatalysts In nature enzymes are catalysts in the metabolic pathway. In biochemistry catalysis is also observed with abzymes, ribozymes and deoxyribozymes. Biocatalysts can be thought of as a mixture of a homogenous and heterogeneous catalyst. This is because the enzyme is in solution itself, but the reaction takes place on the enzyme surface. ## Electrocatalysts In the context of electrochemistry, specifically in fuel cell engineering, various metal-rich catalysts are used to promote the efficiency of a half reaction that occurs within the fuel cell. One common type of fuel cell electrocatalyst is based upon tiny nanoparticles of platinum which adorn slightly larger carbon particles. When this type of platinum electrocatalyst is in contact with one of the electrodes in a fuel cell, it increases the rate of the redox half reaction in which oxygen gas is reduced to water (or hydroxide or hydrogen peroxide). # Significance Catalysis is of paramount importance in the chemical industry. The production of most industrially important chemicals involves catalysis. The earliest commercial processes are the Haber process for ammonia synthesis and the Fischer-Tropsch synthesis. Research into catalysis is a major field in applied science, and involves many fields of chemistry, notably in organometallic chemistry, and physics. Catalysis is important in many aspects of environmental science, from the catalytic converter in automobiles to the causes of the ozone hole. Catalytic, rather than stoichiometric reactions are preferred in environmentally friendly green chemistry due to the reduced amount of waste generated. # Notable examples Estimates are that 90% of all commercially produced chemical products involve catalysts at some stage in the process of their manufacture.[1] Manganese dioxide is used in the laboratory to prepare oxygen by the decomposition of hydrogen peroxide to oxygen and water. Well-known applications of synthetic catalysts are: - Catalytic converters made from platinum and manganese break down some of the more harmful byproducts of automobile exhaust. There is a honey comb affect and the surface area is as big as a football pitch. - the Haber process for the synthesis of ammonia from nitrogen and hydrogen, where iron is the catalyst. Examples of catalysts that perform specific transformations on functional groups: - Transformations of olefinic groups: the Ziegler-Natta catalyst used to mass produce polyethylene and polypropylene. the Grubbs' catalyst for olefin metathesis. the Monsanto process the Wacker process the Heck reaction. - the Ziegler-Natta catalyst used to mass produce polyethylene and polypropylene. - the Grubbs' catalyst for olefin metathesis. - the Monsanto process - the Wacker process - the Heck reaction. These given examples show that different catalysts perform other transformations on the same functional groups, where the reaction would not proceed, proceed very slowly, or proceed in an unselective manner without the presence of the catalyst. The most common catalyst is the proton. Many transition metals and transition metal complexes are used in catalysis as well. # New directions - organocatalysis While transition metal catalysts are well established, a new trend is toward organocatalysis which use comparatively simple organic molecules as catalysts. While typically, catalyst loading is much higher than transition metal-based catalysts, the catalysts are usually commercially available in bulk, helping to reduce costs drastically. Organocatalysts of the "new generation" are competitive to traditional metal-containing catalysts and are owing to low product inhibition applicable in substoichiometric quantities. The chemical character of organocatalysts offers new and attractive perspectives and advantages to synthetically working chemists. # Catalytic processes - Acid-base catalysis - Catalytic converters made from platinum and rhodium break down some of the more harmful byproducts of automobile exhaust. - Fuel cells - Fischer-Tropsch synthesis. - Haber process (synthesis of ammonia from nitrogen and hydrogen, where ordinary iron is used as a catalyst) - Hydrogenation - Methanol synthesis - Nitric acid production - Petroleum refining and processing Alkylation Catalytic cracking - breaking long-chain hydrocarbons into smaller pieces Naphtha reforming - Alkylation - Catalytic cracking - breaking long-chain hydrocarbons into smaller pieces - Naphtha reforming - Steam reforming of hydrocarbons to produce synthesis gas - Sulfuric acid production - Transesterification - Olefin polymerisation	https://www.wikidoc.org/index.php/Catalyse
77d179426fb4ba091af4b8faa4a40b63136df10f	wikidoc	Cataplexy	Cataplexy # Overview Cataplexy is a medical condition which often affects people who have narcolepsy, a disorder whose principal signs are EDS (Excessive Daytime Sleepiness), sleep attacks, sleep paralysis, hypnopompic hallucinations and disturbed night-time sleep. Cataplexy is sometimes confused with epilepsy, where a series of flashes or other stimuli cause superficially similar seizures. The term cataplexy originates from the Greek kata, meaning down, and plexis, meaning a stroke or seizure. # Causes ## Common Causes - Encephalitis - Head trauma - Hydrocephalus - Hypocretin deficiency - Hypothalamus lesions - Narcolepsy - Neurodegenerative diseases - Niemann pick disease - Sleep attacks - Sleep paralysis ## Causes by Organ System ## Causes in Alphabetical Order - Astrocytoma - Encephalitis - Glioblastoma - Glioma - Head trauma - Hydrocephalus - Hypnagogic hallucinations - Hypocretin deficiency - Hypothalamus lesions - Ischemia - Modafinil - Multiple sclerosis - Narcolepsy - Neurodegenerative diseases - Niemann pick disease - Paraneoplasia syndrome - Provigil - Sleep attacks - Sleep paralysis - Subependynoma - Surgical tumor resection # Presentation Cataplexy manifests itself as muscular weakness which may range from a barely perceptible slackening of the facial muscles to the dropping of the jaw or head, weakness at the knees, or a total collapse. Usually the speech is slurred, vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. These attacks are triggered by strong emotions such as exhilaration, anger, fear, surprise, orgasm, awe, embarrassment and laughter. Cataplexy may be partial or complete, affecting a range of muscle groups, from those controlling facial features to (less commonly) those controlling the entire body. - Arm weakness - Sagging jaw - Drooping head - Slumping of the shoulders - Slurred speech - Generalized weakness - Knee buckling When cataplexy happens often, or cataplexy attacks make patients fall or drop things, it can have serious affects on normal activities. It can cause accidents and be embarrassing when it happens at work or with friends. For example, a narcoleptic may not pick up a baby because they are afraid they may drop them. # Treatment Despite its relation to narcolepsy, in most cases, cataplexy must be treated differently and separate medication must be taken. For many years, cataplexy has been treated with tricyclic antidepressants such as imipramine, clomipramine or protriptyline. However these can have unpleasant side-effects and so have been generally replaced by newer drugs such as Effexor, a more recent antidepressant. Xyrem, the brand-name of the compound (sodium)gamma-Hydroxybutyrate GHB, has been shown to treat not only cataplexic attacks, but in narcoleptics, it has also been shown to significantly reduce daytime sleepiness. Monoamine oxidase inhibitors may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis and hypnagogic hallucinations. A person's efforts to stave off cataplectic attacks by avoiding these emotions may greatly diminish their lives, and they may become severely restricted emotionally if diagnosis and treatment is not begun as soon as possible. # Diagnosis Cataplexy in severe cases can cause vital signs to be hard to detect without a continuous auditory pulse oximeter (a well-known heart monitor). As an anecdotal example, one Allison Burchell, a sufferer of severe Cataplexy, has been sent to the morgue three times.	Cataplexy For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S. # Overview Cataplexy is a medical condition which often affects people who have narcolepsy, a disorder whose principal signs are EDS (Excessive Daytime Sleepiness), sleep attacks, sleep paralysis, hypnopompic hallucinations[1] and disturbed night-time sleep. Cataplexy is sometimes confused with epilepsy, where a series of flashes or other stimuli cause superficially similar seizures. The term cataplexy originates from the Greek kata, meaning down, and plexis, meaning a stroke or seizure. # Causes ## Common Causes - Encephalitis - Head trauma - Hydrocephalus - Hypocretin deficiency - Hypothalamus lesions - Narcolepsy - Neurodegenerative diseases - Niemann pick disease - Sleep attacks - Sleep paralysis ## Causes by Organ System ## Causes in Alphabetical Order - Astrocytoma - Encephalitis - Glioblastoma - Glioma - Head trauma - Hydrocephalus - Hypnagogic hallucinations - Hypocretin deficiency - Hypothalamus lesions - Ischemia - Modafinil - Multiple sclerosis - Narcolepsy - Neurodegenerative diseases - Niemann pick disease - Paraneoplasia syndrome - Provigil - Sleep attacks - Sleep paralysis - Subependynoma - Surgical tumor resection # Presentation Cataplexy manifests itself as muscular weakness which may range from a barely perceptible slackening of the facial muscles to the dropping of the jaw or head, weakness at the knees, or a total collapse. Usually the speech is slurred, vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. These attacks are triggered by strong emotions such as exhilaration, anger, fear, surprise, orgasm, awe, embarrassment and laughter. Cataplexy may be partial or complete, affecting a range of muscle groups, from those controlling facial features to (less commonly) those controlling the entire body. [2] - Arm weakness - Sagging jaw - Drooping head - Slumping of the shoulders - Slurred speech - Generalized weakness - Knee buckling When cataplexy happens often, or cataplexy attacks make patients fall or drop things, it can have serious affects on normal activities. It can cause accidents and be embarrassing when it happens at work or with friends. For example, a narcoleptic may not pick up a baby because they are afraid they may drop them. [3] # Treatment Despite its relation to narcolepsy, in most cases, cataplexy must be treated differently and separate medication must be taken. For many years, cataplexy has been treated with tricyclic antidepressants such as imipramine, clomipramine or protriptyline. However these can have unpleasant side-effects and so have been generally replaced by newer drugs such as Effexor, a more recent antidepressant. Xyrem, the brand-name of the compound (sodium)gamma-Hydroxybutyrate GHB, has been shown to treat not only cataplexic attacks, but in narcoleptics, it has also been shown to significantly reduce daytime sleepiness.[4] Monoamine oxidase inhibitors may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis and hypnagogic hallucinations.[1] A person's efforts to stave off cataplectic attacks by avoiding these emotions may greatly diminish their lives, and they may become severely restricted emotionally if diagnosis and treatment is not begun as soon as possible. [5] # Diagnosis Cataplexy in severe cases can cause vital signs to be hard to detect without a continuous auditory pulse oximeter (a well-known heart monitor). As an anecdotal example, one Allison Burchell, a sufferer of severe Cataplexy, has been sent to the morgue three times.[6]	https://www.wikidoc.org/index.php/Cataplexy
b4873240b2114bc5d095c3f58e63ba96d26bbd36	wikidoc	Catatonia	Catatonia # Overview Catatonia is a syndrome of psychic and motoric disturbances. In the current Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association (DSM-V), catatonia became recognized as a separate disorder. Catatonia is also associated with psychiatric conditions such as schizophrenia (catatonic type), bipolar disorder, post-traumatic stress disorder, depression and other mental disorders, as well as drug abuse and/or overdose. It may also be seen in many medical disorders including infections (such as encephalitis), autoimmune disorders, focal neurologic lesions (including strokes), metabolic disturbances and abrupt or overly rapid withdrawal from benzodiazepines. It can be an adverse reaction to prescribed medication. It bears similarity to conditions such as encephalitis lethargica and neuroleptic malignant syndrome. There are a variety of treatments available, and depending on the case, one or more drugs may be used, including antipsychotics and benzodiazepines. # Clinical features Patients with catatonia may experience an extreme loss of motor ability or constant hyperactive motor activity. Catatonic patients will sometimes hold rigid poses for hours and will ignore any external stimuli. Patients with catatonic excitement can die of exhaustion if not treated. Patients may also show stereotyped, repetitive movements. They may show specific types of movement known as "waxy flexibility" in which they maintain positions after being placed in them by someone else, or gegenhalten (lit. "counterhold"), in which they resist movement in proportion to the force applied by the examiner. They may repeat meaningless phrases or speak only to repeat what the examiner says. ## Subtypes Stupor is a motionless, apathetic state in which one is oblivious or does not react to external stimuli. Motor activity is nearly non-existent. Individuals in this state make little or no eye contact with others and may be mute and rigid. One might remain in one position for a long period of time, and then go directly to another position immediately after the first position. Catatonic excitement is state of constant purposeless agitation and excitation. Individuals in this state are extremely hyperactive although the activity seems to lack purpose. # Causes ## Common Causes - Acute intermittent porphyria - Acute stress disorder - Addison's Disease - Alcohol intoxication - Anorexia nervosa - Arachnoid cyst in right parietal region - Astrocytoma - Autistic disorder - Bilateral hemorrhagic lesions of temporal lobes - Brain cyst - Brain disorders - Brain trauma - Brain tumour - Brief psychotic disorder - Bronchorrhea - Catatonic schizophrenia - Central pontine myelinolysis - Cerebellar catalepsy - Cerebral hemorrhage - Cerebral infarct - Cerebrovascular disease - Cns bleed - Conversion disorder - Cortical basal ganglionic degeneration - Cortical venous thrombosis - Delirium - Drug withdrawal - Dystonia - Emotional trauma - Encephalitis - Encephalopathy - Familial fatal insomnia - Frontal lobe brain damage - Frontal lobotomy - Head trauma - Heat stroke - Hepatic encephalopathy - Hepatic failure - Hereditary coproporphyria - Homocystinuria - Huntington's disease - Hydrocephalus - Hyperparathyroidism - Hyperthyroidism - Hyponatremia - Hypopituitarism secondary to postpartum hemorrhage - Hypothermia - Idiopathic recurring stupor - Inherited neurometabolic disorders - Intestinal atony - Locked-in syndrome - Lorazepam - Meningitis - Meningoencephalitis - Mental illness - Multiple sclerosis - Neoplasms - Neuroleptic malignant syndrome - Neurosyphilis - Nonconvulsive status epilepticus - Pallidoluysian atrophy - Paraneoplastic encephalitis - Parkinson's disease - Postencephalitic parkinsonism - Posttraumatic stress disorder - Presenile dementia, kraepelin type - catatonia - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Reactive psychosis - Schizencephaly - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Sedative withdrawal - Seizures - Sibutramine - Status epilepticus - Stiff-man syndrome - Stroke - Strychnine poisoning - Stupor - Subarachnoid hemorrhage - Subdural hematoma - Subthalamic mesencephalic tumor - Surgical removal of cerebellar tumor - Syndrome of inappropriate antidiuretic hormone (siadh) - Syphilis - Systemic lupus erythematosus - Tay-sachs disease - Temporal lobe epilepsy - Thrombotic thrombocytopenic purpura - Tuberculosis - Tuberous sclerosis - Tumors - Typhoid fever - Vegetative state - Viral encephalitis - Wilson's disease ## Causes by Organ System ## Causes in Alphabetical Order - Acute intermittent porphyria - Acute stress disorder - Addison's disease - Aids - Akinetic-rigid syndrome - Alcohol intoxication - Anorexia nervosa - Arachnoid cyst in right parietal region - Astrocytoma - Atrophy of left amygdala - Autistic disorder - Bacterial septicemia - Basilar artery thrombosis - Bilateral hemorrhagic lesions of temporal lobes - Brain cyst - Brain disorders - Brain trauma - Brain tumour - Brief psychotic disorder - Bronchorrhea - Carbon monoxide poisoning - Carcinoid tumors - Catatonic schizophrenia - Central pontine myelinolysis - Cerebellar catalepsy - Cerebral hemorrhage - Cerebral infarct - Cerebrovascular disease - Cns bleed - Conversion disorder - Cortical basal ganglionic degeneration - Cortical venous thrombosis - Delirium - Depression - Diabetic ketoacidosis - Drug withdrawal - Dystonia - Electrolyte imbalances - Emotional trauma - Encephalitis - Encephalopathy - Familial fatal insomnia - Fever - Fibromuscular dysplasia with dissection of basilar artery - Frontal lobe brain damage - Frontal lobotomy - Head trauma - Heat stroke - Hepatic encephalopathy - Hepatic failure - Hereditary coproporphyria - Homocystinuria - Huntington's disease - Hydrocephalus - Hypercalcemia - Hyperparathyroidism - Hyperthyroidism - Hyponatremia - Hypopituitarism secondary to postpartum hemorrhage - Hypothermia - Hysteria - Idiopathic recurring stupor - Inherited neurometabolic disorders - Intestinal atony - Locked-in syndrome - Lorazepam - Malaria - Malignant hyperthermia - Medications - Meningitis - Meningoencephalitis - Mental illness - Mood disorders - Multiple sclerosis - Neoplasms - Neuroleptic malignant syndrome - Neurosyphilis - Nonconvulsive status epilepticus - Pallidoluysian atrophy - Paraneoplastic encephalitis - Parkinson's disease - Pervasive developmental disorders - Poisoning - Postencephalitic parkinsonism - Posttraumatic stress disorder - Presenile dementia, kraepelin type - catatonia - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Reactive psychosis - Renal failure - Schizencephaly - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Sedative withdrawal - Seizures - Sibutramine - Status epilepticus - Stiff-man syndrome - Stroke - Strychnine poisoning - Stupor - Subarachnoid hemorrhage - Subdural hematoma - Substance intoxication - Subthalamic mesencephalic tumor - Surgical removal of cerebellar tumor - Syndrome of inappropriate antidiuretic hormone (siadh) - Syphilis - Systemic lupus erythematosus - Tay-sachs disease - Temporal lobe epilepsy - Tetanus - Thermal injury - Thrombotic thrombocytopenic purpura - Tuberculosis - Tuberous sclerosis - Tumors - Typhoid fever - Uremia - Vegetative state - Viral encephalitis - Wilson's disease # Catatonia Associated with Another Mental Disorder ## Risk Factors - Bipolar disorders - Depressive disorders - Schizophrenia ## Natural History, Complications and Prognosis Poor prognostic factors include: - Bipolar disorder - Depressive disorder - Mental disorder - Metabolic conditions - Infectious conditions - Psychotic disorder ## DSM-V Diagnostic Criteria for Catatonic Disorder Due to Another Medical Condition # Catatonia Due to Another Medical Condition ## Differential Diagnosis - Brief psychotic disorder - Cerebrovascular disease - Diabetic ketoacidosis - Encephalitis - Neoplasms - Head trauma - Hepatic encephalopathy - Hypercalcemia - Homocystinuria - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Substance/medication-induced psychotic disorder - Neuroleptic malignant syndrome - Neuroleptic-induced movement disorder ## DSM-V Diagnostic Criteria for Catatonia due to Another Medical Condition # Treatment Initial treatment is aimed at providing relief from the catatonic state. Benzodiazepines are the first line of treatment, and high doses are often required. A test dose of 1-2 mg intramuscular lorazepam will often result in marked improvement within half an hour. In France, zolpidem has also been used in diagnosis and response may occur within the same time period. Ultimately the underlying cause needs to be treated. Electroconvulsive therapy is an effective treatment for catatonia as well as for most of the underlying causes (e.g. psychosis, mania, depression). Antipsychotics should be used with care as they can worsen catatonia and are the cause of neuroleptic malignant syndrome, a dangerous condition that can mimic catatonia and requires the immediate discontinuation of the antipsychotic.	Catatonia Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2] Luke Rusowicz-Orazem, B.S. # Overview Catatonia is a syndrome of psychic and motoric disturbances. In the current Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association (DSM-V), catatonia became recognized as a separate disorder. Catatonia is also associated with psychiatric conditions such as schizophrenia (catatonic type), bipolar disorder, post-traumatic stress disorder, depression and other mental disorders, as well as drug abuse and/or overdose. It may also be seen in many medical disorders including infections (such as encephalitis), autoimmune disorders, focal neurologic lesions (including strokes), metabolic disturbances and abrupt or overly rapid withdrawal from benzodiazepines.[1] It can be an adverse reaction to prescribed medication. It bears similarity to conditions such as encephalitis lethargica and neuroleptic malignant syndrome. There are a variety of treatments available, and depending on the case, one or more drugs may be used, including antipsychotics and benzodiazepines. # Clinical features Patients with catatonia may experience an extreme loss of motor ability or constant hyperactive motor activity. Catatonic patients will sometimes hold rigid poses for hours and will ignore any external stimuli. Patients with catatonic excitement can die of exhaustion if not treated. Patients may also show stereotyped, repetitive movements. They may show specific types of movement known as "waxy flexibility" in which they maintain positions after being placed in them by someone else, or gegenhalten (lit. "counterhold"), in which they resist movement in proportion to the force applied by the examiner. They may repeat meaningless phrases or speak only to repeat what the examiner says. ## Subtypes Stupor is a motionless, apathetic state in which one is oblivious or does not react to external stimuli. Motor activity is nearly non-existent. Individuals in this state make little or no eye contact with others and may be mute and rigid. One might remain in one position for a long period of time, and then go directly to another position immediately after the first position. Catatonic excitement is state of constant purposeless agitation and excitation. Individuals in this state are extremely hyperactive although the activity seems to lack purpose. # Causes ## Common Causes - Acute intermittent porphyria - Acute stress disorder - Addison's Disease - Alcohol intoxication - Anorexia nervosa - Arachnoid cyst in right parietal region - Astrocytoma - Autistic disorder - Bilateral hemorrhagic lesions of temporal lobes - Brain cyst - Brain disorders - Brain trauma - Brain tumour - Brief psychotic disorder - Bronchorrhea - Catatonic schizophrenia - Central pontine myelinolysis - Cerebellar catalepsy - Cerebral hemorrhage - Cerebral infarct - Cerebrovascular disease - Cns bleed - Conversion disorder - Cortical basal ganglionic degeneration - Cortical venous thrombosis - Delirium - Drug withdrawal - Dystonia - Emotional trauma - Encephalitis - Encephalopathy - Familial fatal insomnia - Frontal lobe brain damage - Frontal lobotomy - Head trauma - Heat stroke - Hepatic encephalopathy - Hepatic failure - Hereditary coproporphyria - Homocystinuria - Huntington's disease - Hydrocephalus - Hyperparathyroidism - Hyperthyroidism - Hyponatremia - Hypopituitarism secondary to postpartum hemorrhage - Hypothermia - Idiopathic recurring stupor - Inherited neurometabolic disorders - Intestinal atony - Locked-in syndrome - Lorazepam - Meningitis - Meningoencephalitis - Mental illness - Multiple sclerosis - Neoplasms - Neuroleptic malignant syndrome - Neurosyphilis - Nonconvulsive status epilepticus - Pallidoluysian atrophy - Paraneoplastic encephalitis - Parkinson's disease - Postencephalitic parkinsonism - Posttraumatic stress disorder - Presenile dementia, kraepelin type - catatonia - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Reactive psychosis - Schizencephaly - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Sedative withdrawal - Seizures - Sibutramine - Status epilepticus - Stiff-man syndrome - Stroke - Strychnine poisoning - Stupor - Subarachnoid hemorrhage - Subdural hematoma - Subthalamic mesencephalic tumor - Surgical removal of cerebellar tumor - Syndrome of inappropriate antidiuretic hormone (siadh) - Syphilis - Systemic lupus erythematosus - Tay-sachs disease - Temporal lobe epilepsy - Thrombotic thrombocytopenic purpura - Tuberculosis - Tuberous sclerosis - Tumors - Typhoid fever - Vegetative state - Viral encephalitis - Wilson's disease ## Causes by Organ System ## Causes in Alphabetical Order - Acute intermittent porphyria - Acute stress disorder - Addison's disease - Aids - Akinetic-rigid syndrome - Alcohol intoxication - Anorexia nervosa - Arachnoid cyst in right parietal region - Astrocytoma - Atrophy of left amygdala - Autistic disorder - Bacterial septicemia - Basilar artery thrombosis - Bilateral hemorrhagic lesions of temporal lobes - Brain cyst - Brain disorders - Brain trauma - Brain tumour - Brief psychotic disorder - Bronchorrhea - Carbon monoxide poisoning - Carcinoid tumors - Catatonic schizophrenia - Central pontine myelinolysis - Cerebellar catalepsy - Cerebral hemorrhage - Cerebral infarct - Cerebrovascular disease - Cns bleed - Conversion disorder - Cortical basal ganglionic degeneration - Cortical venous thrombosis - Delirium - Depression - Diabetic ketoacidosis - Drug withdrawal - Dystonia - Electrolyte imbalances - Emotional trauma - Encephalitis - Encephalopathy - Familial fatal insomnia - Fever - Fibromuscular dysplasia with dissection of basilar artery - Frontal lobe brain damage - Frontal lobotomy - Head trauma - Heat stroke - Hepatic encephalopathy - Hepatic failure - Hereditary coproporphyria - Homocystinuria - Huntington's disease - Hydrocephalus - Hypercalcemia - Hyperparathyroidism - Hyperthyroidism - Hyponatremia - Hypopituitarism secondary to postpartum hemorrhage - Hypothermia - Hysteria - Idiopathic recurring stupor - Inherited neurometabolic disorders - Intestinal atony - Locked-in syndrome - Lorazepam - Malaria - Malignant hyperthermia - Medications - Meningitis - Meningoencephalitis - Mental illness - Mood disorders - Multiple sclerosis - Neoplasms - Neuroleptic malignant syndrome - Neurosyphilis - Nonconvulsive status epilepticus - Pallidoluysian atrophy - Paraneoplastic encephalitis - Parkinson's disease - Pervasive developmental disorders - Poisoning - Postencephalitic parkinsonism - Posttraumatic stress disorder - Presenile dementia, kraepelin type - catatonia - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Reactive psychosis - Renal failure - Schizencephaly - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Sedative withdrawal - Seizures - Sibutramine - Status epilepticus - Stiff-man syndrome - Stroke - Strychnine poisoning - Stupor - Subarachnoid hemorrhage - Subdural hematoma - Substance intoxication - Subthalamic mesencephalic tumor - Surgical removal of cerebellar tumor - Syndrome of inappropriate antidiuretic hormone (siadh) - Syphilis - Systemic lupus erythematosus - Tay-sachs disease - Temporal lobe epilepsy - Tetanus - Thermal injury - Thrombotic thrombocytopenic purpura - Tuberculosis - Tuberous sclerosis - Tumors - Typhoid fever - Uremia - Vegetative state - Viral encephalitis - Wilson's disease # Catatonia Associated with Another Mental Disorder ## Risk Factors - Bipolar disorders - Depressive disorders - Schizophrenia[2] ## Natural History, Complications and Prognosis Poor prognostic factors include: - Bipolar disorder - Depressive disorder - Mental disorder - Metabolic conditions - Infectious conditions - Psychotic disorder[2] ## DSM-V Diagnostic Criteria for Catatonic Disorder Due to Another Medical Condition[2] # Catatonia Due to Another Medical Condition ## Differential Diagnosis - Brief psychotic disorder - Cerebrovascular disease - Diabetic ketoacidosis - Encephalitis - Neoplasms - Head trauma - Hepatic encephalopathy - Hypercalcemia - Homocystinuria - Schizoaffective disorder - Schizophrenia - Schizophreniform disorder - Substance/medication-induced psychotic disorder - Neuroleptic malignant syndrome - Neuroleptic-induced movement disorder[2] ## DSM-V Diagnostic Criteria for Catatonia due to Another Medical Condition[2] # Treatment Initial treatment is aimed at providing relief from the catatonic state. Benzodiazepines are the first line of treatment, and high doses are often required. A test dose of 1-2 mg intramuscular lorazepam will often result in marked improvement within half an hour. In France, zolpidem has also been used in diagnosis and response may occur within the same time period. Ultimately the underlying cause needs to be treated. Electroconvulsive therapy is an effective treatment for catatonia as well as for most of the underlying causes (e.g. psychosis, mania, depression). Antipsychotics should be used with care as they can worsen catatonia and are the cause of neuroleptic malignant syndrome, a dangerous condition that can mimic catatonia and requires the immediate discontinuation of the antipsychotic.	https://www.wikidoc.org/index.php/Catatonia
942726f44ab413d10bb46bc7a4321026693eb281	wikidoc	Catharsis	Catharsis Catharsis (Template:Polytonic) is a Greek word meaning "purification" or "cleansing" derived from the ancient Greek gerund καθαίρειν transliterated as kathairein "to purify, purge," and adjective katharos "pure or clean" (ancient and modern Greek: καθαρός). # Dramaturgical uses The term in drama refers to a sudden emotional breakdown or climax that constitutes overwhelming feelings of great sorrow, pity, laughter or any extreme change in emotion that results in the restoration, renewal and revitalization for living. Using the term 'catharsis' to refer to a form of emotional cleansing was first done by the Greek philosopher Aristotle in his work Poetics. It refers to the sensation, or literary effect, that would ideally overcome an audience upon finishing watching a tragedy (a release of pent-up emotion or energy). In his previous works, he used the term in its medical sense (usually referring to the evacuation of the 'katamenia', the menstrual fluid or other reproductive material). Because of this, F. L. Lucas maintains that catharsis cannot be properly translated as purification or cleansing, but only as purgation. Since before Poetics catharsis was purely a medical term, Aristotle is employing it as a medical metaphor. "It is the human soul that is purged of its excessive passions.". Lessing sidesteps the medical aspect of the issue and translates catharsis as a purification, an experience that brings pity and fear into their proper balance: "In real life, he explained, men are sometimes too much addicted to pity or fear, sometimes too little; tragedy brings them back to a virtuous and happy mean.". Tragedy is then a corrective; through watching tragedy the audience learns how to feel these emotions at the proper levels. Some modern interpreters of the work infer that catharsis is pleasurable because audience members felt ekstasis (Greek: Template:Polytonic) (literally: astonishment, meaning: trance) from the fact that there existed those who could suffer a worse fate than them was to them a relief. Any translator attempting to interpret Aristotle's meaning of the term should take into account that Poetics is largely a response to Plato's claim that poetry encourages men to be hysterical and uncontrolled. In response to Plato, Aristotle maintains that poetry makes them less, not more, emotional, by giving a periodic and healthy outlet to their feelings. In literary aesthetics, catharsis is developed by the conjunction of stereotyped characters and unique or surprising actions. Throughout a play we do not expect the nature of a character to change significantly, rather pre-existing elements are revealed in a relatively straight-forward way as the character is confronted with unique actions in time. This can be clearly seen in Oedipus Rex where King Oedipus is confronted with ever more outrageous actions until emptying generated by the death of his mother-wife and his act of self-blinding. As a literary effect, catharsis should be compared with the equivalent effects for epic and poetic forms of kairosis and kenosis. In contemporary aesthetics catharsis may also refer to any emptying of emotion experienced by an audience in relation to drama. This exstasis can be perceived in comedy, melodrama and most other dramatic forms. Deliberate attempts, on political or aesthetic bases, to subvert the structure of catharsis in theatre have occurred. For example, Bertold Brecht viewed catharsis as a pap for the bourgeois theatre audience, and designed dramas which left significant emotions unresolved, as a way to force social action upon the audience. In Brecht's theory, the absence of a cathartic resolving action would require the audience to take political action in the real world in order to fill the emotional gap they experience. This technique can be seen as early as his agit-prop play The Measures Taken. # "Catharsis" before tragedy Catharsis before the sixth-century rise of tragedy is, for the Western World, essentially a historical footnote to the Aristotelian conception. The practice of purification did not yet appear in Homer, as later Greek commentators noted: the Aithiopis, an epic in the Trojan War cycle, narrates the purification of Achilles after his murder of Thersites. Catharsis describes the result of means taken to cleanse away blood-guilt—"blood is purified through blood" (Burkert 1992:56) a process in the development of Hellenic culture in which the oracle of Delphi took a prominent role. The classic example, of Orestes, belongs to tragedy, but the procedure given by Aeschylus is ancient: the blood of a sacrificed piglet is allowed to wash over the blood-polluted man, and running water washes away the blood. The identical ritual is represented, Burkert informs us (1992:57) on a krater found at Canicattini, to cure the daughters of Proetus of their madness, caused by some ritual transgression. To the question of whether the ritual procures atonement or just healing, Burkert answers: "To raise the question is to see the irrelevance of this distinction" (1992:57). The Greek nosos embraces both physical sickness and social ills. # Medical uses The term catharsis has been used for centuries as a medical term meaning a "purging." Most commonly in a medical context, it euphemistically refers to a purging of the bowels. A drug, herb, or other agent administered as a strong laxative is termed a cathartic. The term catharsis has also been adopted by modern psychotherapy, particularly Freudian psychoanalysis, to describe the act of expressing deep emotions often associated with events in the individual's past which have never before been adequately expressed. Catharsis is also an emotional release associated with talking about the underlying causes of a problem (it was first mentioned by Aristotle: catharsis associated with audience watching tragic plays) It can also describe the effect producing an outlet for violence by acting as a form of release for violent behaviour. For example in forms of media or in a dream. # Religion Another meaning under the heading of 'purging' can concern body and soul — in it concerns efforts made to come to terms with guilt and sin, penance such as by chastisement (in modern use of that word, the meaning of punishment has taken over from the original sense of purification), such as practiced by flagellants; a testimony to the age of this use is the very name of the Cathars (a medieval sect). In Mysticism, the end of human life and of philosophy is to realize the mystical return of the soul to God. Freeing itself from the sensuous world by katharsis, the purified human soul ascends by successive steps through the various degrees of the metaphysical order, until it unites itself in a clear and completely conscious contemplation to the One, and unifies into the state of ecstasis. Thus in the neo-Platonism of Plotinus, the first step in the return of the soul to God is the act by which the soul, withdrawing from the world of sense by a process of purification (katharsis), frees itself from the trammels of matter. A point to note here is that psychology and philosophy were not separate in Classical Philosophy (Greek through Roman period). Thus in classical mysticism, as well as current mystical traditions, katharsis is a process leading to the transcending of psychological, as well as spiritual, traumas and negativities. ## Cathartic Sacrifice In early cults, the distinction between sacred and unclean is far from complete or well defined (see Taboo); consequently we find two types of cathartic sacrifice: one to cleanse of impurity and make fit for common use, another to rid of sanctity and in like manner render suitable for human use or intercourse. - The most conspicuous example of the first class is the scapegoat. Two goats were provided by the ancient Hebrews on the Day of Atonement; the high priest sent one into the desert, after confessing on it the sins of Israel; it was not permitted to run free but was probably cast over a precipice; the other was sacrificed as a sin-offering. In like manner in the purification of lepers two birds were used; the throat of one was cut, the living bird dipped in the blood mingled with water and the leper sprinkled; then the bird was set free to carry away the leprosy. In both these rites we seem to have a duplication of ritual, and the parallelism of sacrifice and liberation is clear. - As an example of the second class may be taken the sacrifice of the bull to the Rigvedic god Rudra. MM. Hubert and Mauss interpret this to mean that the sanctity of the remainder of the herd was concentrated on a single animal; the god, incarnate in the herd, was eliminated by the sacrifice, and the cattle saved from the dangers to which their association with the god exposed them. The Feast of First fruits is another example of the same sort; comparable with this concentration of holiness is the respect or veneration shown to a single animal as representative of its species (see animal worship). In both these cases the object of the rite is the elimination of impurity or of a source of danger. But the Nazarite was equally bound to lay aside his holiness before mixing with common folk and returning to ordinary life; this he did by a sacrifice, which, with the offering of his hair upon the altar, freed him from his vow and reduced him to the same level of sanctity as ordinary men.	Catharsis Catharsis (Template:Polytonic) is a Greek word meaning "purification" or "cleansing" derived from the ancient Greek gerund καθαίρειν transliterated as kathairein "to purify, purge," and adjective katharos "pure or clean" (ancient and modern Greek: καθαρός). # Dramaturgical uses The term in drama refers to a sudden emotional breakdown or climax that constitutes overwhelming feelings of great sorrow, pity, laughter or any extreme change in emotion that results in the restoration, renewal and revitalization for living. Using the term 'catharsis' to refer to a form of emotional cleansing was first done by the Greek philosopher Aristotle in his work Poetics. It refers to the sensation, or literary effect, that would ideally overcome an audience upon finishing watching a tragedy (a release of pent-up emotion or energy). In his previous works, he used the term in its medical sense (usually referring to the evacuation of the 'katamenia', the menstrual fluid or other reproductive material).[1] Because of this, F. L. Lucas maintains that catharsis cannot be properly translated as purification or cleansing, but only as purgation. Since before Poetics catharsis was purely a medical term, Aristotle is employing it as a medical metaphor. "It is the human soul that is purged of its excessive passions.".[2] Lessing sidesteps the medical aspect of the issue and translates catharsis as a purification, an experience that brings pity and fear into their proper balance: "In real life, he explained, men are sometimes too much addicted to pity or fear, sometimes too little; tragedy brings them back to a virtuous and happy mean.".[3] Tragedy is then a corrective; through watching tragedy the audience learns how to feel these emotions at the proper levels. Some modern interpreters of the work infer that catharsis is pleasurable because audience members felt ekstasis (Greek: Template:Polytonic) (literally: astonishment, meaning: trance) from the fact that there existed those who could suffer a worse fate than them was to them a relief[citation needed]. Any translator attempting to interpret Aristotle's meaning of the term should take into account that Poetics is largely a response to Plato's claim that poetry encourages men to be hysterical and uncontrolled. In response to Plato, Aristotle maintains that poetry makes them less, not more, emotional, by giving a periodic and healthy outlet to their feelings. In literary aesthetics, catharsis is developed by the conjunction of stereotyped characters and unique or surprising actions. Throughout a play we do not expect the nature of a character to change significantly, rather pre-existing elements are revealed in a relatively straight-forward way as the character is confronted with unique actions in time. This can be clearly seen in Oedipus Rex where King Oedipus is confronted with ever more outrageous actions until emptying generated by the death of his mother-wife and his act of self-blinding. As a literary effect, catharsis should be compared with the equivalent effects for epic and poetic forms of kairosis and kenosis. In contemporary aesthetics catharsis may also refer to any emptying of emotion experienced by an audience in relation to drama. This exstasis can be perceived in comedy, melodrama and most other dramatic forms. Deliberate attempts, on political or aesthetic bases, to subvert the structure of catharsis in theatre have occurred. For example, Bertold Brecht viewed catharsis as a pap for the bourgeois theatre audience, and designed dramas which left significant emotions unresolved, as a way to force social action upon the audience. In Brecht's theory, the absence of a cathartic resolving action would require the audience to take political action in the real world in order to fill the emotional gap they experience. This technique can be seen as early as his agit-prop play The Measures Taken. # "Catharsis" before tragedy Catharsis before the sixth-century rise of tragedy is, for the Western World, essentially a historical footnote to the Aristotelian conception. The practice of purification did not yet appear in Homer, as later Greek commentators noted:[4] the Aithiopis, an epic in the Trojan War cycle, narrates the purification of Achilles after his murder of Thersites. Catharsis describes the result of means taken to cleanse away blood-guilt—"blood is purified through blood" (Burkert 1992:56) a process in the development of Hellenic culture in which the oracle of Delphi took a prominent role. The classic example, of Orestes, belongs to tragedy, but the procedure given by Aeschylus is ancient: the blood of a sacrificed piglet is allowed to wash over the blood-polluted man, and running water washes away the blood.[5] The identical ritual is represented, Burkert informs us (1992:57) on a krater found at Canicattini, to cure the daughters of Proetus of their madness, caused by some ritual transgression. To the question of whether the ritual procures atonement or just healing, Burkert answers: "To raise the question is to see the irrelevance of this distinction" (1992:57). The Greek nosos embraces both physical sickness and social ills. # Medical uses The term catharsis has been used for centuries as a medical term meaning a "purging." Most commonly in a medical context, it euphemistically refers to a purging of the bowels. A drug, herb, or other agent administered as a strong laxative is termed a cathartic. The term catharsis has also been adopted by modern psychotherapy, particularly Freudian psychoanalysis, to describe the act of expressing deep emotions often associated with events in the individual's past which have never before been adequately expressed. Catharsis is also an emotional release associated with talking about the underlying causes of a problem (it was first mentioned by Aristotle: catharsis associated with audience watching tragic plays) It can also describe the effect producing an outlet for violence by acting as a form of release for violent behaviour. For example in forms of media or in a dream. # Religion Another meaning under the heading of 'purging' can concern body and soul — in it concerns efforts made to come to terms with guilt and sin, penance such as by chastisement (in modern use of that word, the meaning of punishment has taken over from the original sense of purification), such as practiced by flagellants; a testimony to the age of this use is the very name of the Cathars (a medieval sect). In Mysticism, the end of human life and of philosophy is to realize the mystical return of the soul to God. Freeing itself from the sensuous world by katharsis, the purified human soul ascends by successive steps through the various degrees of the metaphysical order, until it unites itself in a clear and completely conscious contemplation to the One, and unifies into the state of ecstasis. Thus in the neo-Platonism of Plotinus, the first step in the return of the soul to God is the act by which the soul, withdrawing from the world of sense by a process of purification (katharsis), frees itself from the trammels of matter. A point to note here is that psychology and philosophy were not separate in Classical Philosophy (Greek through Roman period). Thus in classical mysticism, as well as current mystical traditions, katharsis is a process leading to the transcending of psychological, as well as spiritual, traumas and negativities. ## Cathartic Sacrifice In early cults, the distinction between sacred and unclean is far from complete or well defined (see Taboo); consequently we find two types of cathartic sacrifice: one to cleanse of impurity and make fit for common use, another to rid of sanctity and in like manner render suitable for human use or intercourse. - The most conspicuous example of the first class is the scapegoat. Two goats were provided by the ancient Hebrews on the Day of Atonement; the high priest sent one into the desert, after confessing on it the sins of Israel; it was not permitted to run free but was probably cast over a precipice; the other was sacrificed as a sin-offering. In like manner in the purification of lepers two birds were used; the throat of one was cut, the living bird dipped in the blood mingled with water and the leper sprinkled; then the bird was set free to carry away the leprosy. In both these rites we seem to have a duplication of ritual, and the parallelism of sacrifice and liberation is clear. - As an example of the second class may be taken the sacrifice of the bull to the Rigvedic god Rudra. MM. Hubert and Mauss interpret this to mean that the sanctity of the remainder of the herd was concentrated on a single animal; the god, incarnate in the herd, was eliminated by the sacrifice, and the cattle saved from the dangers to which their association with the god exposed them. The Feast of First fruits is another example of the same sort; comparable with this concentration of holiness is the respect or veneration shown to a single animal as representative of its species (see animal worship). In both these cases the object of the rite is the elimination of impurity or of a source of danger. But the Nazarite was equally bound to lay aside his holiness before mixing with common folk and returning to ordinary life; this he did by a sacrifice, which, with the offering of his hair upon the altar, freed him from his vow and reduced him to the same level of sanctity as ordinary men.	https://www.wikidoc.org/index.php/Catharsis
7a2e1724d9857121e4d8b1aae948ecbdd88a4f54	wikidoc	Cathartic	Cathartic # Overview In medicine, a cathartic is a substance which accelerates defecation. This is in contrast to a laxative, which is a substance which eases defecation, usually by softening the stool. It is possible for a substance to be both a laxative and a cathartic. However, agents such as psyllium seed husks increase the bulk of the stool. Cathartics such as sorbitol are sometimes used in response to poisoning. As an adjective, cathartic means psychotherapeutic, healthful, emotionally beneficial; releasing; emotionally purging: viewing art or listening to music may be a kind of cathartic experience. In general cathartics are; - causing emptying of the bowels. - an agent that empties the bowels. - producing emotional catharsis. - bulk cathartic one stimulating bowel evacuation by increasing fecal volume. - lubricant cathartic one that acts by softening the feces and reducing friction between them and the intestinal wall. - saline cathartic one that increases fluidity of intestinal contents by retention of water by osmotic forces and indirectly increases motor activity. - stimulant cathartic one that directly increases motor activity of the intestinal tract.	Cathartic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In medicine, a cathartic is a substance which accelerates defecation. This is in contrast to a laxative, which is a substance which eases defecation, usually by softening the stool.[1] It is possible for a substance to be both a laxative and a cathartic. However, agents such as psyllium seed husks increase the bulk of the stool.[2] Cathartics such as sorbitol are sometimes used in response to poisoning.[3] As an adjective, cathartic means psychotherapeutic, healthful, emotionally beneficial; releasing; emotionally purging: viewing art or listening to music may be a kind of cathartic experience. In general cathartics are; - causing emptying of the bowels. - an agent that empties the bowels. - producing emotional catharsis. - bulk cathartic one stimulating bowel evacuation by increasing fecal volume. - lubricant cathartic one that acts by softening the feces and reducing friction between them and the intestinal wall. - saline cathartic one that increases fluidity of intestinal contents by retention of water by osmotic forces and indirectly increases motor activity. - stimulant cathartic one that directly increases motor activity of the intestinal tract.	https://www.wikidoc.org/index.php/Cathartic
00b727108d28471342bb34713f928ca16d53d5d0	wikidoc	Causality	Causality # Overview Causality or causation denotes a logical relationship between one event (called cause) and another event (called effect) which is the direct consequence (result) of the first. While this informal understanding will suffice in everyday usage, the philosophical analysis of causality or causation has proved exceedingly difficult. The work of philosophers to understand causality and how best to characterize it extends over millennia. In the western philosophical tradition explicit discussion stretches back at least as far as Aristotle, and the topic remains a staple in contemporary philosophy journals. Though cause and effect are typically related to events, other candidates include processes, properties, variables, facts, and states of affairs; which of these comprise the correct causal relata, and how best to characterize the nature of the relationship between them, has as yet no universally accepted answer, and remains under discussion. According to Sowa (2000), up until the twentieth century, three assumptions described by Max Born in 1949 were dominant in the definition of causality: - "Causality postulates that there are laws by which the occurrence of an entity B of a certain class depends on the occurrence of an entity A of another class, where the word entity means any physical object, phenomenon, situation, or event. A is called the cause, B the effect. - "Antecedence postulates that the cause must be prior to, or at least simultaneous with, the effect. - "Contiguity postulates that cause and effect must be in spatial contact or connected by a chain of intermediate things in contact." (Born, 1949, as cited in Sowa, 2000) However, according to Sowa (2000), "relativity and quantum mechanics have forced physicists to abandon these assumptions as exact statements of what happens at the most fundamental levels, but they remain valid at the level of human experience." It should be noted here, however, that physicists themselves never denied causality or stated that causality is violated in quantum mechanics or relativity. Vice versa, any experiment designed to show violation of causality so far failed to do so. # History ## Western philosophy ### Aristotle In his Posterior Analytics and Metaphysics, Aristotle wrote, "All causes are beginnings...", "... we have scientific knowledge when we know the cause...", and "... to know a thing's nature is to know the reason why it is..." This formulation set the guidelines for subsequent causal theories by specifying the number, nature, principles, elements, varieties, order of causes as well as the modes of causation. Aristotle's account of the causes of things is a comprehensive model. Aristotle's theory enumerates the possible causes which fall into several wide groups, amounting to the ways the question "why" may be answered; namely, by reference to the material worked upon (as by an artisan) or what might be called the substratum; to the essence, i.e., the pattern, the form, or the structure by reference to which the "matter" or "substratum" is to be worked; to the primary moving agent of change or the agent and its action; and to the goal, the plan, the end, or the good that the figurative artisan intended to obtain. As a result, the major kinds of causes come under the following divisions: - The material cause is that "raw material" from which a thing is produced as from its parts, constituents, substratum, or materials. This rubric limits the explanation of cause to the parts (the factors, elements, constituents, ingredients) forming the whole (the system, structure, compound, complex, composite, or combination) (the part-whole causation). - The formal cause tells us what, by analogy to the plans of an artisan, a thing is intended and planned to be. Any thing is thought to be determined by its definition, form (mold), pattern, essence, whole, synthesis, or archetype. This analysis embraces the account of causes in terms of fundamental principles or general laws, as the intended whole (macrostructure) is the cause that explains the production of its parts (the whole-part causation). - The efficient cause is that external entity from which the change or the ending of the change first starts. It identifies 'what makes of what is made and what causes change of what is changed' and so suggests all sorts of agents, nonliving or living, acting as the sources of change or movement or rest. Representing the current understanding of causality as the relation of cause and effect, this analysis covers the modern definitions of "cause" as either the agent, agency, particular causal events, or the relevant causal states of affairs. - The final cause is that for the sake of which a thing exists, or is done - including both purposeful and instrumental actions. The final cause, or telos, is the purpose, or end, that something is supposed to serve; or it is that from which, and that to which, the change is. This analysis also covers modern ideas of mental causation involving such psychological causes as volition, need, motivation, or motives; rational, irrational, ethical - all that gives purpose to behavior. Additionally, things can be causes of one another, reciprocally causing each other, as hard work causes fitness, and vice versa - although not in the same way or by means of the same function: the one is as the beginning of change, the other is as its goal. (Thus Aristotle first suggested a reciprocal or circular causality - as a relation of mutual dependence, action, or influence of cause and effect.) Also; Aristotle indicated that the same thing can be the cause of contrary effects - as its presence and absence may result in different outcomes. In speaking thus he formulated what currently is ordinarily termed a "causal factor," e.g., atmospheric pressure as it affects chemical or physical reactions. Aristotle marked two modes of causation: proper (prior) causation and accidental (chance) causation. All causes, proper and incidental, can be spoken as potential or as actual, particular or generic. The same language refers to the effects of causes; so that generic effects assigned to generic causes, particular effects to particular causes, and operating causes to actual effects. It is also essential that ontological causality does not suggest the temporal relation of before and after - between the cause and the effect; that spontaneity (in nature) and chance (in the sphere of moral actions) are among the causes of effects belonging to the efficient causation, and that no incidental, spontaneous, or chance cause can be prior to a proper, real, or underlying cause per se. All investigations of causality coming later in history will consist in imposing a favorite hierarchy on the order (priority) of causes; such as "final > efficient > material > formal" (Aquinas), or in restricting all causality to the material and efficient causes or, to the efficient causality (deterministic or chance), or just to regular sequences and correlations of natural phenomena (the natural sciences describing how things happen rather than asking why they happen). ### Causality, determinism, and existentialism The deterministic world-view is one in which the universe is no more than a chain of events following one after another according to the law of cause and effect. To hold this worldview, as an incompatibilist, there is no such thing as "free will". However, compatibilists argue that determinism is compatible with, or even necessary for, free will. Learning to bear the burden of a meaningless universe, and justify one's own existence, is the first step toward becoming the "Übermensch" (English: "overman" or "superman") that Nietzsche speaks of extensively in his philosophical writings. Existentialists have suggested that people have the courage to accept that while no meaning has been designed in the universe, we each can provide a meaning for ourselves. Though philosophers have pointed out the difficulties in establishing theories of the validity of causal relations, there is yet the plausible example of causation afforded daily which is our own ability to be the cause of events. This concept of causation does not prevent seeing ourselves as moral agents. ## Indian philosophy Theories of causality in Indian philosophy focus mainly on the relationship between cause and effect. The various philosophical schools (darsanas) provide different theories. The doctrine of satkaryavada affirms that the effect inheres in the cause in some way. The effect is thus either a real or apparent modification of the cause. The doctrine of asatkaryavada affirms that the effect does not inhere in the cause, but is a new arising. Among the Buddhist thinkers, Nagarjuna uses a variety of arguments to deny the validity of the cause and effect relationship. See Nyaya for some details of the theory of causation in the Nyaya school. # Logic ## Necessary and sufficient causes Causes are often distinguished into two types: Necessary and sufficient. Necessary causes: If x is a necessary cause of y, then the presence of y necessarily implies the presence of x. The presence of x, however, does not imply that y will occur. Sufficient causes: If x is a sufficient cause of y, then the presence of x necessarily implies the presence of y. However, another cause z may alternatively cause y. Thus the presence of y does not imply the presence of x. J. L. Mackie argues that usual talk of "cause", in fact, refers to INUS conditions (insufficient and non-redundant parts of unnecessary but sufficient causes). For example; consider the short circuit as a cause of the house burning down. Consider the collection of events, the short circuit, the proximity of flammable material, and the absence of firefighters. Considered together these are unnecessary but sufficient to the house's destruction (since many other collection of events certainly could have destroyed the house). Within this collection; the short circuit is an insufficient but non-redundant part (since the short circuit by itself would not cause the fire, but the fire will not happen without it with everything else being equal). So the short circuit is an INUS cause of the house burning down. ## Causality contrasted with conditionals Conditional statements are not statements of causality. Perhaps the most important distinction is that statements of causality require the antecedent to precede the consequent in time, whereas this temporal order is not required by a conditional statement. Since many different statements may be presented using "If...then..." in English (and, arguably, because this form is far more commonly used to make a statement of causality), they are commonly confused; they are distinct, however. For example all of the following statements are true interpreting "If... then..." as the material conditional: - If George Bush was president of the United States in 2004, then Germany is in Europe. - If George Washington was president of the United States in 2004, then Germany is in Europe. - If George Washington was president of the United States in 2004, then Germany is not in Europe. The first is true since both the antecedent and the consequent are true. The second is true because the antecedent is false and the consequent is true. The third is true because both the consequent and antecedent are both false. These statement are trivial examples. Of course, none of these statements express a causal connection between the antecedent and consequent, but they are true because they do not have the combination of having both true antecedent and false consequent. The ordinary indicative conditional seems to have some more structure than the material conditional - for instance, none of the three statements above seem to be correct under an ordinary indicative reading, though the first is closest. But the sentence - If Shakespeare of Stratford on Avon didn't write Macbeth then someone else did. seems to be true, even though there is no straightforward causal relation (in this hypothetical situation) between Shakespeare's not writing Macbeth and someone else's actually writing it. Another sort of conditional, known as the counterfactual conditional has a stronger connection with causality. However, not even all counterfactual statements count as examples of causality. Consider the following two statements: - If A were a triangle, then A would have three sides. - If switch S were thrown, then bulb B would light. In the first case it would not be correct to say that A's being a triangle caused it to have three sides, since the relationship between triangularity and three-sidedness is one of definition. It is actually the three sides that determine A's state as a triangle. Nonetheless, even interpreted counterfactually, the first statement is true. It is probably important to fully grasp the concept of conditionals before the literature on causality can be understood. A crucial stumbling block is that, in everyday usage, conditionals are usually used to describe a general situation. For example "if I drop my coffee, then my shoe gets wet" relates an infinite number of possible events; it is shorthand for "for any fact that would count as 'dropping my coffee', some fact that counts as 'my shoe gets wet' will be true". This general statement will be strictly false if there is any circumstance where I drop my coffee and my shoe doesn't get wet. However, an "if... then..." statement in logic typically relates two specific events or facts - a specific coffee-dropping did or did not occur, and a specific shoe-wetting did or did not follow. Thus, with explicit events in mind, if I drop my coffee and wet my shoe then it is true that "if I dropped my coffee then I wet my shoe", regardless of the fact that yesterday I dropped a coffee in the trash for the opposite effect - the conditional relates to specific facts. More counter-intuitively, if I didn't drop my coffee at all then it is also true that "if I drop my coffee then I wet my shoe", or "dropping my coffee implies I wet my shoe", regardless of whether I wet my shoe or not by any means. This usage would not be counter-intuitive if it weren't for the everyday usage. Briefly, "if X then Y" is equivalent to the first-order logic statement "A implies B" or "not B-and-not-A", where A and B are predicates, but the more familiar usage of an "if A then B" statement would need to be written symbolically using a higher order logic using quantifiers ("for all" and "there exists"). # Theories ## Counterfactual theories The philosopher David Lewis notably suggested that all statements about causality can be understood as counterfactual statements. So, for instance, the statement that John's smoking caused his premature death is equivalent to saying that had John not smoked he would not have prematurely died. (In addition, it need also be true that John did smoke and did prematurely die, although this requirement is not unique to Lewis' theory.) However, simple logics prove this to be false: the proposition p → q (John smoked, therefore he died prematurely) is logically equivalent to ¬q → ¬p (John did not die prematurely, therefore he did not smoke) (We can also say that p → q ¬q → ¬p, meaning that p → q is logically equivalent to ¬q → ¬p, is a tautology). Saying that John didn't smoke, and therefore didn't die prematurely (¬p → ¬q) is a proposition that cannot be deduced from p → q without extra information. Translating causal into counterfactual statements would only be beneficial if the latter were less problematic than the former. This is indeed the case, as is demonstrated by the structural account of counterfactual conditionals devised by the computer scientist Judea Pearl (2000). This account provides clear semantics and effective algorithms for computing counterfactuals which, in contrast to Lewis' closest world semantics does not rely on the ambiguous notion of similarity among worlds. For instance, one can compute unambiguously the probability that John would be alive had he not smoked given that, in reality, John did smoke and did die. The quest for a counterfactual interpretation of causal statements is therefore justified. One problem Lewis' theory confronts is causal preemption. Suppose that John did smoke and did in fact die as a result of that smoking. However, there was a murderer who was bent on killing John, and would have killed him a second later had he not first died from smoking. Here we still want to say that smoking caused John's death. This presents a problem for Lewis' theory since, had John not smoked, he still would have died prematurely. Lewis himself discusses this example, and it has received substantial discussion (cf.). A structural solution to this problem has been given in . ## Probabilistic causation Interpreting causation as a deterministic relation means that if A causes B, then A must always be followed by B. In this sense, war does not cause deaths, nor does smoking cause cancer. As a result, many turn to a notion of probabilistic causation. Informally, A probabilistically causes B if A's occurrence increases the probability of B. This is sometimes interpreted to reflect imperfect knowledge of a deterministic system but other times interpreted to mean that the causal system under study has an inherently chancy nature. ## Causal Calculus When experiments are infeasible or illegal, the derivation of cause effect relationship from observational studies must rest on some qualitative theoretical assumptions, for example, that symptoms do not cause diseases, usually expressed in the form of missing arrows in causal graphs such as Bayesian Networks or path diagrams. The mathematical theory underlying these derivations relies on the distinction between conditional probabilities, as in P(cancer\|smoking), and interventional probabilities, as in P(cancer\|do(smoking)). The former reads: "the probability of finding cancer in a person known to smoke" while the latter reads: "the probability of finding cancer in a person forced to smoke". The former is a statistical notion that can be estimated directly in observational studies, while the latter is a causal notion (also called "causal effect") which is what we estimate in a controlled randomized experiment. The theory of "causal calculus" permits one to infer interventional probabilities from conditional probabilities in causal Bayesian Networks with unmeasured variables. One very practical result of this theory is the characterization of confounding variables, namely, a sufficient set of variables that, if adjusted for, would yield the correct causal effect between variables of interest. It can be shown that a sufficient set for estimating the causal effect of X on Y is any set of non-descendants of X that d-separate X from Y after removing all arrows emanating from X. This criterion, called "backdoor", provides a mathematical definition of "confounding" and helps researchers identify accessible sets of variables worthy of measurement. ## Structure Learning While derivations in Causal Calculus rely on the structure of the causal graph, parts of the causal structure can, under certain assumptions, be learned from statistical data. The basic idea goes back to a recovery algorithm developed by Rebane and Pearl (1987) and rests -n the distinction between the three possible types of causal substructures allowed in a directed acyclic graph (DAG): - X \rightarrow Y \rightarrow Z - X \leftarrow Y \rightarrow Z - X \rightarrow Y \leftarrow Z Type 1 and type 2 represent the same statistical dependencies (i.e., X and Z are independent given Y) and are, therefore, indistinguishable. Type 3, however, can be uniquely identified, since X and Z are marginally independent and all other pairs are dependent. Thus, while the skeletons (the graphs stripped -f arrows) of these three triplets are identical, the directionality -f the arrows is partially identifiable. The same distinction applies when X and Z have common ancestors, except that one must first condition on those ancestors. Algorithms have been developed to systematically determine the skeleton of the underlying graph and, then, orient all arrows whose directionality is dictated by the conditional independencies observed Alternative methods of structure learning search through the many possible causal structures among the variables, and remove ones which are strongly incompatible with the observed correlations. In general this leaves a set of possible causal relations, which should then be tested by designing appropriate experiments. If experimental data is already available, the algorithms can take advantage of that as well. In contrast with Bayesian Networks, path analysis and its generalization, structural equation modeling, serve better to estimate a known causal effect or test a causal model than to generate causal hypotheses. For nonexperimental data, causal direction can be hinted if information about time is available. This is because (according to many, though not all, theories) causes must precede their effects temporally. This can be set up by simple linear regression models, for instance, with an analysis of covariance in which baseline and follow up values are known for a theorized cause and effect. The addition of time as a variable, though not proving causality, is a big help in supporting a pre-existing theory of causal direction. For instance, our degree of confidence in the direction and nature of causality is much greater when supported by data from a longitudinal study than by data from a cross-sectional study. ## Derivation theories The Nobel Prize holder Herbert Simon and Philosopher Nicholas Rescher claim that the asymmetry of the causal relation is unrelated to the asymmetry of any mode of implication that contraposes. Rather, a causal relation is not a relation between values of variables, but a function of one variable (the cause) on to another (the effect). So, given a system of equations, and a set of variables appearing in these equations, we can introduce an asymmetric relation among individual equations and variables that corresponds perfectly to our commonsense notion of a causal ordering. The system of equations must have certain properties, most importantly, if some values are chosen arbitrarily, the remaining values will be determined uniquely through a path of serial discovery that is perfectly causal. They postulate the inherent serialization of such a system of equations may correctly capture causation in all empirical fields, including physics and economics. ## Manipulation theories Some theorists have equated causality with manipulability. Under these theories, x causes y just in case one can change x in order to change y. This coincides with commonsense notions of causations, since often we ask causal questions in order to change some feature of the world. For instance, we are interested in knowing the causes of crime so that we might find ways of reducing it. These theories have been criticized on two primary grounds. First, theorists complain that these accounts are circular. Attempting to reduce causal claims to manipulation requires that manipulation is more basic than causal interaction. But describing manipulations in non-causal terms has provided a substantial difficulty. The second criticism centers around concerns of anthropocentrism. It seems to many people that causality is some existing relationship in the world that we can harness for our desires. If causality is identified with our manipulation, then this intuition is lost. In this sense, it makes humans overly central to interactions in the world. Some attempts to save manipulability theories are recent accounts that don't claim to reduce causality to manipulation. These account use manipulation as a sign or feature in causation without claiming that manipulation is more fundamental than causation. ## Process theories Some theorists are interested in distinguishing between causal processes and non-causal processes (Russell 1948; Salmon 1984). These theorists often want to distinguish between a process and a pseudo-process. As an example, a ball moving through the air (a process) is contrasted with the motion of a shadow (a pseudo-process). The former is causal in nature while the latter is not. Salmon (1984) claims that causal processes can be identified by their ability to transmit an alteration over space and time. An alteration of the ball (a mark by a pen, perhaps) is carried with it as the ball goes through the air. On the other hand an alteration of the shadow (insofar as it is possible) will not be transmitted by the shadow as it moves along. These theorists claim that the important concept for understanding causality is not causal relationships or causal interactions, but rather identifying causal processes. The former notions can then be defined in terms of causal processes. # Fields ## Science Using the scientific method, scientists set up experiments to determine causality in the physical world. In addition, many scientists in a variety of fieldsTemplate:Specify disagree that experiments are necessary to determine causality. For example, the link between smoking and lung cancer is considered proven by health agencies of the United States government, but experimental methods (for example, randomized controlled trials) were not used to establish that link. This view has been controversial. In addition, many philosophers are beginning to turn to more relativized notions of causality. Rather than providing a theory of causality in toto, they opt to provide a theory of causality in biology or causality in physics. ### Physics Physicists conclude that certain elemental forces: gravity, the strong and weak nuclear forces, and electromagnetism are said to be the four fundamental forces which are the causes of all other events in the universe. Causality is hard to interpret to ordinary language from many different physical theories. One problem is typified by the moon's gravity. It isn't accurate to say, "the moon exerts a gravitic pull and then the tides rise." In Newtonian mechanics gravity, rather, is a law expressing a constant observable relationship among masses, and the movement of the tides is an example of that relationship. There are no discrete events or "pulls" that can be said to precede the rising of tides. Interpreting gravity causally is even more complicated in general relativity. Another important implication of Causality in physics is its intimate connection to the Second Law of Thermodynamics (see the fluctuation theorem). Quantum mechanics is yet another branch of physics in which the nature of causality is somewhat unclear. The treatment of the concept of causality within the Second Law of Thermodynamics yields a loss in the translation. The statistical basis of the maintenance of the exchange of entropy confines the subject to an extent such that the observer loses perspective. The 2nd Law states that "in a closed system, disorder increases". This is a corollary of the concept that an effect cannot be greater than the cause. Consider information content. Applying the 2nd Law, the information content in a closed system cannot increase. If the boundaries of the system are penetrated then a system can increase in information content but the loss is felt elsewhere. Strict adherence to the principles of the second law preclude boundary violation. However, this is not to say a closed system cannot increase in order locally. Take AI for example. The 2nd law does not preclude the existence of an artificial intelligence capable of growing greater than its creator since energy must constantly be supplied to the system. In physics matter and energy are considered forms of information. Thus, the AI could grow in order and comlexity, but only at the expense of an equal or greater increase in entropy in the form of dissipated energy, allowing the system to increase in disorder globally. ### Engineering A causal system is a system with output and internal states that depends only on the current and previous input values. A system that has some dependence on input values from the future (in addition to possible past or current input values) is termed an acausal system, and a system that depends solely on future input values is an anticausal system. Acausal filters, for example, can only exist as digital filters, because these filters can extract future values from a memory buffer or a file. ## Biology and medicine A. B. Hill built upon the work of Hume and Popper and suggested that the following aspects of an association be considered in attempting to distinguish causal from noncausal associations: 1) strength, 2) consistency, 3) specificity, 4) temporality, 5) biological gradient, 6) plausibility, 7) coherence, 8) experimental evidence, and 9) analogy. ### Psychology The above theories are attempts to define a reflectively stable notion of causality. This process uses our standard causal intuitions to develop a theory that we would find satisfactory in identifying causes. Another avenue of research is to empirically investigate how people (and non-human animals) learn and reason about causal relations in the world. This approach is taken by work in psychology. It also is possible to tackle causalities in surveys with a technique of elaboration. Given a relationship between two variables, what can be learned by introducing a third variable into the analysis (Rosenberg, 1968, xiii)? So elaboration is a device of the analysis that results in different kinds of relationships between variables e.g. suppression, extraneous, and distorter relations. Attribution Attribution theory is the theory concerning how people explain individual occurrences of causation. Attribution can be external (assigning causality to an outside agent or force - claiming that some outside thing motivated the event) or internal (assigning causality to factors within the person - taking personal responsibility or accountability for one's actions and claiming that the person was directly responsible for the event). Taking causation one step further, the type of attribution a person provides influences their future behavior. The intention behind the cause or the effect can be covered by the subject of action (philosophy). See also accident; blame; intent; and responsibility. Causal powers Whereas David Hume argued that causes are inferred from non-causal observations, Immanuel Kant claimed that people have innate assumptions about causes. Within psychology, Patricia Cheng (1997) attempted to reconcile the Humean and Kantian views. According to her power PC theory, people filter observations of events through a basic belief that causes have the power to generate (or prevent) their effects, thereby inferring specific cause-effect relations. The theory assumes probabilistic causation. Pearl (2000) has shown that Cheng's causal power can be given a counterfactual interpretation, (i.e., the probability that, absent x and y, y would be true if x were true) and is computable therefore using structural models. Causation and salience Our view of causation depends on what we consider to be the relevant events. Another way to view the statement, "Lightning causes thunder" is to see both lightning and thunder as two perceptions of the same event, viz., an electric discharge that we perceive first visually and then aurally. Naming and causality While the names we give objects often refer to their appearance, they can also refer to an object's causal powers - what that object can do, the effects it has on other objects or people. David Sobel and Alison Gopnik from the Psychology Department of UC Berkeley designed a device known as the blicket detector which suggests that "when causal property and perceptual features are equally evident, children are equally as likely to use causal powers as they are to use perceptual properties when naming objects". ## Humanities ### History In the discussion of history, events are often considered as if in some way being agents that can then bring about other historical events. Thus, the combination of poor harvests, the hardships of the peasants, high taxes, lack of representation of the people, and kingly ineptitude are among the causes of the French Revolution. This is a somewhat Platonic and Hegelian view that reifies causes as ontological entities. In Aristotelian terminology, this use approximates to the case of the efficient cause. ### Law According to law and jurisprudence, legal cause must be demonstrated in order to hold a defendant liable for a crime or a tort (ie. a civil wrong such as negligence or trespass). It must be proven that causality, or a 'sufficient causal link' relates the defendant's actions to the criminal event or damage in question. ### Religion and theology Cosmological argument One of the classic arguments for the existence of God is known as the "Cosmological argument" or "First cause" argument. It works from the premise that every natural event is the effect of a cause. If this is so, then the events that caused today's events must have had causes themselves, which must have had causes, and so forth. If the chain never ends, then one must uphold the hypothesis of an "actual infinite", which is often regarded as problematic, see Hilbert's paradox of the Grand Hotel. If the chain does end, it must end with a non-natural or supernatural cause at the start of the natural world -- e.g. a creation by God. Sometimes the argument is made in non-temporal terms. The chain doesn't go back in time, it goes downward into the ever-more enduring facts, and thus toward the timeless. Two questions that can help to focus the argument are: - What is an event without cause? - How does an event without a cause occur? Critics of this argument point out problems with it. A question related to this argument is which came first, the chicken or the egg? Karma Karma is the belief held by some major religions that a person's actions cause certain effects in the current life and/or in future life, positively or negatively. For example, if a person always does good deeds then it is believed that he or she will be "rewarded" for his or her behavior with fortunate events such as avoiding fatal accident or winning the lottery. If he or she always commits antagonistic behaviors, then it is believed that he will be punished with unfortunate events. In Buddhist philosophy, especially Zen, the word karma simply means the law of cause and effect, ie. causality. Reverse causality Destiny might be considered reverse causality in that a cause is predated by an effect; e.g., "I found a twenty dollar bill on the ground because later I would need it." Some modern religious movements have postulated along the lines of philosophical idealism that causality is actually reversed from the direction normally presumed, and that causality does not proceed inward, from external random causes toward effects on a perceiving individual, but rather outward, from a perceiving individual's causative mental requests toward responsive external physical effects that only seem to be independent causes. Such thought gives rise to new causality principles such as the doctrine of responsibility assumption.	Causality Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Causality or causation denotes a logical relationship between one event (called cause) and another event (called effect) which is the direct consequence (result) of the first.[1] While this informal understanding will suffice in everyday usage, the philosophical analysis of causality or causation has proved exceedingly difficult. The work of philosophers to understand causality and how best to characterize it extends over millennia. In the western philosophical tradition explicit discussion stretches back at least as far as Aristotle, and the topic remains a staple in contemporary philosophy journals. Though cause and effect are typically related to events, other candidates include processes, properties, variables, facts, and states of affairs; which of these comprise the correct causal relata, and how best to characterize the nature of the relationship between them, has as yet no universally accepted answer, and remains under discussion. According to Sowa (2000),[2] up until the twentieth century, three assumptions described by Max Born in 1949 were dominant in the definition of causality: - "Causality postulates that there are laws by which the occurrence of an entity B of a certain class depends on the occurrence of an entity A of another class, where the word entity means any physical object, phenomenon, situation, or event. A is called the cause, B the effect. - "Antecedence postulates that the cause must be prior to, or at least simultaneous with, the effect. - "Contiguity postulates that cause and effect must be in spatial contact or connected by a chain of intermediate things in contact." (Born, 1949, as cited in Sowa, 2000) However, according to Sowa (2000), "relativity and quantum mechanics have forced physicists to abandon these assumptions as exact statements of what happens at the most fundamental levels, but they remain valid at the level of human experience."[2] It should be noted here, however, that physicists themselves never denied causality or stated that causality is violated in quantum mechanics or relativity. Vice versa, any experiment designed to show violation of causality so far failed to do so. # History ## Western philosophy ### Aristotle In his Posterior Analytics and Metaphysics, Aristotle wrote, "All causes are beginnings..."[3], "... we have scientific knowledge when we know the cause..."[4], and "... to know a thing's nature is to know the reason why it is..."[5] This formulation set the guidelines for subsequent causal theories by specifying the number, nature, principles, elements, varieties, order of causes as well as the modes of causation. Aristotle's account of the causes of things is a comprehensive model. Aristotle's theory enumerates the possible causes which fall into several wide groups, amounting to the ways the question "why" may be answered; namely, by reference to the material worked upon (as by an artisan) or what might be called the substratum; to the essence, i.e., the pattern, the form, or the structure by reference to which the "matter" or "substratum" is to be worked; to the primary moving agent of change or the agent and its action; and to the goal, the plan, the end, or the good that the figurative artisan intended to obtain. As a result, the major kinds of causes come under the following divisions: - The material cause is that "raw material" from which a thing is produced as from its parts, constituents, substratum, or materials. This rubric limits the explanation of cause to the parts (the factors, elements, constituents, ingredients) forming the whole (the system, structure, compound, complex, composite, or combination) (the part-whole causation). - The formal cause tells us what, by analogy to the plans of an artisan, a thing is intended and planned to be. Any thing is thought to be determined by its definition, form (mold), pattern, essence, whole, synthesis, or archetype. This analysis embraces the account of causes in terms of fundamental principles or general laws, as the intended whole (macrostructure) is the cause that explains the production of its parts (the whole-part causation). - The efficient cause is that external entity from which the change or the ending of the change first starts. It identifies 'what makes of what is made and what causes change of what is changed' and so suggests all sorts of agents, nonliving or living, acting as the sources of change or movement or rest. Representing the current understanding of causality as the relation of cause and effect, this analysis covers the modern definitions of "cause" as either the agent, agency, particular causal events, or the relevant causal states of affairs. - The final cause is that for the sake of which a thing exists, or is done - including both purposeful and instrumental actions. The final cause, or telos, is the purpose, or end, that something is supposed to serve; or it is that from which, and that to which, the change is. This analysis also covers modern ideas of mental causation involving such psychological causes as volition, need, motivation, or motives; rational, irrational, ethical - all that gives purpose to behavior. Additionally, things can be causes of one another, reciprocally causing each other, as hard work causes fitness, and vice versa - although not in the same way or by means of the same function: the one is as the beginning of change, the other is as its goal. (Thus Aristotle first suggested a reciprocal or circular causality - as a relation of mutual dependence, action, or influence of cause and effect.) Also; Aristotle indicated that the same thing can be the cause of contrary effects - as its presence and absence may result in different outcomes. In speaking thus he formulated what currently is ordinarily termed a "causal factor," e.g., atmospheric pressure as it affects chemical or physical reactions. Aristotle marked two modes of causation: proper (prior) causation and accidental (chance) causation. All causes, proper and incidental, can be spoken as potential or as actual, particular or generic. The same language refers to the effects of causes; so that generic effects assigned to generic causes, particular effects to particular causes, and operating causes to actual effects. It is also essential that ontological causality does not suggest the temporal relation of before and after - between the cause and the effect; that spontaneity (in nature) and chance (in the sphere of moral actions) are among the causes of effects belonging to the efficient causation, and that no incidental, spontaneous, or chance cause can be prior to a proper, real, or underlying cause per se. All investigations of causality coming later in history will consist in imposing a favorite hierarchy on the order (priority) of causes; such as "final > efficient > material > formal" (Aquinas), or in restricting all causality to the material and efficient causes or, to the efficient causality (deterministic or chance), or just to regular sequences and correlations of natural phenomena (the natural sciences describing how things happen rather than asking why they happen). ### Causality, determinism, and existentialism The deterministic world-view is one in which the universe is no more than a chain of events following one after another according to the law of cause and effect. To hold this worldview, as an incompatibilist, there is no such thing as "free will". However, compatibilists argue that determinism is compatible with, or even necessary for, free will. Learning to bear the burden of a meaningless universe, and justify one's own existence, is the first step toward becoming the "Übermensch" (English: "overman" or "superman") that Nietzsche speaks of extensively in his philosophical writings. Existentialists have suggested that people have the courage to accept that while no meaning has been designed in the universe, we each can provide a meaning for ourselves. Though philosophers have pointed out the difficulties in establishing theories of the validity of causal relations, there is yet the plausible example of causation afforded daily which is our own ability to be the cause of events. This concept of causation does not prevent seeing ourselves as moral agents. ## Indian philosophy Theories of causality in Indian philosophy focus mainly on the relationship between cause and effect. The various philosophical schools (darsanas) provide different theories. The doctrine of satkaryavada affirms that the effect inheres in the cause in some way. The effect is thus either a real or apparent modification of the cause. The doctrine of asatkaryavada affirms that the effect does not inhere in the cause, but is a new arising. Among the Buddhist thinkers, Nagarjuna uses a variety of arguments to deny the validity of the cause and effect relationship. See Nyaya for some details of the theory of causation in the Nyaya school. # Logic ## Necessary and sufficient causes Causes are often distinguished into two types: Necessary and sufficient. [6] Necessary causes: If x is a necessary cause of y, then the presence of y necessarily implies the presence of x. The presence of x, however, does not imply that y will occur. Sufficient causes: If x is a sufficient cause of y, then the presence of x necessarily implies the presence of y. However, another cause z may alternatively cause y. Thus the presence of y does not imply the presence of x. J. L. Mackie argues that usual talk of "cause", in fact, refers to INUS conditions (insufficient and non-redundant parts of unnecessary but sufficient causes). For example; consider the short circuit as a cause of the house burning down. Consider the collection of events, the short circuit, the proximity of flammable material, and the absence of firefighters. Considered together these are unnecessary but sufficient to the house's destruction (since many other collection of events certainly could have destroyed the house). Within this collection; the short circuit is an insufficient but non-redundant part (since the short circuit by itself would not cause the fire, but the fire will not happen without it with everything else being equal). So the short circuit is an INUS cause of the house burning down. ## Causality contrasted with conditionals Conditional statements are not statements of causality. Perhaps the most important distinction is that statements of causality require the antecedent to precede the consequent in time, whereas this temporal order is not required by a conditional statement. Since many different statements may be presented using "If...then..." in English (and, arguably, because this form is far more commonly used to make a statement of causality), they are commonly confused; they are distinct, however. For example all of the following statements are true interpreting "If... then..." as the material conditional: - If George Bush was president of the United States in 2004, then Germany is in Europe. - If George Washington was president of the United States in 2004, then Germany is in Europe. - If George Washington was president of the United States in 2004, then Germany is not in Europe. The first is true since both the antecedent and the consequent are true. The second is true because the antecedent is false and the consequent is true. The third is true because both the consequent and antecedent are both false. These statement are trivial examples. Of course, none of these statements express a causal connection between the antecedent and consequent, but they are true because they do not have the combination of having both true antecedent and false consequent. The ordinary indicative conditional seems to have some more structure than the material conditional - for instance, none of the three statements above seem to be correct under an ordinary indicative reading, though the first is closest. But the sentence - If Shakespeare of Stratford on Avon didn't write Macbeth then someone else did. seems to be true, even though there is no straightforward causal relation (in this hypothetical situation) between Shakespeare's not writing Macbeth and someone else's actually writing it. Another sort of conditional, known as the counterfactual conditional has a stronger connection with causality. However, not even all counterfactual statements count as examples of causality. Consider the following two statements: - If A were a triangle, then A would have three sides. - If switch S were thrown, then bulb B would light. In the first case it would not be correct to say that A's being a triangle caused it to have three sides, since the relationship between triangularity and three-sidedness is one of definition. It is actually the three sides that determine A's state as a triangle. Nonetheless, even interpreted counterfactually, the first statement is true. It is probably important to fully grasp the concept of conditionals before the literature on causality can be understood. A crucial stumbling block is that, in everyday usage, conditionals are usually used to describe a general situation. For example "if I drop my coffee, then my shoe gets wet" relates an infinite number of possible events; it is shorthand for "for any fact that would count as 'dropping my coffee', some fact that counts as 'my shoe gets wet' will be true". This general statement will be strictly false if there is any circumstance where I drop my coffee and my shoe doesn't get wet. However, an "if... then..." statement in logic typically relates two specific events or facts - a specific coffee-dropping did or did not occur, and a specific shoe-wetting did or did not follow. Thus, with explicit events in mind, if I drop my coffee and wet my shoe then it is true that "if I dropped my coffee then I wet my shoe", regardless of the fact that yesterday I dropped a coffee in the trash for the opposite effect - the conditional relates to specific facts. More counter-intuitively, if I didn't drop my coffee at all then it is also true that "if I drop my coffee then I wet my shoe", or "dropping my coffee implies I wet my shoe", regardless of whether I wet my shoe or not by any means. This usage would not be counter-intuitive if it weren't for the everyday usage. Briefly, "if X then Y" is equivalent to the first-order logic statement "A implies B" or "not B-and-not-A", where A and B are predicates, but the more familiar usage of an "if A then B" statement would need to be written symbolically using a higher order logic using quantifiers ("for all" and "there exists"). # Theories ## Counterfactual theories The philosopher David Lewis notably suggested that all statements about causality can be understood as counterfactual statements.[7][8][9] So, for instance, the statement that John's smoking caused his premature death is equivalent to saying that had John not smoked he would not have prematurely died. (In addition, it need also be true that John did smoke and did prematurely die, although this requirement is not unique to Lewis' theory.) However, simple logics prove this to be false: the proposition p → q (John smoked, therefore he died prematurely) is logically equivalent to ¬q → ¬p (John did not die prematurely, therefore he did not smoke) (We can also say that p → q <=> ¬q → ¬p, meaning that p → q is logically equivalent to ¬q → ¬p, is a tautology). Saying that John didn't smoke, and therefore didn't die prematurely (¬p → ¬q) is a proposition that cannot be deduced from p → q without extra information. Translating causal into counterfactual statements would only be beneficial if the latter were less problematic than the former. This is indeed the case, as is demonstrated by the structural account of counterfactual conditionals devised by the computer scientist Judea Pearl (2000).[10] This account provides clear semantics and effective algorithms for computing counterfactuals which, in contrast to Lewis' closest world semantics does not rely on the ambiguous notion of similarity among worlds. For instance, one can compute unambiguously the probability that John would be alive had he not smoked given that, in reality, John did smoke and did die. The quest for a counterfactual interpretation of causal statements is therefore justified. One problem Lewis' theory confronts is causal preemption. Suppose that John did smoke and did in fact die as a result of that smoking. However, there was a murderer who was bent on killing John, and would have killed him a second later had he not first died from smoking. Here we still want to say that smoking caused John's death. This presents a problem for Lewis' theory since, had John not smoked, he still would have died prematurely. Lewis himself discusses this example, and it has received substantial discussion (cf.[11][12][13]). A structural solution to this problem has been given in [Halpern and Pearl, 2005].[14] ## Probabilistic causation Interpreting causation as a deterministic relation means that if A causes B, then A must always be followed by B. In this sense, war does not cause deaths, nor does smoking cause cancer. As a result, many turn to a notion of probabilistic causation. Informally, A probabilistically causes B if A's occurrence increases the probability of B. This is sometimes interpreted to reflect imperfect knowledge of a deterministic system but other times interpreted to mean that the causal system under study has an inherently chancy nature. ## Causal Calculus When experiments are infeasible or illegal, the derivation of cause effect relationship from observational studies must rest on some qualitative theoretical assumptions, for example, that symptoms do not cause diseases, usually expressed in the form of missing arrows in causal graphs such as Bayesian Networks or path diagrams. The mathematical theory underlying these derivations relies on the distinction between conditional probabilities, as in <math>P(cancer\|smoking)</math>, and interventional probabilities, as in <math>P(cancer\|do(smoking))</math>. The former reads: "the probability of finding cancer in a person known to smoke" while the latter reads: "the probability of finding cancer in a person forced to smoke". The former is a statistical notion that can be estimated directly in observational studies, while the latter is a causal notion (also called "causal effect") which is what we estimate in a controlled randomized experiment. The theory of "causal calculus"[10] permits one to infer interventional probabilities from conditional probabilities in causal Bayesian Networks with unmeasured variables. One very practical result of this theory is the characterization of confounding variables, namely, a sufficient set of variables that, if adjusted for, would yield the correct causal effect between variables of interest. It can be shown that a sufficient set for estimating the causal effect of <math>X</math> on <math>Y</math> is any set of non-descendants of <math>X</math> that <math>d</math>-separate <math>X</math> from <math>Y</math> after removing all arrows emanating from <math>X</math>. This criterion, called "backdoor", provides a mathematical definition of "confounding" and helps researchers identify accessible sets of variables worthy of measurement. ## Structure Learning While derivations in Causal Calculus rely on the structure of the causal graph, parts of the causal structure can, under certain assumptions, be learned from statistical data. The basic idea goes back to a recovery algorithm developed by Rebane and Pearl (1987)[15] and rests on the distinction between the three possible types of causal substructures allowed in a directed acyclic graph (DAG): - <math>X \rightarrow Y \rightarrow Z</math> - <math>X \leftarrow Y \rightarrow Z</math> - <math>X \rightarrow Y \leftarrow Z</math> Type 1 and type 2 represent the same statistical dependencies (i.e., <math>X</math> and <math>Z</math> are independent given <math>Y</math>) and are, therefore, indistinguishable. Type 3, however, can be uniquely identified, since <math>X</math> and <math>Z</math> are marginally independent and all other pairs are dependent. Thus, while the skeletons (the graphs stripped of arrows) of these three triplets are identical, the directionality of the arrows is partially identifiable. The same distinction applies when <math>X</math> and <math>Z</math> have common ancestors, except that one must first condition on those ancestors. Algorithms have been developed to systematically determine the skeleton of the underlying graph and, then, orient all arrows whose directionality is dictated by the conditional independencies observed[10] [16] [17] [18]. Alternative methods of structure learning search through the many possible causal structures among the variables, and remove ones which are strongly incompatible with the observed correlations. In general this leaves a set of possible causal relations, which should then be tested by designing appropriate experiments. If experimental data is already available, the algorithms can take advantage of that as well. In contrast with Bayesian Networks, path analysis and its generalization, structural equation modeling, serve better to estimate a known causal effect or test a causal model than to generate causal hypotheses. For nonexperimental data, causal direction can be hinted if information about time is available. This is because (according to many, though not all, theories) causes must precede their effects temporally. This can be set up by simple linear regression models, for instance, with an analysis of covariance in which baseline and follow up values are known for a theorized cause and effect. The addition of time as a variable, though not proving causality, is a big help in supporting a pre-existing theory of causal direction. For instance, our degree of confidence in the direction and nature of causality is much greater when supported by data from a longitudinal study than by data from a cross-sectional study. ## Derivation theories The Nobel Prize holder Herbert Simon and Philosopher Nicholas Rescher[19] claim that the asymmetry of the causal relation is unrelated to the asymmetry of any mode of implication that contraposes. Rather, a causal relation is not a relation between values of variables, but a function of one variable (the cause) on to another (the effect). So, given a system of equations, and a set of variables appearing in these equations, we can introduce an asymmetric relation among individual equations and variables that corresponds perfectly to our commonsense notion of a causal ordering. The system of equations must have certain properties, most importantly, if some values are chosen arbitrarily, the remaining values will be determined uniquely through a path of serial discovery that is perfectly causal. They postulate the inherent serialization of such a system of equations may correctly capture causation in all empirical fields, including physics and economics. ## Manipulation theories Some theorists have equated causality with manipulability.[20][21][22][23] Under these theories, x causes y just in case one can change x in order to change y. This coincides with commonsense notions of causations, since often we ask causal questions in order to change some feature of the world. For instance, we are interested in knowing the causes of crime so that we might find ways of reducing it. These theories have been criticized on two primary grounds. First, theorists complain that these accounts are circular. Attempting to reduce causal claims to manipulation requires that manipulation is more basic than causal interaction. But describing manipulations in non-causal terms has provided a substantial difficulty. The second criticism centers around concerns of anthropocentrism. It seems to many people that causality is some existing relationship in the world that we can harness for our desires. If causality is identified with our manipulation, then this intuition is lost. In this sense, it makes humans overly central to interactions in the world. Some attempts to save manipulability theories are recent accounts that don't claim to reduce causality to manipulation. These account use manipulation as a sign or feature in causation without claiming that manipulation is more fundamental than causation.[10][24] ## Process theories Some theorists are interested in distinguishing between causal processes and non-causal processes (Russell 1948; Salmon 1984).[25][26] These theorists often want to distinguish between a process and a pseudo-process. As an example, a ball moving through the air (a process) is contrasted with the motion of a shadow (a pseudo-process). The former is causal in nature while the latter is not. Salmon (1984)[25] claims that causal processes can be identified by their ability to transmit an alteration over space and time. An alteration of the ball (a mark by a pen, perhaps) is carried with it as the ball goes through the air. On the other hand an alteration of the shadow (insofar as it is possible) will not be transmitted by the shadow as it moves along. These theorists claim that the important concept for understanding causality is not causal relationships or causal interactions, but rather identifying causal processes. The former notions can then be defined in terms of causal processes. # Fields ## Science Using the scientific method, scientists set up experiments to determine causality in the physical world. In addition, many scientists in a variety of fieldsTemplate:Specify disagree that experiments are necessary to determine causality. For example, the link between smoking and lung cancer is considered proven by health agencies of the United States government, but experimental methods (for example, randomized controlled trials) were not used to establish that link. This view has been controversial. In addition, many philosophers are beginning to turn to more relativized notions of causality. Rather than providing a theory of causality in toto, they opt to provide a theory of causality in biology or causality in physics. ### Physics Physicists conclude that certain elemental forces: gravity, the strong and weak nuclear forces, and electromagnetism are said to be the four fundamental forces which are the causes of all other events in the universe. Causality is hard to interpret to ordinary language from many different physical theories. One problem is typified by the moon's gravity. It isn't accurate to say, "the moon exerts a gravitic pull and then the tides rise." In Newtonian mechanics gravity, rather, is a law expressing a constant observable relationship among masses, and the movement of the tides is an example of that relationship. There are no discrete events or "pulls" that can be said to precede the rising of tides. Interpreting gravity causally is even more complicated in general relativity. Another important implication of Causality in physics is its intimate connection to the Second Law of Thermodynamics (see the fluctuation theorem). Quantum mechanics is yet another branch of physics in which the nature of causality is somewhat unclear. The treatment of the concept of causality within the Second Law of Thermodynamics yields a loss in the translation. The statistical basis of the maintenance of the exchange of entropy confines the subject to an extent such that the observer loses perspective. The 2nd Law states that "in a closed system, disorder increases". This is a corollary of the concept that an effect cannot be greater than the cause. Consider information content. Applying the 2nd Law, the information content in a closed system cannot increase. If the boundaries of the system are penetrated then a system can increase in information content but the loss is felt elsewhere. Strict adherence to the principles of the second law preclude boundary violation. However, this is not to say a closed system cannot increase in order locally. Take AI for example. The 2nd law does not preclude the existence of an artificial intelligence capable of growing greater than its creator since energy must constantly be supplied to the system. In physics matter and energy are considered forms of information. Thus, the AI could grow in order and comlexity, but only at the expense of an equal or greater increase in entropy in the form of dissipated energy, allowing the system to increase in disorder globally. ### Engineering A causal system is a system with output and internal states that depends only on the current and previous input values. A system that has some dependence on input values from the future (in addition to possible past or current input values) is termed an acausal system, and a system that depends solely on future input values is an anticausal system. Acausal filters, for example, can only exist as digital filters, because these filters can extract future values from a memory buffer or a file. ## Biology and medicine A. B. Hill built upon the work of Hume and Popper and suggested that the following aspects of an association be considered in attempting to distinguish causal from noncausal associations: 1) strength, 2) consistency, 3) specificity, 4) temporality, 5) biological gradient, 6) plausibility, 7) coherence, 8) experimental evidence, and 9) analogy.[27] ### Psychology The above theories are attempts to define a reflectively stable notion of causality. This process uses our standard causal intuitions to develop a theory that we would find satisfactory in identifying causes. Another avenue of research is to empirically investigate how people (and non-human animals) learn and reason about causal relations in the world. This approach is taken by work in psychology. It also is possible to tackle causalities in surveys with a technique of elaboration. Given a relationship between two variables, what can be learned by introducing a third variable into the analysis (Rosenberg, 1968, xiii)? So elaboration is a device of the analysis that results in different kinds of relationships between variables e.g. suppression, extraneous, and distorter relations. Attribution Attribution theory is the theory concerning how people explain individual occurrences of causation. Attribution can be external (assigning causality to an outside agent or force - claiming that some outside thing motivated the event) or internal (assigning causality to factors within the person - taking personal responsibility or accountability for one's actions and claiming that the person was directly responsible for the event). Taking causation one step further, the type of attribution a person provides influences their future behavior. The intention behind the cause or the effect can be covered by the subject of action (philosophy). See also accident; blame; intent; and responsibility. Causal powers Whereas David Hume argued that causes are inferred from non-causal observations, Immanuel Kant claimed that people have innate assumptions about causes. Within psychology, Patricia Cheng (1997)[28] attempted to reconcile the Humean and Kantian views. According to her power PC theory, people filter observations of events through a basic belief that causes have the power to generate (or prevent) their effects, thereby inferring specific cause-effect relations. The theory assumes probabilistic causation. Pearl (2000)[10] has shown that Cheng's causal power can be given a counterfactual interpretation, (i.e., the probability that, absent <math>x</math> and <math>y</math>, <math>y</math> would be true if <math>x</math> were true) and is computable therefore using structural models. Causation and salience Our view of causation depends on what we consider to be the relevant events. Another way to view the statement, "Lightning causes thunder" is to see both lightning and thunder as two perceptions of the same event, viz., an electric discharge that we perceive first visually and then aurally. Naming and causality While the names we give objects often refer to their appearance, they can also refer to an object's causal powers - what that object can do, the effects it has on other objects or people. David Sobel and Alison Gopnik from the Psychology Department of UC Berkeley designed a device known as the blicket detector which suggests that "when causal property and perceptual features are equally evident, children are equally as likely to use causal powers as they are to use perceptual properties when naming objects". ## Humanities ### History In the discussion of history, events are often considered as if in some way being agents that can then bring about other historical events. Thus, the combination of poor harvests, the hardships of the peasants, high taxes, lack of representation of the people, and kingly ineptitude are among the causes of the French Revolution. This is a somewhat Platonic and Hegelian view that reifies causes as ontological entities. In Aristotelian terminology, this use approximates to the case of the efficient cause. ### Law According to law and jurisprudence, legal cause must be demonstrated in order to hold a defendant liable for a crime or a tort (ie. a civil wrong such as negligence or trespass). It must be proven that causality, or a 'sufficient causal link' relates the defendant's actions to the criminal event or damage in question. ### Religion and theology Cosmological argument One of the classic arguments for the existence of God is known as the "Cosmological argument" or "First cause" argument. It works from the premise that every natural event is the effect of a cause. If this is so, then the events that caused today's events must have had causes themselves, which must have had causes, and so forth. If the chain never ends, then one must uphold the hypothesis of an "actual infinite", which is often regarded as problematic, see Hilbert's paradox of the Grand Hotel. If the chain does end, it must end with a non-natural or supernatural cause at the start of the natural world -- e.g. a creation by God. Sometimes the argument is made in non-temporal terms. The chain doesn't go back in time, it goes downward into the ever-more enduring facts, and thus toward the timeless. Two questions that can help to focus the argument are: - What is an event without cause? - How does an event without a cause occur? Critics of this argument point out problems with it. A question related to this argument is which came first, the chicken or the egg? Karma Karma is the belief held by some major religions that a person's actions cause certain effects in the current life and/or in future life, positively or negatively. For example, if a person always does good deeds then it is believed that he or she will be "rewarded" for his or her behavior with fortunate events such as avoiding fatal accident or winning the lottery. If he or she always commits antagonistic behaviors, then it is believed that he will be punished with unfortunate events. In Buddhist philosophy, especially Zen, the word karma simply means the law of cause and effect, ie. causality. Reverse causality Destiny might be considered reverse causality in that a cause is predated by an effect; e.g., "I found a twenty dollar bill on the ground because later I would need it." Some modern religious movements have postulated along the lines of philosophical idealism that causality is actually reversed from the direction normally presumed, and that causality does not proceed inward, from external random causes toward effects on a perceiving individual, but rather outward, from a perceiving individual's causative mental requests toward responsive external physical effects that only seem to be independent causes. Such thought gives rise to new causality principles such as the doctrine of responsibility assumption.	https://www.wikidoc.org/index.php/Causality
bc4da809f5e2ee0e049abbcb37c262fdf3f97a8f	wikidoc	Corrosive	Corrosive A corrosive substance is one that will destroy or irreversibly damage another substance with which it comes in contact. The main hazards to people include damage to eyes, skin and tissue under the skin, but inhalation or ingestion of a corrosive substance can damage the respiratory and gastrointestinal tracts. A low concentration of a corrosive substance is usually an irritant. Corrosion of non-living surfaces such as metals is a distinct process. For example, a water/air electrochemical cell corrodes iron to rust. In the Globally Harmonized System, both rapid corrosion of metals and chemical corrosion of skin qualify for the "corrosive" symbol. Common corrosives are strong acids and strong bases, or concentrated solutions of certain weak acids and weak bases. Their action on living tissue is based on acid-base catalysis of ester and amide hydrolysis. Both corrosive acids and corrosive bases are able to defat skin by catalyzing the hydrolysis of fats, which are chemically esters). Proteins are chemically amides, which can also be hydrolyzed by acid-base catalysis. Strong acids and bases denature proteins and also hydrate easily. Hydration removes water from the tissue and is significantly exothermic. For example, concentrated sulfuric acid causes thermal burns in addition to chemical burns. There are also more specific corrosives. Hydrofluoric acid, for example, is initially painless but easily permeates tissue to selectively attack bone. Although zinc chloride solutions are also regularly acidic (by the Brønsted definition), the zinc cation also specifically attacks hydroxyl groups as a Lewis acid. This explains the ability of zinc chloride solutions to react with cellulose and corrode through paper and silk. The word 'corrosion' is derived from the latin verb corrode which means 'to gnaw' indicating how these substance seem to 'gnaw' their way through the flesh. # Corrosive substances Common corrosive chemicals are classified into: - Acids - Strong acids — the most common are sulfuric acid, nitric acid and hydrochloric acid (H2SO4, HNO3 and HCl, respectively). - Some concentrated weak acids, for example acetic acid - Solutions of Lewis acids with specific reactivity, e.g. solutions of zinc chloride - Bases - Caustics or alkalis, such as sodium hydroxide (NaOH) and potassium hydroxide (KOH) - Alkali metals in the metallic form (e.g. elemental sodium) and hydrides of alkali and alkaline earth metals hydrate to give caustics - Some concentrated weak bases, such as ammonia when anhydrous or in a concentrated solution - Dehydrating agents such as phosphorus pentoxide, calcium oxide, anhydrous zinc chloride, also elemental alkali metals - Electrophilic halogens: elemental fluorine, chlorine, bromine and iodine, and electrophilic salts such as sodium hypochlorite or N-chloro compounds such as chloramine-T; halide ions are not corrosive - Organic halides and organic acid halides such as acetyl chloride and benzyl chloroformate - Acid anhydrides - Some organic materials such as phenol ("carbolic acid") - Extremely electrophilic reagents such as dimethyl sulfate	Corrosive A corrosive substance is one that will destroy or irreversibly damage another substance with which it comes in contact. The main hazards to people include damage to eyes, skin and tissue under the skin, but inhalation or ingestion of a corrosive substance can damage the respiratory and gastrointestinal tracts. A low concentration of a corrosive substance is usually an irritant. Corrosion of non-living surfaces such as metals is a distinct process. For example, a water/air electrochemical cell corrodes iron to rust. In the Globally Harmonized System, both rapid corrosion of metals and chemical corrosion of skin qualify for the "corrosive" symbol. Common corrosives are strong acids and strong bases, or concentrated solutions of certain weak acids and weak bases. Their action on living tissue is based on acid-base catalysis of ester and amide hydrolysis. Both corrosive acids and corrosive bases are able to defat skin by catalyzing the hydrolysis of fats, which are chemically esters). Proteins are chemically amides, which can also be hydrolyzed by acid-base catalysis. Strong acids and bases denature proteins and also hydrate easily. Hydration removes water from the tissue and is significantly exothermic. For example, concentrated sulfuric acid causes thermal burns in addition to chemical burns. There are also more specific corrosives. Hydrofluoric acid, for example, is initially painless but easily permeates tissue to selectively attack bone. Although zinc chloride solutions are also regularly acidic (by the Brønsted definition), the zinc cation also specifically attacks hydroxyl groups as a Lewis acid. This explains the ability of zinc chloride solutions to react with cellulose and corrode through paper and silk. The word 'corrosion' is derived from the latin verb corrode which means 'to gnaw' indicating how these substance seem to 'gnaw' their way through the flesh. # Corrosive substances Common corrosive chemicals are classified into: - Acids - Strong acids — the most common are sulfuric acid, nitric acid and hydrochloric acid (H2SO4, HNO3 and HCl, respectively). - Some concentrated weak acids, for example acetic acid - Solutions of Lewis acids with specific reactivity, e.g. solutions of zinc chloride - Bases - Caustics or alkalis, such as sodium hydroxide (NaOH) and potassium hydroxide (KOH) - Alkali metals in the metallic form (e.g. elemental sodium) and hydrides of alkali and alkaline earth metals hydrate to give caustics - Some concentrated weak bases, such as ammonia when anhydrous or in a concentrated solution - Dehydrating agents such as phosphorus pentoxide, calcium oxide, anhydrous zinc chloride, also elemental alkali metals - Electrophilic halogens: elemental fluorine, chlorine, bromine and iodine, and electrophilic salts such as sodium hypochlorite or N-chloro compounds such as chloramine-T[1]; halide ions are not corrosive - Organic halides and organic acid halides such as acetyl chloride and benzyl chloroformate - Acid anhydrides - Some organic materials such as phenol ("carbolic acid") - Extremely electrophilic reagents such as dimethyl sulfate	https://www.wikidoc.org/index.php/Caustic_(substance)
f0c980016ad67b9e500dfabfd996098d25c3442d	wikidoc	Caverject	Caverject Caverject is an injection of a chemical called alprostadil, produced by Upjohn, used to treat Erectile dysfunction (impotence in men). Caverject Sterile Powder contains alprostadil as the naturally occurring form of prostaglandin E1 (PGE1) and designated chemically as (11alpha, 13E, 15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. The molecular weight is 354.49. Alprostadil is a white to off-white crystalline powder with a melting point between 115° and 116°C. Its solubility at 35°C is 8000 micrograms (mcg) per 100 milliliter double distilled water. # Usage Caverject is administered via small-needle injection into an area of the penis known as the corpus cavernosum. It works by relaxing smooth muscle tissue which, in turn, enhances blood flow to the penis, creating an erection. The drug is indicated for the treatment of erectile dysfunction whether the cause is neurological, vascular, psychological or of mixed origin. Patients selected for treatment with Caverject receive initial injections from medically-trained personnel to determine optimum dosing. Usual dosing is from 5 mg to 20 mg. Up to 60 mg can be injected at one time. Caverject can be administered by the patient once he has been trained to self-inject. The syringes are self-contained and easy to use. A kit contains the alcohol wipes used before and after to clean the penis, the needle which is attached to the syringe, and a preloaded syringe. Penile Injection using Caverject System (note placement of needle) - Immediate Effect (notice swelling) - Resultant Erection (~10 minutes later) # Directions First the user must remove the wipes and clean the injection site. The site chosen should be free of visible veins and on either side of shaft of penis. After attaching the needle the user must twist the syringe to mix the diluent (sterile, normal saline) and the drug. The syringe is then held upward and the excess air expelled by pushing the syringe as far as it will go. The dosage ring (blue) is turned until the desired dosage (5 mg, 10 mg, 15 mg, or 20 mg) is displayed. The needle is exposed by removing the needle cap and protector. The penis is secured with one hand. (Only one hand is visible in the photo because the other hand was holding the camera.) The other hand is used to insert the needle in the desired location and depress the top of the syringe all the way down. The needle is then withdrawn and the cap and protector replaced. The other wipe is used to clean any blood off the penis. Results usually take 5 to 20 minutes. The duration of the erection is related to the dosage, among other factor, and may last 30 mintutes to over an hour. Because of the very fine needle used the injection is seldom felt and generally not painful. # Side Effects Caverject may cause mild pain, irritation or slight bleeding at the injection site. There is also a possibility to develop: tenderness or swelling of the penis, redness/lumps/unusual curving of the penis. Caverject can cause priapism and long-term use carries a 3% risk of developing fibrosis of the penis.	Caverject Template:Cleanup Caverject is an injection of a chemical called alprostadil, produced by Upjohn, used to treat Erectile dysfunction (impotence in men). Caverject Sterile Powder contains alprostadil as the naturally occurring form of prostaglandin E1 (PGE1) and designated chemically as (11alpha, 13E, 15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. The molecular weight is 354.49. Alprostadil is a white to off-white crystalline powder with a melting point between 115° and 116°C. Its solubility at 35°C is 8000 micrograms (mcg) per 100 milliliter double distilled water. # Usage Caverject is administered via small-needle injection into an area of the penis known as the corpus cavernosum. It works by relaxing smooth muscle tissue which, in turn, enhances blood flow to the penis, creating an erection. The drug is indicated for the treatment of erectile dysfunction whether the cause is neurological, vascular, psychological or of mixed origin. Patients selected for treatment with Caverject receive initial injections from medically-trained personnel to determine optimum dosing. Usual dosing is from 5 mg to 20 mg. Up to 60 mg can be injected at one time. Caverject can be administered by the patient once he has been trained to self-inject. The syringes are self-contained and easy to use. A kit contains the alcohol wipes used before and after to clean the penis, the needle which is attached to the syringe, and a preloaded syringe. Penile Injection using Caverject System (note placement of needle) - Immediate Effect (notice swelling) - Resultant Erection (~10 minutes later) # Directions First the user must remove the wipes and clean the injection site. The site chosen should be free of visible veins and on either side of shaft of penis. After attaching the needle the user must twist the syringe to mix the diluent (sterile, normal saline) and the drug. The syringe is then held upward and the excess air expelled by pushing the syringe as far as it will go. The dosage ring (blue) is turned until the desired dosage (5 mg, 10 mg, 15 mg, or 20 mg) is displayed. The needle is exposed by removing the needle cap and protector. The penis is secured with one hand. (Only one hand is visible in the photo because the other hand was holding the camera.) The other hand is used to insert the needle in the desired location and depress the top of the syringe all the way down. The needle is then withdrawn and the cap and protector replaced. The other wipe is used to clean any blood off the penis. Results usually take 5 to 20 minutes. The duration of the erection is related to the dosage, among other factor, and may last 30 mintutes to over an hour. Because of the very fine needle used the injection is seldom felt and generally not painful. # Side Effects Caverject may cause mild pain, irritation or slight bleeding at the injection site. There is also a possibility to develop: tenderness or swelling of the penis, redness/lumps/unusual curving of the penis. Caverject can cause priapism and long-term use carries a 3% risk of developing fibrosis of the penis. # External links	https://www.wikidoc.org/index.php/Caverject
87a92e291f308cfa2ab1d9d5b6fbda9beda7a1c4	wikidoc	Resonator	Resonator A resonator is a device or system that exhibits resonance or resonant behavior, that is, it naturally oscillates at some frequencies, called its resonance frequencies, with greater amplitude than at others. Although its usage has broadened, the term usually refers to a physical object that oscillates at specific frequencies because its dimensions are an integral multiple of the wavelength at those frequencies. The oscillations or waves in a resonator can be either electromagnetic or mechanical. Resonators are used to either generate waves of specific frequencies or to select specific frequencies from a signal. Musical instruments use acoustic resonators that produce sound waves of specific tones. A cavity resonator, usually used in reference to electromagnetic resonators, is one in which the waves exist in a hollow space inside the device. Acoustic cavity resonators, in which sound is produced by air vibrating in a cavity with one opening, are known as Helmholtz resonators. # Electromagnetic A distributed parameter resonator of the distributed network type has capacitance, inductance, and resistance which cannot be isolated into separate lumped capacitors, inductors, or resistors. The time factor of propagation of wave energy in the network is appreciable. Resonators can be of the dielectric type or magnetic type. A hollow conductor that uses resonance to amplify an electromagnetic wave is called a cavity resonator. In the context of electronic components, resonator may refer to a ceramic resonator, a device used to produce an oscillation of a specific frequency, primarily for use as the clock signal for digital circuits. A single layer coil (or solenoid) that is used as a secondary or tertiary winding in a Tesla Coil or Magnifying Transmitter is also called a resonator. ## Cavity resonators The cavity has interior surfaces which reflect a wave of a specific frequency. When a wave that is resonant with the cavity enters, it bounces back and forth within the cavity, with low loss (See standing wave). As more wave energy enters the cavity, it combines with and reinforces the standing wave, increasing its intensity. ### Examples Some examples of cavity resonators include the tube of a flute, the body of a violin (this being an example of a Helmholtz resonator), and the magnetron tube in a microwave oven (see also klystron). The cavity magnetron is a vacuum tube with a filament in the center of an evacuated, lobed, circular chamber. A perpendicular magnetic field is imposed by a permanent magnet. The magnetic field causes the electrons, attracted to the (relatively) positive outer part of the chamber, to spiral outward in a circular path rather than moving directly to this anode. Spaced about the rim of the chamber are cylindrical cavities. The cavities are open along their length and so connect the common cavity space.As electrons sweep past these openings they induce a resonant high frequency radio field in the cavity, which in turn causes the electrons to bunch into groups. A portion of this field is extracted with a short antenna that is connected to a waveguide (a metal tube usually of rectangular cross section). The waveguide directs the extracted RF energy to the load, which may be a cooking chamber in a microwave oven or a high gain antenna in the case of radar. The klystron tube waveguide is a beam tube including at least two apertured cavity resonators. The beam of charged particles passes through the apertures of the resonators in succession. A collector electrode is provided to intercept the beam after passing through the resonators. The first resonator causes bunching of the particles passing through it. The bunched particles travel in a field-free region where further bunching occurs, then the bunched particles enter the second resonator giving up their energy to excite it into oscillations. It is a particle accelerator that works in conjunction with a specifically tuned cavity by the configuration of the structures. On the beamline of an accelerator system, there are specific sections that are cavity resonators for RF. The reflex klystron is a klystron utilizing only a single apertured cavity resonator through which the beam of charged particles passes, first in one direction. A repeller electrode is provided to repel (or redirect) the beam after passage through the resonator back through the resonator in the other direction and in proper phase to reinforce the oscillations set up in the resonator. In a laser, light is amplified in a cavity resonator which is usually composed of two or more mirrors. Thus an optical cavity, also known as a resonator, is a cavity with walls which reflect electromagnetic waves (light). This will allow standing wave modes to exist with little loss outside the cavity. ### Patents The USPTO classifies devices and systems where the resonator device is an enclosure or cavity so constructed that the field configuration excited within the boundaries of the device includes longitudinal as well as transverse field components as Class 333, Wave transmission lines and networks, and Subclass 227. # Acoustic resonators The most familiar audio resonator is perhaps the Helmholtz resonator although many other structures can exhibit audio resonances. ## Automobiles A resonator is one part in exhaust systems that works with the muffler to reduce noise, by making sound waves "cancel each other out". The "exhaust note" is an important feature for many vehicle owners, so both the original manufacturers and the after-market suppliers use the resonator to enhance the sound. ## Musical instruments Most musical instruments include resonators to enhance the sound of the instrument. An example would be the hollow shell (also known as a sound box) of an acoustic guitar, which permits the strummed strings to set up resonant vibrations and hence project a louder sound. Marimbas, xylophones, and other similar musical percussion often have carefully-tuned pipes underneath each bar to allow resonance to occur when the key is struck, as well as higher-order harmonics. ### Percussion instruments In many keyboard percussion instruments, below the centre of each note is a tube, which is an acoustic cavity resonator, referred to simply as the resonator. The length of the tube varies according to the pitch of the note, with higher notes having shorter resonators. The tube is open at the top end and closed at the bottom end, creating a column of air which resonates when the note is struck. This adds depth and volume to the note. In string instruments, the body of the instrument is a resonator. The tremolo effect of a vibraphone is obtained by a mechanism which opens and shuts the resonators. ### Stringed instruments String instruments such as the bluegrass banjo may also have resonators. Many five-string banjos have removable resonators, to allow the instrument to be used with resonator in bluegrass style, or without in folk music style. The term resonator, used by itself, may also refer to the resonator guitar. The modern ten-string guitar, invented by Narciso Yepes, adds four string resonators to the traditional classical guitar. By tuning these resonators in a very specific way (C, Bb, Ab, Gb) and making use of their strongest partials (corresponding to the octaves and fifths of the strings' fundamental tones), the bass strings of the guitar now resonate equally with any of the 12 tones of the chromatic octave.	Resonator Template:Electromagnetism3 A resonator is a device or system that exhibits resonance or resonant behavior, that is, it naturally oscillates at some frequencies, called its resonance frequencies, with greater amplitude than at others. Although its usage has broadened, the term usually refers to a physical object that oscillates at specific frequencies because its dimensions are an integral multiple of the wavelength at those frequencies. The oscillations or waves in a resonator can be either electromagnetic or mechanical. Resonators are used to either generate waves of specific frequencies or to select specific frequencies from a signal. Musical instruments use acoustic resonators that produce sound waves of specific tones. A cavity resonator, usually used in reference to electromagnetic resonators, is one in which the waves exist in a hollow space inside the device. Acoustic cavity resonators, in which sound is produced by air vibrating in a cavity with one opening, are known as Helmholtz resonators. # Electromagnetic A distributed parameter resonator of the distributed network type has capacitance, inductance, and resistance which cannot be isolated into separate lumped capacitors, inductors, or resistors. The time factor of propagation of wave energy in the network is appreciable. Resonators can be of the dielectric type or magnetic type. A hollow conductor that uses resonance to amplify an electromagnetic wave is called a cavity resonator. In the context of electronic components, resonator may refer to a ceramic resonator, a device used to produce an oscillation of a specific frequency, primarily for use as the clock signal for digital circuits. A single layer coil (or solenoid) that is used as a secondary or tertiary winding in a Tesla Coil or Magnifying Transmitter is also called a resonator. ## Cavity resonators The cavity has interior surfaces which reflect a wave of a specific frequency. When a wave that is resonant with the cavity enters, it bounces back and forth within the cavity, with low loss (See standing wave). As more wave energy enters the cavity, it combines with and reinforces the standing wave, increasing its intensity. ### Examples Some examples of cavity resonators include the tube of a flute, the body of a violin (this being an example of a Helmholtz resonator), and the magnetron tube in a microwave oven (see also klystron). The cavity magnetron is a vacuum tube with a filament in the center of an evacuated, lobed, circular chamber. A perpendicular magnetic field is imposed by a permanent magnet. The magnetic field causes the electrons, attracted to the (relatively) positive outer part of the chamber, to spiral outward in a circular path rather than moving directly to this anode. Spaced about the rim of the chamber are cylindrical cavities. The cavities are open along their length and so connect the common cavity space.As electrons sweep past these openings they induce a resonant high frequency radio field in the cavity, which in turn causes the electrons to bunch into groups. A portion of this field is extracted with a short antenna that is connected to a waveguide (a metal tube usually of rectangular cross section). The waveguide directs the extracted RF energy to the load, which may be a cooking chamber in a microwave oven or a high gain antenna in the case of radar. The klystron tube waveguide is a beam tube including at least two apertured cavity resonators. The beam of charged particles passes through the apertures of the resonators in succession. A collector electrode is provided to intercept the beam after passing through the resonators. The first resonator causes bunching of the particles passing through it. The bunched particles travel in a field-free region where further bunching occurs, then the bunched particles enter the second resonator giving up their energy to excite it into oscillations. It is a particle accelerator that works in conjunction with a specifically tuned cavity by the configuration of the structures. On the beamline of an accelerator system, there are specific sections that are cavity resonators for RF. The reflex klystron is a klystron utilizing only a single apertured cavity resonator through which the beam of charged particles passes, first in one direction. A repeller electrode is provided to repel (or redirect) the beam after passage through the resonator back through the resonator in the other direction and in proper phase to reinforce the oscillations set up in the resonator. In a laser, light is amplified in a cavity resonator which is usually composed of two or more mirrors. Thus an optical cavity, also known as a resonator, is a cavity with walls which reflect electromagnetic waves (light). This will allow standing wave modes to exist with little loss outside the cavity. ### Patents The USPTO classifies devices and systems where the resonator device is an enclosure or cavity so constructed that the field configuration excited within the boundaries of the device includes longitudinal as well as transverse field components as Class 333, Wave transmission lines and networks, and Subclass 227. # Acoustic resonators The most familiar audio resonator is perhaps the Helmholtz resonator although many other structures can exhibit audio resonances. ## Automobiles A resonator is one part in exhaust systems that works with the muffler to reduce noise, by making sound waves "cancel each other out"[1]. The "exhaust note" is an important feature for many vehicle owners, so both the original manufacturers and the after-market suppliers use the resonator to enhance the sound. ## Musical instruments Most musical instruments include resonators to enhance the sound of the instrument. An example would be the hollow shell (also known as a sound box) of an acoustic guitar, which permits the strummed strings to set up resonant vibrations and hence project a louder sound. Marimbas, xylophones, and other similar musical percussion often have carefully-tuned pipes underneath each bar to allow resonance to occur when the key is struck, as well as higher-order harmonics. ### Percussion instruments In many keyboard percussion instruments, below the centre of each note is a tube, which is an acoustic cavity resonator, referred to simply as the resonator. The length of the tube varies according to the pitch of the note, with higher notes having shorter resonators. The tube is open at the top end and closed at the bottom end, creating a column of air which resonates when the note is struck. This adds depth and volume to the note. In string instruments, the body of the instrument is a resonator. The tremolo effect of a vibraphone is obtained by a mechanism which opens and shuts the resonators. ### Stringed instruments String instruments such as the bluegrass banjo may also have resonators. Many five-string banjos have removable resonators, to allow the instrument to be used with resonator in bluegrass style, or without in folk music style. The term resonator, used by itself, may also refer to the resonator guitar. The modern ten-string guitar, invented by Narciso Yepes, adds four string resonators to the traditional classical guitar. By tuning these resonators in a very specific way (C, Bb, Ab, Gb) and making use of their strongest partials (corresponding to the octaves and fifths of the strings' fundamental tones), the bass strings of the guitar now resonate equally with any of the 12 tones of the chromatic octave.	https://www.wikidoc.org/index.php/Cavity_resonator
a053a470b01eceb967a5150183b03f765f6189b6	wikidoc	Cediranib	Cediranib # Overview Cediranib (tentative trade name Recentin), also known as AZD2171, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. It is being developed by AstraZeneca as a possible chemotherapeutic agent for oral administration. As of 2007, it is undergoing Phase I clinical trials for the treatment of non-small cell lung cancer and colorectal cancer in adults, as well as tumors of the central nervous system in children. # Further reading - Wedge S, Kendrew J, Hennequin L; et al. (2005). "AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer". Cancer Res. 65 (10): 4389–400. PMID 15899831.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}	Cediranib # Overview Cediranib (tentative trade name Recentin), also known as AZD2171, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. It is being developed by AstraZeneca as a possible chemotherapeutic agent for oral administration. As of 2007, it is undergoing Phase I clinical trials for the treatment of non-small cell lung cancer and colorectal cancer in adults, as well as tumors of the central nervous system in children. # Further reading - Wedge S, Kendrew J, Hennequin L; et al. (2005). "AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer". Cancer Res. 65 (10): 4389–400. PMID 15899831.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} # External links - AZD2171—AstraZeneca Pipeline Template:WH Template:WS	https://www.wikidoc.org/index.php/Cediranib
a086e015539ffc6bba3992ca760c88b14c60ef2d	wikidoc	Cefalexin	Cefalexin # 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 Cefalexin is a {{{drugClass}}} that is FDA approved for the treatment of infections of respiratory tract, nasopharynx, otitis media, skin and skin structure and genitourinary tract infections including acute prostatitis.. Common adverse reactions include diarrhea, dyspepsia, gastritis, and abdominal pain, rash, dizziness, fatigue and headache.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cephalexin capsules are indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms: Respiratory tract infections caused by Streptococcus pneumoniae and (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.) Otitis media due to Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxella catarrhalis Skin and skin structure infections caused by Staphylococcus aureus and/or Streptococcus pyogenes Bone infections caused by Staphylococcus aureus and/or Proteus mirabilis Genitourinary tract infections, including acute prostatitis, caused by Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae Note: Culture and susceptibility tests should be initiated prior to and during therapy. Renal function studies should be performed when indicated. To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin and other antibacterial drugs, cephalexin capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Cephalexin capsules are administered orally. Adults — The adult dosage ranges from 1 to 4 g daily in divided doses. The 333 mg and the 750 mg strengths should be administered such that the daily dose is within 1 to 4 grams per day. The usual adult dose is 250 mg every 6 hours. For the following infections, a dosage of 500 mg may be administered every 12 hours: streptococcal pharyngitis, skin and skin structure infections, and uncomplicated cystitis in patients over 15 years of age. Cystitis therapy should be continued for 7 to 14 days. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cephalexin greater than 4 g are required, parenteral cephalosporins, in appropriate doses, should be considered. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use Bacterial endocarditis; Prophylaxis ### Non–Guideline-Supported Use - Dosing Information - Dosage There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefalexin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Pediatric Patients — The usual recommended daily dosage for pediatric patients is 25 to 50 mg/kg in divided doses. For streptococcal pharyngitis in patients over 1 year of age and for skin and skin structure infections, the total daily dose may be divided and administered every 12 hours. In severe infections, the dosage may be doubled. In the therapy of otitis media, clinical studies have shown that a dosage of 75 to 100 mg/kg/day in 4 divided doses is required. In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cephalexin should be administered for at least 10 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Developed by: - Class of Recommendation: - Strength of Evidence: - Dosing Information - Dosage There is limited information regarding Off-Label Guideline-Supported Use of Cefalexin in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Dosage There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefalexin in pediatric patients. # Contraindications Cephalexin capsules are contraindicated in patients with known allergy to the cephalosporin group of antibiotics. # Warnings Before therapy with cephalexin is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalexin, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cephalexin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs. Any patient who has demonstrated some form of allergy, particularly to drugs, should receive antibiotics cautiously. No exception should be made with regard to cephalexin capsules. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cephalexin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.difficile, and surgical evaluation should be instituted as clinically indicated. # Adverse Reactions ## Clinical Trials Experience Gastrointestinal — Onset of pseudomembranous colitis may occur during or after antibacterial treatment (See WARNINGS section). Nausea and vomiting have been reported rarely. The most frequent side effect has been diarrhea. It was very rarely severe enough to warrant cessation of therapy. Dyspepsia, gastritis, and abdominal pain have also occurred. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely. Hypersensitivity — Allergic reactions in the form of rash, urticaria, angioedema, and, rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been observed. These reactions usually subsided upon discontinuation of the drug. In some of these reactions, supportive therapy may be necessary. Anaphylaxis has also been reported. Other reactions have included genital and anal pruritus, genital moniliasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported rarely. Eosinophilia, neutropenia, thrombocytopenia, hemolytic anemia, and slight elevations in AST and ALT have been reported. In addition to the adverse reactions listed above that have been observed in patients treated with cephalexin, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: Adverse Reactions — Fever, colitis, aplastic anemia, hemorrhage, renal dysfunction, and toxic nephropathy. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see INDICATIONS AND USAGE and PRECAUTIONS, GENERAL section). If seizures associated with drug therapy should occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Altered LaboratoryTests — Prolonged prothrombin time, increased BUN, increased creatinine, elevated alkaline phosphatase, elevated bilirubin, elevated LDH, pancytopenia, leukopenia, and agranulocytosis. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Cefalexin in the drug label. # Drug Interactions Metformin — In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin mean Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. No information is available about the interaction of cephalexin and metformin following multiple doses of either drug. Although not observed in this study, adverse effects could potentially arise from coadministration of cephalexin and metformin by inhibition of tubular secretion via organic cationic transporter systems. Accordingly, careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin. Probenecid — As with other β-lactams, the renal excretion of cephalexin is inhibited by probenecid. Drug / Laboratory Test Interactions As a result of administration of cephalexin capsules, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solutions and also with Clinitest® tablets. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Teratogenic effects — Pregnancy Category B — Reproduction studies have been performed on mice and rats using oral doses of cephalexin monohydrate 0.6 and 1.5 times the maximum daily human dose (66 mg/kg/day) based upon mg/m2, and have revealed no harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefalexin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cefalexin during labor and delivery. ### Nursing Mothers The excretion of cephalexin in human milk increased up to 4 hours after a 500 mg dose; the drug reached a maximum level of 4 µg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when cephalexin capsule is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of cephalexin in pediatric patients was established in clinical trials for the dosages described in the DOSAGE AND ADMINISTRATION section. In these trials, pediatric patients may have received cephalexin capsules or cephalexin for oral suspension. Cephalexin capsules should only be used in children and adolescents capable of ingesting the capsule. ### Geriatic Use Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 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 (see PRECAUTIONS, GENERAL section). ### Gender There is no FDA guidance on the use of Cefalexin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cefalexin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cefalexin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Cefalexin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cefalexin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cefalexin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Cefalexin in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Cefalexin in the drug label. # Overdosage Signs and Symptoms — Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. If other symptoms are present, it is probably secondary to an underlying disease state, an allergic reaction, or toxicity due to ingestion of a second medication. Treatment — To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Unless 5 to 10 times the normal dose of cephalexin has been ingested, gastrointestinal decontamination should not be necessary. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin; however, it would be extremely unlikely that one of these procedures would be indicated. The oral median lethal dose of cephalexin in rats is >5000 mg/kg. # Pharmacology There is limited information regarding Cefalexin Pharmacology in the drug label. ## Mechanism of Action ## Structure - Cephalexin, USP is a semisynthetic cephalosporin antibiotic intended for oral administration. It is 7-(D-α-Amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate. Cephalexin has the molecular formula C16H17N3O4S H2O and the molecular weight is 365.41. Cephalexin has the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Cefalexin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Cefalexin in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Cefalexin in the drug label. # Clinical Studies Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of cephalexin. Tests to determine the mutagenic potential of cephalexin have not been performed. In male and female rats, fertility and reproductive performance were not affected by cephalexin oral doses up to 1.5 times the highest recommended human dose based upon mg/m2. # How Supplied Cephalexin capsules, USP are available in: The 250 mg capsules are a white to off white powder filled into size 2 capsules (white opaque cap and white opaque body) that are imprinted with 801 on the cap in black. They are available as follows: Bottles of 100 NDC 15749-801-02 Bottles of 500 NDC 15749-801-08 The 500 mg capsules are a white to off white powder filled into size 0 capsules (white opaque cap and white opaque body) that are imprinted with 802 on the cap in black. They are available as follows: Bottles of 100 NDC 15749-802-02 Bottles of 500 NDC 15749-802-08 ## Storage Store at 20°C to 25°C (68°F to 77°F) [ # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be counseled that antibacterial drugs including cephalexin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Cefalexin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Cefalexin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, 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 Cefalexin is a {{{drugClass}}} that is FDA approved for the treatment of infections of respiratory tract, nasopharynx, otitis media, skin and skin structure and genitourinary tract infections including acute prostatitis.. Common adverse reactions include diarrhea, dyspepsia, gastritis, and abdominal pain, rash, dizziness, fatigue and headache.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cephalexin capsules are indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms: Respiratory tract infections caused by Streptococcus pneumoniae and (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.) Otitis media due to Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxella catarrhalis Skin and skin structure infections caused by Staphylococcus aureus and/or Streptococcus pyogenes Bone infections caused by Staphylococcus aureus and/or Proteus mirabilis Genitourinary tract infections, including acute prostatitis, caused by Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae Note: Culture and susceptibility tests should be initiated prior to and during therapy. Renal function studies should be performed when indicated. To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin and other antibacterial drugs, cephalexin capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Cephalexin capsules are administered orally. Adults — The adult dosage ranges from 1 to 4 g daily in divided doses. The 333 mg and the 750 mg strengths should be administered such that the daily dose is within 1 to 4 grams per day. The usual adult dose is 250 mg every 6 hours. For the following infections, a dosage of 500 mg may be administered every 12 hours: streptococcal pharyngitis, skin and skin structure infections, and uncomplicated cystitis in patients over 15 years of age. Cystitis therapy should be continued for 7 to 14 days. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cephalexin greater than 4 g are required, parenteral cephalosporins, in appropriate doses, should be considered. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use Bacterial endocarditis; Prophylaxis ### Non–Guideline-Supported Use - Dosing Information - Dosage There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefalexin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Pediatric Patients — The usual recommended daily dosage for pediatric patients is 25 to 50 mg/kg in divided doses. For streptococcal pharyngitis in patients over 1 year of age and for skin and skin structure infections, the total daily dose may be divided and administered every 12 hours. In severe infections, the dosage may be doubled. In the therapy of otitis media, clinical studies have shown that a dosage of 75 to 100 mg/kg/day in 4 divided doses is required. In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cephalexin should be administered for at least 10 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Developed by: - Class of Recommendation: - Strength of Evidence: - Dosing Information - Dosage There is limited information regarding Off-Label Guideline-Supported Use of Cefalexin in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Dosage There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefalexin in pediatric patients. # Contraindications Cephalexin capsules are contraindicated in patients with known allergy to the cephalosporin group of antibiotics. # Warnings Before therapy with cephalexin is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalexin, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cephalexin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs. Any patient who has demonstrated some form of allergy, particularly to drugs, should receive antibiotics cautiously. No exception should be made with regard to cephalexin capsules. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cephalexin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.difficile, and surgical evaluation should be instituted as clinically indicated. # Adverse Reactions ## Clinical Trials Experience Gastrointestinal — Onset of pseudomembranous colitis may occur during or after antibacterial treatment (See WARNINGS section). Nausea and vomiting have been reported rarely. The most frequent side effect has been diarrhea. It was very rarely severe enough to warrant cessation of therapy. Dyspepsia, gastritis, and abdominal pain have also occurred. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely. Hypersensitivity — Allergic reactions in the form of rash, urticaria, angioedema, and, rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been observed. These reactions usually subsided upon discontinuation of the drug. In some of these reactions, supportive therapy may be necessary. Anaphylaxis has also been reported. Other reactions have included genital and anal pruritus, genital moniliasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported rarely. Eosinophilia, neutropenia, thrombocytopenia, hemolytic anemia, and slight elevations in AST and ALT have been reported. In addition to the adverse reactions listed above that have been observed in patients treated with cephalexin, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: Adverse Reactions — Fever, colitis, aplastic anemia, hemorrhage, renal dysfunction, and toxic nephropathy. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see INDICATIONS AND USAGE and PRECAUTIONS, GENERAL section). If seizures associated with drug therapy should occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Altered LaboratoryTests — Prolonged prothrombin time, increased BUN, increased creatinine, elevated alkaline phosphatase, elevated bilirubin, elevated LDH, pancytopenia, leukopenia, and agranulocytosis. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Cefalexin in the drug label. # Drug Interactions Metformin — In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin mean Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. No information is available about the interaction of cephalexin and metformin following multiple doses of either drug. Although not observed in this study, adverse effects could potentially arise from coadministration of cephalexin and metformin by inhibition of tubular secretion via organic cationic transporter systems. Accordingly, careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin. Probenecid — As with other β-lactams, the renal excretion of cephalexin is inhibited by probenecid. Drug / Laboratory Test Interactions As a result of administration of cephalexin capsules, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solutions and also with Clinitest® tablets. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Teratogenic effects — Pregnancy Category B — Reproduction studies have been performed on mice and rats using oral doses of cephalexin monohydrate 0.6 and 1.5 times the maximum daily human dose (66 mg/kg/day) based upon mg/m2, and have revealed no harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefalexin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cefalexin during labor and delivery. ### Nursing Mothers The excretion of cephalexin in human milk increased up to 4 hours after a 500 mg dose; the drug reached a maximum level of 4 µg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when cephalexin capsule is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of cephalexin in pediatric patients was established in clinical trials for the dosages described in the DOSAGE AND ADMINISTRATION section. In these trials, pediatric patients may have received cephalexin capsules or cephalexin for oral suspension. Cephalexin capsules should only be used in children and adolescents capable of ingesting the capsule. ### Geriatic Use Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 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 (see PRECAUTIONS, GENERAL section). ### Gender There is no FDA guidance on the use of Cefalexin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cefalexin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cefalexin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Cefalexin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cefalexin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cefalexin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Cefalexin in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Cefalexin in the drug label. # Overdosage Signs and Symptoms — Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. If other symptoms are present, it is probably secondary to an underlying disease state, an allergic reaction, or toxicity due to ingestion of a second medication. Treatment — To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Unless 5 to 10 times the normal dose of cephalexin has been ingested, gastrointestinal decontamination should not be necessary. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin; however, it would be extremely unlikely that one of these procedures would be indicated. The oral median lethal dose of cephalexin in rats is >5000 mg/kg. # Pharmacology There is limited information regarding Cefalexin Pharmacology in the drug label. ## Mechanism of Action - ## Structure - Cephalexin, USP is a semisynthetic cephalosporin antibiotic intended for oral administration. It is 7-(D-α-Amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate. Cephalexin has the molecular formula C16H17N3O4S H2O and the molecular weight is 365.41. Cephalexin has the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Cefalexin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Cefalexin in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Cefalexin in the drug label. # Clinical Studies Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of cephalexin. Tests to determine the mutagenic potential of cephalexin have not been performed. In male and female rats, fertility and reproductive performance were not affected by cephalexin oral doses up to 1.5 times the highest recommended human dose based upon mg/m2. # How Supplied Cephalexin capsules, USP are available in: The 250 mg capsules are a white to off white powder filled into size 2 capsules (white opaque cap and white opaque body) that are imprinted with 801 on the cap in black. They are available as follows: Bottles of 100 NDC 15749-801-02 Bottles of 500 NDC 15749-801-08 The 500 mg capsules are a white to off white powder filled into size 0 capsules (white opaque cap and white opaque body) that are imprinted with 802 on the cap in black. They are available as follows: Bottles of 100 NDC 15749-802-02 Bottles of 500 NDC 15749-802-08 ## Storage Store at 20°C to 25°C (68°F to 77°F) [ # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be counseled that antibacterial drugs including cephalexin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Cefalexin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cefalexin
17cf641b7cf5794d56efe0fd4704eaa0b3a5caa3	wikidoc	Cefovecin	Cefovecin # Overview Cefovecin (INN) is an antibiotic of the cephalosporin class, licensed for the treatment of skin infections in cats and dogs. It is marketed by Zoetis under the trade name Convenia. It is the first single-dose injectable antibiotic for dogs and cats that assures owner compliance with dosing for the animal. It is used for the treatment of skin infections caused by Pasturella multocida in cats, and Streptococcus intermedius/S. canis in dogs. The advantage of using injectable antibiotics is not missing a dose that can allow partially resistant microbes to recover during missed doses. It is highly effective, but should not be used in pregnant or lactating animals or in animals with a history of allergies to penicillin or cephalosporin drugs. # Approval and usage Cefovecin was first authorized for use in the European Union in June 2006, and was approved for use in the United States in June 2008. It is approved as a broad-spectrum, fourth-generation cephalosporin for subcutaneous injection lasting 14 days for treating skin and soft tissue infections. # Precautions Contraindications include known allergies to cefovecin or antibiotics containing β-lactam rings such as penicillin or cephalosporins. Adverse reactions can include anaphylaxis. It is not for use in humans and should be kept out of reach of children. Individuals with similar known allergies should avoid dermal contact when handling the drugs. Adverse reactions in dogs can include lethargy, decreased appetite, vomiting, diarrhea, blood in feces, and flatulence. Adverse reactions in cats can include vomiting, diarrhea, decreased appetite, lethargy, odd hyperactive behavior, and inappropriate urination. Mildly increased serum ALT and gamma glutamyl transferase have been noted. # Effectiveness Cefovecin functions by interfering with cell wall synthesis. The chemical covalently binds to the so-called penicillin-binding proteins. Due to the high protein-binding of the chemical, it is not effective against Pseudomonas spp., or enterococci. In drug studies, cefovecin administered to dogs was 92.4% effective against skin infections (secondary superficial pyoderma, abscesses, and infected wounds). In cats, it was 96.8% effective against skin infections.	Cefovecin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cefovecin (INN) is an antibiotic of the cephalosporin class, licensed for the treatment of skin infections in cats and dogs. It is marketed by Zoetis under the trade name Convenia. It is the first single-dose injectable antibiotic for dogs and cats that assures owner compliance with dosing for the animal. It is used for the treatment of skin infections caused by Pasturella multocida in cats, and Streptococcus intermedius/S. canis in dogs. The advantage of using injectable antibiotics is not missing a dose that can allow partially resistant microbes to recover during missed doses. It is highly effective, but should not be used in pregnant or lactating animals or in animals with a history of allergies to penicillin or cephalosporin drugs.[1] # Approval and usage Cefovecin was first authorized for use in the European Union in June 2006,[2] and was approved for use in the United States in June 2008.[3] It is approved as a broad-spectrum, fourth-generation cephalosporin for subcutaneous injection lasting 14 days for treating skin and soft tissue infections.[4] # Precautions Contraindications include known allergies to cefovecin or antibiotics containing β-lactam rings such as penicillin or cephalosporins. Adverse reactions can include anaphylaxis. It is not for use in humans and should be kept out of reach of children. Individuals with similar known allergies should avoid dermal contact when handling the drugs. Adverse reactions in dogs can include lethargy, decreased appetite, vomiting, diarrhea, blood in feces, and flatulence. Adverse reactions in cats can include vomiting, diarrhea, decreased appetite, lethargy, odd hyperactive behavior, and inappropriate urination. Mildly increased serum ALT and gamma glutamyl transferase have been noted.[5] # Effectiveness Cefovecin functions by interfering with cell wall synthesis. The chemical covalently binds to the so-called penicillin-binding proteins. Due to the high protein-binding of the chemical, it is not effective against Pseudomonas spp., or enterococci. In drug studies, cefovecin administered to dogs was 92.4% effective against skin infections (secondary superficial pyoderma, abscesses, and infected wounds). In cats, it was 96.8% effective against skin infections.[6]	https://www.wikidoc.org/index.php/Cefovecin
51b1449477c77869f8a2a61d6078c4f481a388d7	wikidoc	Cefprozil	Cefprozil # 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 Cefprozil is a 2nd generation cephalosporin that is FDA approved for the treatment of mild to moderate infections of upper respiratory tract, lower respiratory tract, and uncomplicated skin and Skin-structure infections. Common adverse reactions include diarrhea, nausea, ALT/SGPT level raised, AST/SGOT level raised and vaginitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cefprozil tablets are indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below: - Pharyngitis/tonsillitis caused by Streptococcus pyogenes. - Dosage: 500 mg daily for 10 days - Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 500 mg each 12 hours for 10 days - Acute Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 250 mg each 12 hours for 10 days - Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 500 mg each 12 hours for 10 days - Caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes. Abscesses usually require surgical drainage. - 250 mg each 12 hours for 10 days, or - 500 mg daily for 10 days, or - 500 mg each 12 hours for 10 days ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cefprozil in adult patients. ### Non–Guideline-Supported Use - Osteomyelitis - Pneumonia # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Cefprozil tablets are indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below: - Pharyngitis/tonsillitis caused by Streptococcus pyogenes - Dosage for children between 2-12 years: 7.5 mg/kg daily for 110 days - Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage for 6 month - 12 years: 15 mg/kg each 12 hours for 10 days. - Acute Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage for 6 months - 12 years: 7.5 mg/kg for 10 days or 15 mg/kg each 12 hours for 10 days. - Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes. Abscesses usually require surgical drainage. - Dosage for children between 2-12 years: 20 mg/kg daily for 10 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cefprozil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefprozil in pediatric patients. # Contraindications Cefprozil tablets are contraindicated in patients with known allergy to the cephalosporin class of antibiotics. # Warnings BEFORE THERAPY WITH CEFPROZIL IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFPROZIL, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-SENSITIVITY AMONG β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFPROZIL OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefprozil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. # Adverse Reactions ## Clinical Trials Experience The most common adverse effects observed in patients treated with cefprozil are: - Gastrointestinal: Diarrhea (2.9%), nausea (3.5%), vomiting (1%), and abdominal pain (1%). - Hepatobiliary: Elevations of AST (SGOT) (2%), ALT (SGPT) (2%), alkaline phosphatase (0.2%), and bilirubin values (<0.1%). As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely. - Hypersensitivity: Rash (0.9%), urticaria (0.1%). Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy. - CNS: Dizziness (1%). hyperactivity, headache, nervousness, insomnia, confusion, and somnolence have been reported rarely (<1%). All were reversible. - Hematopoietic: Decreased leukocyte count (0.2%), eosinophilia (2.3%). - Renal: Elevated BUN (0.1%), serum creatinine (0.1%). - Other: Diaper rash and superinfection (1.5%), genital pruritus and vaginitis (1.6%). In addition to the adverse reactions listed above which have been observed in patients treated with cefprozil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Aplastic anemia, hemolytic anemia, hemorrhage, renal dysfunction, toxic epidermal necrolysis, toxic nephropathy, prolonged prothrombin time, positive Coombs’ test, elevated LDH, pancytopenia, neutropenia, agranulocytosis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. ## Postmarketing Experience The following adverse events, regardless of established causal relationship to cefprozil tablets, have been rarely reported during postmarketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum-sickness like reactions, Stevens-Johnson syndrome, and thrombocytopenia. # Drug Interactions - Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the AUC for cefprozil. - The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in rabbits, mice, and rats using oral doses of cefprozil of 0.8, 8.5, and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m2, and have revealed no harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefprozil in women who are pregnant. ### Labor and Delivery Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed. ### Nursing Mothers Small amounts of cefprozil (<0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 mcg/mL. Caution should be exercised when cefprozil tablets are administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown. ### Pediatric Use The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of cefprozil tablets for the treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections have been established in the age groups 2 to 12 years. Use of cefprozil for the treatment of these infections is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of cefprozil in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults. Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis, or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported. ### Geriatic Use Of the more than 4500 adults treated with cefprozil tablets in clinical studies, 14% were 65 years and older, while 5% were 75 years and older. When geriatric patients received the usual recommended adult doses, their clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals to the effects of cefprozil tablets cannot be excluded. Cefprozil 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 Cefprozil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cefprozil with respect to specific racial populations. ### Renal Impairment In patients with known or suspected renal impairment, careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of cefprozil tablets should be reduced in these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. Cephalosporins, including cefprozil tablets, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function. ### Hepatic Impairment In patients with impaired hepatic function, the half-life increases to approximately 2 hours. The magnitude of the changes does not warrant a dosage adjustment for patients with impaired hepatic function. ### Females of Reproductive Potential and Males Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m2. ### Immunocompromised Patients There is no FDA guidance one the use of Cefprozil in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Cefprozil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cefprozil and IV administrations. # Overdosage Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weanling, or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality. Cefprozil is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will aid in the removal of cefprozil from the body. # Pharmacology ## Mechanism of Action Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. ## Structure The structural formula is: ## Pharmacodynamics There is limited information regarding Cefprozil Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetic data were derived from the capsule formulation; however, bioequivalence has been demonstrated for the oral solution, capsule, tablet, and suspension formulations under fasting conditions. Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours, while the steady-state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 mL/min/kg and 2.3 mL/min/kg, respectively. Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 mcg/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. During the first 4-hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 mcg/mL, 1000 mcg/mL, and 2900 mcg/mL, respectively. Administration of cefprozil with food did not affect the extent of absorption (AUC) or the peak plasma concentration (Cmax) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (Tmax). The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid. Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 mcg/mL to 20 mcg/mL. There was no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1000 mg every 8 hours for 10 days. ## Nonclinical Toxicology Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests, but not with enzyme-based tests for glycosuria. A false negative reaction may occur in the ferricyanide test for blood glucose. The presence of cefprozil in the blood does not interfere with the assay of plasma or urine creatinine by the alkaline picrate method. Long term in vivo studies have not been performed to evaluate the carcinogenic potential of cefprozil. Cefprozil was not found to be mutagenic in either the Ames Salmonella or E. coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m2. # Clinical Studies In a controlled clinical study of acute otitis media performed in the United States where significant rates of β-lactamase-producing organisms were found, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes i.e., clinical success) and safety results were obtained: The incidences of adverse events, primarily diarrhea and rash*, were clinically and statistically significantly higher in the control arm versus the cefprozil arm. In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of β-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained: The incidence of adverse events in the cefprozil arm was comparable to the incidence of adverse events in the control arm (agent that contained a specific β-lactamase inhibitor). # How Supplied - Cefprozil Tablets 250 mg - Bottles of 100 - NDC 57237-036-01 - Cefprozil Tablets 500 mg - Bottles of 50 - NDC 57237-037-50 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be counseled that antibacterial drugs including cefprozil tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefprozil tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefprozil tablets or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol Alcohol-Cefprozil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cefzil # Look-Alike Drug Names There is limited information regarding Cefprozil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cefprozil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Cefprozil is a 2nd generation cephalosporin that is FDA approved for the treatment of mild to moderate infections of upper respiratory tract, lower respiratory tract, and uncomplicated skin and Skin-structure infections. Common adverse reactions include diarrhea, nausea, ALT/SGPT level raised, AST/SGOT level raised and vaginitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cefprozil tablets are indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below: - Pharyngitis/tonsillitis caused by Streptococcus pyogenes. - Dosage: 500 mg daily for 10 days - Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 500 mg each 12 hours for 10 days - Acute Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 250 mg each 12 hours for 10 days - Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage: 500 mg each 12 hours for 10 days - Caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes. Abscesses usually require surgical drainage. - 250 mg each 12 hours for 10 days, or - 500 mg daily for 10 days, or - 500 mg each 12 hours for 10 days ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cefprozil in adult patients. ### Non–Guideline-Supported Use - Osteomyelitis - Pneumonia # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Cefprozil tablets are indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below: - Pharyngitis/tonsillitis caused by Streptococcus pyogenes - Dosage for children between 2-12 years: 7.5 mg/kg daily for 110 days - Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage for 6 month - 12 years: 15 mg/kg each 12 hours for 10 days. - Acute Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Dosage for 6 months - 12 years: 7.5 mg/kg for 10 days or 15 mg/kg each 12 hours for 10 days. - Secondary Bacterial Infection of Acute Bronchitis and Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains), and Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains). - Caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes. Abscesses usually require surgical drainage. - Dosage for children between 2-12 years: 20 mg/kg daily for 10 days. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cefprozil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefprozil in pediatric patients. # Contraindications Cefprozil tablets are contraindicated in patients with known allergy to the cephalosporin class of antibiotics. # Warnings BEFORE THERAPY WITH CEFPROZIL IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFPROZIL, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-SENSITIVITY AMONG β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFPROZIL OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefprozil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. # Adverse Reactions ## Clinical Trials Experience The most common adverse effects observed in patients treated with cefprozil are: - Gastrointestinal: Diarrhea (2.9%), nausea (3.5%), vomiting (1%), and abdominal pain (1%). - Hepatobiliary: Elevations of AST (SGOT) (2%), ALT (SGPT) (2%), alkaline phosphatase (0.2%), and bilirubin values (<0.1%). As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely. - Hypersensitivity: Rash (0.9%), urticaria (0.1%). Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy. - CNS: Dizziness (1%). hyperactivity, headache, nervousness, insomnia, confusion, and somnolence have been reported rarely (<1%). All were reversible. - Hematopoietic: Decreased leukocyte count (0.2%), eosinophilia (2.3%). - Renal: Elevated BUN (0.1%), serum creatinine (0.1%). - Other: Diaper rash and superinfection (1.5%), genital pruritus and vaginitis (1.6%). In addition to the adverse reactions listed above which have been observed in patients treated with cefprozil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Aplastic anemia, hemolytic anemia, hemorrhage, renal dysfunction, toxic epidermal necrolysis, toxic nephropathy, prolonged prothrombin time, positive Coombs’ test, elevated LDH, pancytopenia, neutropenia, agranulocytosis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. ## Postmarketing Experience The following adverse events, regardless of established causal relationship to cefprozil tablets, have been rarely reported during postmarketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum-sickness like reactions, Stevens-Johnson syndrome, and thrombocytopenia. # Drug Interactions - Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the AUC for cefprozil. - The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in rabbits, mice, and rats using oral doses of cefprozil of 0.8, 8.5, and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m2, and have revealed no harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefprozil in women who are pregnant. ### Labor and Delivery Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed. ### Nursing Mothers Small amounts of cefprozil (<0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 mcg/mL. Caution should be exercised when cefprozil tablets are administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown. ### Pediatric Use The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of cefprozil tablets for the treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections have been established in the age groups 2 to 12 years. Use of cefprozil for the treatment of these infections is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of cefprozil in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults. Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis, or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported. ### Geriatic Use Of the more than 4500 adults treated with cefprozil tablets in clinical studies, 14% were 65 years and older, while 5% were 75 years and older. When geriatric patients received the usual recommended adult doses, their clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals to the effects of cefprozil tablets cannot be excluded. Cefprozil 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 Cefprozil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cefprozil with respect to specific racial populations. ### Renal Impairment In patients with known or suspected renal impairment, careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of cefprozil tablets should be reduced in these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. Cephalosporins, including cefprozil tablets, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function. ### Hepatic Impairment In patients with impaired hepatic function, the half-life increases to approximately 2 hours. The magnitude of the changes does not warrant a dosage adjustment for patients with impaired hepatic function. ### Females of Reproductive Potential and Males Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m2. ### Immunocompromised Patients There is no FDA guidance one the use of Cefprozil in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Cefprozil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cefprozil and IV administrations. # Overdosage Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weanling, or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality. Cefprozil is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will aid in the removal of cefprozil from the body. # Pharmacology ## Mechanism of Action Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. ## Structure The structural formula is: ## Pharmacodynamics There is limited information regarding Cefprozil Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetic data were derived from the capsule formulation; however, bioequivalence has been demonstrated for the oral solution, capsule, tablet, and suspension formulations under fasting conditions. Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours, while the steady-state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 mL/min/kg and 2.3 mL/min/kg, respectively. Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 mcg/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. During the first 4-hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 mcg/mL, 1000 mcg/mL, and 2900 mcg/mL, respectively. Administration of cefprozil with food did not affect the extent of absorption (AUC) or the peak plasma concentration (Cmax) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (Tmax). The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid. Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 mcg/mL to 20 mcg/mL. There was no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1000 mg every 8 hours for 10 days. ## Nonclinical Toxicology Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests, but not with enzyme-based tests for glycosuria. A false negative reaction may occur in the ferricyanide test for blood glucose. The presence of cefprozil in the blood does not interfere with the assay of plasma or urine creatinine by the alkaline picrate method. Long term in vivo studies have not been performed to evaluate the carcinogenic potential of cefprozil. Cefprozil was not found to be mutagenic in either the Ames Salmonella or E. coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m2. # Clinical Studies In a controlled clinical study of acute otitis media performed in the United States where significant rates of β-lactamase-producing organisms were found, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes i.e., clinical success) and safety results were obtained: The incidences of adverse events, primarily diarrhea and rash*, were clinically and statistically significantly higher in the control arm versus the cefprozil arm. In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of β-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained: The incidence of adverse events in the cefprozil arm was comparable to the incidence of adverse events in the control arm (agent that contained a specific β-lactamase inhibitor). # How Supplied - Cefprozil Tablets 250 mg - Bottles of 100 - NDC 57237-036-01 - Cefprozil Tablets 500 mg - Bottles of 50 - NDC 57237-037-50 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be counseled that antibacterial drugs including cefprozil tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefprozil tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefprozil tablets or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol Alcohol-Cefprozil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cefzil [1] # Look-Alike Drug Names There is limited information regarding Cefprozil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cefprozil
ff6ad9d5cf1eeb94bdb490b558d1e0b66b9ab3c5	wikidoc	Cefradine	Cefradine # Overview Cefradine (INN) (formerly cephradine BAN) is a first generation cephalosporin antibiotic. # Indications It has similar spectrum of activity to cefalexin. RESPIRATORY TRACT INFECTIONS (e.g., tonsillitis, pharyngitis, and lobar pneumonia) caused by group A beta-hemolytic streptococci and S. pneumoniae (formerly D. pneumonia). (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Velosef is generally effective in the eradication of streptococci from the nasopharynx; substantial data establishing the efficacy of Velosef in the subsequent prevention of rheumatic fever are not available at present.) OTITIS MEDIA caused by group A beta-hemolytic streptococci, S. pneumoniae (formerly D. pneumoniae), H. influenzae, and staphylococci. SKIN AND SKIN STRUCTURE INFECTIONS caused by staphylococci (penicillin-susceptible and penicillin-resistant) and beta-hemolytic streptococci. URINARY TRACT INFECTIONS, including prostatitis, caused by E. coli, P. mirabilis, Klebsiella species, and enterococci (S. faecalis). The high concentrations of cephradine achievable in the urinary tract will be effective against many strains of enterococci for which disc susceptibility studies indicate relative resistance. It is to be noted that among beta-lactam antibiotics, ampicillin is the drug of choice for enterococcal urinary tract (E. faecalis) infection. # Formulations Capsules containing 250 mg or 500 mg, Syrup containing 250 mg/5 ml, or vials for injection containing 500 mg or 1 g. # Brand Names International Brands Velocef, Infexin (by Merck Pvt, Ltd) Intracef (by Beximco Pharma) SEFRIL(The ACME laboratories Ltd., Bangladesh), REOCEF(Rephco Pharmaceuticals Ltd., Bangladesh). Lebac (by Square pharmaceuticals Ltd., Bangladesh)	Cefradine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cefradine (INN) (formerly cephradine BAN) is a first generation cephalosporin antibiotic. # Indications It has similar spectrum of activity to cefalexin. RESPIRATORY TRACT INFECTIONS (e.g., tonsillitis, pharyngitis, and lobar pneumonia) caused by group A beta-hemolytic streptococci and S. pneumoniae (formerly D. pneumonia). (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Velosef is generally effective in the eradication of streptococci from the nasopharynx; substantial data establishing the efficacy of Velosef in the subsequent prevention of rheumatic fever are not available at present.) OTITIS MEDIA caused by group A beta-hemolytic streptococci, S. pneumoniae (formerly D. pneumoniae), H. influenzae, and staphylococci. SKIN AND SKIN STRUCTURE INFECTIONS caused by staphylococci (penicillin-susceptible and penicillin-resistant) and beta-hemolytic streptococci. URINARY TRACT INFECTIONS, including prostatitis, caused by E. coli, P. mirabilis, Klebsiella species, and enterococci (S. faecalis). The high concentrations of cephradine achievable in the urinary tract will be effective against many strains of enterococci for which disc susceptibility studies indicate relative resistance. It is to be noted that among beta-lactam antibiotics, ampicillin is the drug of choice for enterococcal urinary tract (E. faecalis) infection. # Formulations Capsules containing 250 mg or 500 mg, Syrup containing 250 mg/5 ml, or vials for injection containing 500 mg or 1 g. # Brand Names International Brands Velocef, Infexin (by Merck Pvt, Ltd) Intracef (by Beximco Pharma) SEFRIL(The ACME laboratories Ltd., Bangladesh), REOCEF(Rephco Pharmaceuticals Ltd., Bangladesh). Lebac (by Square pharmaceuticals Ltd., Bangladesh)	https://www.wikidoc.org/index.php/Cefradine
303a289be051298f92df95635f07f07499af5473	wikidoc	Celecoxib	Celecoxib # 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 Celecoxib is an analgesic that is FDA approved for the treatment of osteoarthritis ，rheumatoid arthritis ，juvenile rheumatoid arthritis, ankylosing Spondylitis，acute pain and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension,diarrhea, nausea and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Osteoarthritis - Dosing information - Recommended oral dosage: 200 mg PO qd or as 100 mg PO bid # Rheumatoid Arthritis - Dosing information - Recommended oral dosage: 100 to 200 mg PO bid # Ankylosing Spondylitis - Dosing information - Recommended dosage: 200 mg daily PO qd or bid. - If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. - If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. # Management of Acute Pain and Treatment of Primary Dysmenorrhea Dosing information - Initial recommended dosage: 400 mg , followed by an additional 200 mg dose if needed on the first day. - On subsequent days, the recommended dose：200 mg PO bid. # Special Populations Hepatic insufficiency Dosing information - The daily recommended dose of Celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Celecoxib in patients with severe hepatic impairment is not recommended Poor Metabolizers of CYP2C9 Substrates Dosing information - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C93/3). Consider using alternative management in JRA patients who are poor metabolizers. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use Gout - Developed by: American College of Rheumatology (ACR) - Class of Recommendation: Not applicable - Level of Evidence: Level B Dosing Information - 800 mg followed by 400 mg on day 1 and then 400 mg twice daily for 1 week ### Non–Guideline-Supported Use # Prophylaxis of Colorectal adenoma Dosing information - 200 mg PO bid # Coronary stent stenosis Dosing information - 400 mg once just prior to coronary intervention followed by 200 mg twice daily for 6 months # Schizophrenia Dosing information - 400 mg/day # Systemic lupus erythematosus Dosing information - Not applicable 12139371 # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Juvenile Rheumatoid Arthritis Dosing information - Recommended oral dosage: for pediatric patients (age 2 years and older) is based on weight. - For patients ≥10 kg to ≤25 kg - Recommended dosage:50 mg PO bid. - For patients >25 kg - Recommended dosage:100 mg PO bid - For patients who have difficulty swallowing capsules, the contents of a Celecoxib capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2–8° C/ 35–45° F). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Celecoxib in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Celecoxib in pediatric patients. # Contraindications - Celecoxib is contraindicated: - In patients with known hypersensitivity to celecoxib, aspirin, or other NSAIDs. - In patients who have demonstrated allergic-type reactions to sulfonamides. - In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients - For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery - In patients with active gastrointestinal bleeding. # Warnings ## Cardiovascular Thrombotic Events - Chronic use of Celecoxib may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Celecoxib) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for Celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with Celecoxib 200 mg twice daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction . - All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with Celecoxib, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and Celecoxib does increase the risk of serious GI events . - Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke ## Hypertension - As with all NSAIDs, Celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Celecoxib and throughout the course of therapy. The rates of hypertension from the CLASS trial in the Celecoxib, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively . ## Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs, including Celecoxib . In the CLASS study , the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on Celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Celecoxib should be used with caution in patients with fluid retention or heart failure. ## Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation - NSAIDs, including Celecoxib, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA . With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during Celecoxib therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. - Celecoxib is contraindicated in patients with active GI bleeding. ## Hepatic Effects - Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including Celecoxib . In controlled clinical trials of Celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for Celecoxib and 5% for placebo, and approximately 0.2% of patients taking Celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Celecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Celecoxib should be discontinued. ## Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with Celecoxib have shown renal effects similar to those observed with comparator NSAIDs. - No information is available from controlled clinical studies regarding the use of Celecoxib in patients with advanced renal disease. Therefore, treatment with Celecoxib is not recommended in these patients with advanced renal disease. If Celecoxib therapy must be initiated, close monitoring of the patient's renal function is advisable. ## Anaphylactoid reactions - As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Celecoxib. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving Celecoxib. Celecoxib should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs . Emergency help should be sought in cases where an anaphylactoid reaction occurs. ## Skin Reactions - Celecoxib is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. ## Pregnancy - In late pregnancy, starting at 30 weeks gestation, Celecoxib should be avoided because it may cause premature closure of the ductus arterioles. ## corticosteroid Treatment - Celecoxib cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. ## Hematological Effects - Anemia is sometimes seen in patients receiving Celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with Celecoxib and 0.4% with placebo. Patients on long-term treatment with Celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages. ## Disseminated Intravascular Coagulation (DIC) - Celecoxib should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation. ## Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. ## Laboratory Tests - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, Celecoxib should be discontinued. - In controlled clinical trials, elevated BUN occurred more frequently in patients receiving Celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. ## Inflammation - The pharmacological activity of Celecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. ## Concomitant NSAID Use - The concomitant use of Celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. # Adverse Reactions ## Clinical Trials Experience - Of the Celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of Celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received Celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. - 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. ## Pre-marketing Controlled Arthritis Trials - Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving Celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. - In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving Celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the Celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of Celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. ## The Celecoxib Long-Term Arthritis Safety Study - Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on Celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with Celecoxib was maintained with or without ASA use - Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for Celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). ## Juvenile Rheumatoid Arthritis Study - In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg BID, 82 patients were treated with celecoxib 6 mg/kg BID, and 83 patients were treated with naproxen 7.5 mg/kg BID. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg BID had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups. - In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg BID. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged. ## Other Pre-Approval Studies - Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with Celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RAstudies. - Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with Celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of Celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. ## The APC and PreSAP Trials - Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to Celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years - Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from Celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with Celecoxib were greater as compared to the arthritis pre-marketing trials were as follows: - The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking Celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies: ## Postmarketing Experience There is limited information regarding Celecoxib Postmarketing Experience in the drug label. # Drug Interactions General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9. - In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. ## Warfarin - Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing Celecoxib therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily 2–5 mg doses of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving Celecoxib concurrently with warfarin. ## Lithium - In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when Celecoxib is introduced or withdrawn. ## Aspirin - Celecoxib can be used with low-dose aspirin. However, concomitant administration of aspirin with Celecoxib increases the rate of GI ulceration or other complications, compared to use of Celecoxib alone. Because of its lack of platelet effects, Celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. ## ACE-inhibitors and Angiotensin II Antagonists - Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking Celecoxib concomitantly with ACE-inhibitors and angiotensin II antagonists - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. ## Fluconazole - Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole. ## Furosemide - Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. ## Methotrexate - In an interaction study of rheumatoid arthritis patients taking methotrexate, Celecoxib did not have an effect on the pharmacokinetics of methotrexate . ## Concomitant NSAID Use - The concomitant use of Celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward. Teratogenic effects: Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0–24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Celecoxib produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of Celecoxib during the third trimester of pregnancy should be avoided. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Celecoxib in women who are pregnant. ### Labor and Delivery - Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0–24 at 200 mg BID). The effects of Celecoxib on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celecoxib in breast milk. The calculated average daily infant dose was 10–40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when Celecoxib is administered to a nursing woman. ### Pediatric Use - Celecoxib is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to Celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to Celecoxib or other COX-2 selective and non-selective NSAIDs - The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests - Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers ### Geriatic Use - Of the total number of patients who received Celecoxib in pre-approval clinical trials, more than 3,300 were 65–74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients ### Gender There is no FDA guidance on the use of Celecoxib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Celecoxib with respect to specific racial populations. ### Renal Impairment - Celecoxib is not recommended in patients with severe renal insufficiency ### Hepatic Impairment - The daily recommended dose of Celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Celecoxib in patients with severe hepatic impairment is not recommended ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Celecoxib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Celecoxib in patients who are immunocompromised. ### Poor Metabolizers of CYP2C9 Substrates - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e., CYP2C93/3). Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. # Administration and Monitoring ### Administration - Oral ### Monitoring - FDA Package Insert for Celecoxib contains no information regarding drug monitoring. # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - No overdoses of Celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action - Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, Celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, Celecoxib reduced the incidence and multiplicity of tumors. ## Structure - Celecoxib (celecoxib) is chemically designated as 4- benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38; the chemical structure is as follows: - Celecoxib oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg of celecoxib, together with inactive ingredients including: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate. ## Pharmacodynamics Platelets: In clinical trials using normal volunteers, Celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, Celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of Celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of Celecoxib. Fluid Retention: Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone. ## Pharmacokinetics Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax and AUC. Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 3. Food Effects: When Celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. - Coadministration of Celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Celecoxib, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption. - In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t1/2 after administration of capsule contents on applesauce. Distribution: In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. Metabolism: Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min. Geriatric: At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose. Pediatric: The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient. Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg twice daily (see Dosage and Administration (2.3). Celecoxib has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks. Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown. Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily recommended dose of Celecoxib capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of Celecoxib in patients with severe hepatic impairment is not recommended. Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35–60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, Celecoxib is not recommended in patients with severe renal insufficiency. Drug interactions - In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. - In vivo studies have shown the following: Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Fluconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole. Other Drugs: The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found. # Pharmacogenomics - CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C92 and CYP2C93 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C93/3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C91/1 or I/3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 2, 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/*3 genotype is 0.3% to 1.0% in various ethnic groups. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2-to 4-fold the human exposure as measured by the AUC0–24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as measured by the AUC0–24 at 200 mg twice daily) for two years. - Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. - Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11-fold human exposure at 200 mg twice daily based on the AUC0–24). ## Animal Toxicology - An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown. # Clinical Studies ## Osteoarthritis - Celecoxib has demonstrated significant reduction in joint pain compared to placebo. Celecoxib was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with Celecoxib 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, Celecoxib doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24–48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of Celecoxib was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily. ## Rheumatoid arthritis - Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Celecoxib was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. Celecoxib doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily. - Although Celecoxib 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100–200 mg twice daily. ## Juvenile Rheumatoid Arthritis - In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA (with currently inactive systemic features), received one of the following treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg BID, celecoxib 6 mg/kg BID, and naproxen 7.5 mg/kg BID treatment groups, respectively. - The efficacy and safety of Celecoxib for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to Celecoxib has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to Celecoxib or other COX-2 selective and non-selective NSAIDs. ## Ankylosing Spondylitis - Celecoxib was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg Celecoxib doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to Celecoxib 400 mg, 53%, than to Celecoxib 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks. ## Analgesia, including Primary Dysmenorrhea - In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, Celecoxib relieved pain that was rated by patients as moderate to severe. Single doses of Celecoxib provided pain relief within 60 minutes. ## Special Studies Adenomatous Polyp Prevention Studies: - Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year studies involving patients with Sporadic Adenomatous Polyps treated with Celecoxib: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated): - In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 – 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. - In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 – 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. - Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk. Celecoxib Long-Term Arthritis Safety Study (CLASS): - This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received Celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for Celecoxib (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: Celecoxib, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between Celecoxib and the combined group of ibuprofen and diclofenac were not statistically significant. - Patients on Celecoxib and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively . - The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with Celecoxib 400 mg twice daily are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates between Celecoxib alone and Celecoxib with ASA groups may be due to the higher risk for GI events in ASA users. - In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking Celecoxib alone or Celecoxib with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease. - Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the Celecoxib, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for Celecoxib, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree. Endoscopic Studies: The correlation between findings of short-term endoscopic studies with Celecoxib and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving Celecoxib in controlled and open-labeled trials. - A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking Celecoxib 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, Celecoxib was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial - The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of Celecoxib (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of Celecoxib the incidence ranged between 2.7%–5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with Celecoxib and naproxen. - In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the Celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users. - n-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin. # How Supplied - Celecoxib 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body, supplied as: NDC Number Size 0025-1515-01 bottle of 60 - Celecoxib 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as: NDC Number Size 0025-1520-31 bottle of 100 0025-1520-51 bottle of 500 0025-1520-34 carton of 100 unit dose Celecoxib 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as: NDC Number Size 0025-1525-31 bottle of 100 0025-1525-51 bottle of 500 0025-1525-34 carton of 100 unit dose Celecoxib 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body, supplied as: NDC Number Size 0025-1530-02 bottle of 60 0025-1530-01 carton of 100 unit dose ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the following information before initiating therapy with Celecoxib and periodically during the course of ongoing therapy. ## Medication Guide - Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using Celecoxib. ## Cardiovascular Effects - Patients should be informed that Celecoxib may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. - Patients should be informed that Celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, and that Celecoxib may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. . ## Gastrointestinal Effects - Patients should be informed that Celecoxib can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis. . ## Hepatic Effects - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur . ## Adverse Skin Reactions - Patients should be informed that Celecoxib is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms. - Patients should be advised to stop Celecoxib immediately if they develop any type of rash and contact their physician as soon as possible. - Patients with prior history of sulfa allergy should not take Celecoxib . ## Weight Gain and Edema - Long-term administration of NSAIDs including Celecoxib has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly. - Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with Celecoxib . ## Anaphylactoid reactions - Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms . ## Effects During Pregnancy - Patients should be informed that in late pregnancy Celecoxib should be avoided because it may cause premature closure of the ductus arterioles ## Preexisting Asthma - Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take Celecoxib. Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking Celecoxib # Precautions with Alcohol - Alcohol-Celecoxib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CELEBREX # Look-Alike Drug Names - Celecoxib - CeleXA Celecoxib - Cerebyx # Drug Shortage Status # Price	Celecoxib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Celecoxib is an analgesic that is FDA approved for the treatment of osteoarthritis ，rheumatoid arthritis ，juvenile rheumatoid arthritis, ankylosing Spondylitis，acute pain and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension,diarrhea, nausea and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Osteoarthritis - Dosing information - Recommended oral dosage: 200 mg PO qd or as 100 mg PO bid # Rheumatoid Arthritis - Dosing information - Recommended oral dosage: 100 to 200 mg PO bid # Ankylosing Spondylitis - Dosing information - Recommended dosage: 200 mg daily PO qd or bid. - If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. - If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. # Management of Acute Pain and Treatment of Primary Dysmenorrhea Dosing information - Initial recommended dosage: 400 mg , followed by an additional 200 mg dose if needed on the first day. - On subsequent days, the recommended dose：200 mg PO bid. # Special Populations Hepatic insufficiency Dosing information - The daily recommended dose of Celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Celecoxib in patients with severe hepatic impairment is not recommended Poor Metabolizers of CYP2C9 Substrates Dosing information - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C93/3). Consider using alternative management in JRA patients who are poor metabolizers. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use Gout - Developed by: American College of Rheumatology (ACR) - Class of Recommendation: Not applicable - Level of Evidence: Level B Dosing Information - 800 mg followed by 400 mg on day 1 and then 400 mg twice daily for 1 week ### Non–Guideline-Supported Use # Prophylaxis of Colorectal adenoma Dosing information - 200 mg PO bid[1] # Coronary stent stenosis Dosing information - 400 mg once just prior to coronary intervention followed by 200 mg twice daily for 6 months[2] # Schizophrenia Dosing information - 400 mg/day[3] # Systemic lupus erythematosus Dosing information - Not applicable 12139371 # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Juvenile Rheumatoid Arthritis Dosing information - Recommended oral dosage: for pediatric patients (age 2 years and older) is based on weight. - For patients ≥10 kg to ≤25 kg - Recommended dosage:50 mg PO bid. - For patients >25 kg - Recommended dosage:100 mg PO bid - For patients who have difficulty swallowing capsules, the contents of a Celecoxib capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2–8° C/ 35–45° F). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Celecoxib in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Celecoxib in pediatric patients. # Contraindications - Celecoxib is contraindicated: - In patients with known hypersensitivity to celecoxib, aspirin, or other NSAIDs. - In patients who have demonstrated allergic-type reactions to sulfonamides. - In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients - For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery - In patients with active gastrointestinal bleeding. # Warnings ## Cardiovascular Thrombotic Events - Chronic use of Celecoxib may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Celecoxib) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for Celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with Celecoxib 200 mg twice daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction . - All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with Celecoxib, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and Celecoxib does increase the risk of serious GI events . - Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke ## Hypertension - As with all NSAIDs, Celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Celecoxib and throughout the course of therapy. The rates of hypertension from the CLASS trial in the Celecoxib, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively . ## Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs, including Celecoxib . In the CLASS study , the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on Celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Celecoxib should be used with caution in patients with fluid retention or heart failure. ## Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation - NSAIDs, including Celecoxib, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA . With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during Celecoxib therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. - Celecoxib is contraindicated in patients with active GI bleeding. ## Hepatic Effects - Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including Celecoxib . In controlled clinical trials of Celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for Celecoxib and 5% for placebo, and approximately 0.2% of patients taking Celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Celecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Celecoxib should be discontinued. ## Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with Celecoxib have shown renal effects similar to those observed with comparator NSAIDs. - No information is available from controlled clinical studies regarding the use of Celecoxib in patients with advanced renal disease. Therefore, treatment with Celecoxib is not recommended in these patients with advanced renal disease. If Celecoxib therapy must be initiated, close monitoring of the patient's renal function is advisable. ## Anaphylactoid reactions - As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Celecoxib. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving Celecoxib. Celecoxib should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs . Emergency help should be sought in cases where an anaphylactoid reaction occurs. ## Skin Reactions - Celecoxib is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. ## Pregnancy - In late pregnancy, starting at 30 weeks gestation, Celecoxib should be avoided because it may cause premature closure of the ductus arterioles. ## corticosteroid Treatment - Celecoxib cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. ## Hematological Effects - Anemia is sometimes seen in patients receiving Celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with Celecoxib and 0.4% with placebo. Patients on long-term treatment with Celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages. ## Disseminated Intravascular Coagulation (DIC) - Celecoxib should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation. ## Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. ## Laboratory Tests - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, Celecoxib should be discontinued. - In controlled clinical trials, elevated BUN occurred more frequently in patients receiving Celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. ## Inflammation - The pharmacological activity of Celecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. ## Concomitant NSAID Use - The concomitant use of Celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. # Adverse Reactions ## Clinical Trials Experience - Of the Celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of Celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received Celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. - 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. ## Pre-marketing Controlled Arthritis Trials - Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving Celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. - In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving Celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the Celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of Celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. ## The Celecoxib Long-Term Arthritis Safety Study - Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on Celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with Celecoxib was maintained with or without ASA use - Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for Celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). ## Juvenile Rheumatoid Arthritis Study - In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg BID, 82 patients were treated with celecoxib 6 mg/kg BID, and 83 patients were treated with naproxen 7.5 mg/kg BID. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg BID had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups. - In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg BID. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged. ## Other Pre-Approval Studies - Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with Celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RAstudies. - Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with Celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of Celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. ## The APC and PreSAP Trials - Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to Celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years - Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from Celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with Celecoxib were greater as compared to the arthritis pre-marketing trials were as follows: - The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking Celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies: ## Postmarketing Experience There is limited information regarding Celecoxib Postmarketing Experience in the drug label. # Drug Interactions General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9. - In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. ## Warfarin - Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing Celecoxib therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily 2–5 mg doses of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving Celecoxib concurrently with warfarin. ## Lithium - In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when Celecoxib is introduced or withdrawn. ## Aspirin - Celecoxib can be used with low-dose aspirin. However, concomitant administration of aspirin with Celecoxib increases the rate of GI ulceration or other complications, compared to use of Celecoxib alone. Because of its lack of platelet effects, Celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. ## ACE-inhibitors and Angiotensin II Antagonists - Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking Celecoxib concomitantly with ACE-inhibitors and angiotensin II antagonists - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. ## Fluconazole - Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole. ## Furosemide - Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. ## Methotrexate - In an interaction study of rheumatoid arthritis patients taking methotrexate, Celecoxib did not have an effect on the pharmacokinetics of methotrexate . ## Concomitant NSAID Use - The concomitant use of Celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward. Teratogenic effects: Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0–24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Celecoxib produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of Celecoxib during the third trimester of pregnancy should be avoided. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Celecoxib in women who are pregnant. ### Labor and Delivery - Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0–24 at 200 mg BID). The effects of Celecoxib on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celecoxib in breast milk. The calculated average daily infant dose was 10–40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when Celecoxib is administered to a nursing woman. ### Pediatric Use - Celecoxib is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to Celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to Celecoxib or other COX-2 selective and non-selective NSAIDs - The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests - Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers ### Geriatic Use - Of the total number of patients who received Celecoxib in pre-approval clinical trials, more than 3,300 were 65–74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients ### Gender There is no FDA guidance on the use of Celecoxib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Celecoxib with respect to specific racial populations. ### Renal Impairment - Celecoxib is not recommended in patients with severe renal insufficiency ### Hepatic Impairment - The daily recommended dose of Celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Celecoxib in patients with severe hepatic impairment is not recommended ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Celecoxib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Celecoxib in patients who are immunocompromised. ### Poor Metabolizers of CYP2C9 Substrates - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e., CYP2C93/3). Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. # Administration and Monitoring ### Administration - Oral ### Monitoring - FDA Package Insert for Celecoxib contains no information regarding drug monitoring. # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - No overdoses of Celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action - Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, Celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, Celecoxib reduced the incidence and multiplicity of tumors. ## Structure - Celecoxib (celecoxib) is chemically designated as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38; the chemical structure is as follows: - Celecoxib oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg of celecoxib, together with inactive ingredients including: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate. ## Pharmacodynamics Platelets: In clinical trials using normal volunteers, Celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, Celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of Celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of Celecoxib. Fluid Retention: Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone. ## Pharmacokinetics Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax and AUC. Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 3. Food Effects: When Celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. - Coadministration of Celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Celecoxib, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption. - In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t1/2 after administration of capsule contents on applesauce. Distribution: In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. Metabolism: Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min. Geriatric: At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose. Pediatric: The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient. Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg twice daily (see Dosage and Administration (2.3). Celecoxib has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks. Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown. Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily recommended dose of Celecoxib capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of Celecoxib in patients with severe hepatic impairment is not recommended. Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35–60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, Celecoxib is not recommended in patients with severe renal insufficiency. Drug interactions - In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. - In vivo studies have shown the following: Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Fluconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole. Other Drugs: The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found. # Pharmacogenomics - CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C92 and CYP2C93 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C93/3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C91/1 or I/3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 2, 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/*3 genotype is 0.3% to 1.0% in various ethnic groups. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2-to 4-fold the human exposure as measured by the AUC0–24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as measured by the AUC0–24 at 200 mg twice daily) for two years. - Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. - Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11-fold human exposure at 200 mg twice daily based on the AUC0–24). ## Animal Toxicology - An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown. # Clinical Studies ## Osteoarthritis - Celecoxib has demonstrated significant reduction in joint pain compared to placebo. Celecoxib was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with Celecoxib 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, Celecoxib doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24–48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of Celecoxib was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily. ## Rheumatoid arthritis - Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Celecoxib was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. Celecoxib doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily. - Although Celecoxib 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100–200 mg twice daily. ## Juvenile Rheumatoid Arthritis - In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA (with currently inactive systemic features), received one of the following treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg BID, celecoxib 6 mg/kg BID, and naproxen 7.5 mg/kg BID treatment groups, respectively. - The efficacy and safety of Celecoxib for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to Celecoxib has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to Celecoxib or other COX-2 selective and non-selective NSAIDs. ## Ankylosing Spondylitis - Celecoxib was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg Celecoxib doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to Celecoxib 400 mg, 53%, than to Celecoxib 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks. ## Analgesia, including Primary Dysmenorrhea - In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, Celecoxib relieved pain that was rated by patients as moderate to severe. Single doses of Celecoxib provided pain relief within 60 minutes. ## Special Studies Adenomatous Polyp Prevention Studies: - Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year studies involving patients with Sporadic Adenomatous Polyps treated with Celecoxib: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated): - In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 – 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. - In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 – 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. - Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk. Celecoxib Long-Term Arthritis Safety Study (CLASS): - This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received Celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for Celecoxib (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: Celecoxib, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between Celecoxib and the combined group of ibuprofen and diclofenac were not statistically significant. - Patients on Celecoxib and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively . - The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with Celecoxib 400 mg twice daily are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates between Celecoxib alone and Celecoxib with ASA groups may be due to the higher risk for GI events in ASA users. - In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking Celecoxib alone or Celecoxib with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease. - Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the Celecoxib, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for Celecoxib, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree. Endoscopic Studies: The correlation between findings of short-term endoscopic studies with Celecoxib and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving Celecoxib in controlled and open-labeled trials. - A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking Celecoxib 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, Celecoxib was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial - The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of Celecoxib (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of Celecoxib the incidence ranged between 2.7%–5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with Celecoxib and naproxen. - In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the Celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users. - n-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin. # How Supplied - Celecoxib 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body, supplied as: NDC Number Size 0025-1515-01 bottle of 60 - Celecoxib 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as: NDC Number Size 0025-1520-31 bottle of 100 0025-1520-51 bottle of 500 0025-1520-34 carton of 100 unit dose Celecoxib 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as: NDC Number Size 0025-1525-31 bottle of 100 0025-1525-51 bottle of 500 0025-1525-34 carton of 100 unit dose Celecoxib 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body, supplied as: NDC Number Size 0025-1530-02 bottle of 60 0025-1530-01 carton of 100 unit dose ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the following information before initiating therapy with Celecoxib and periodically during the course of ongoing therapy. ## Medication Guide - Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using Celecoxib. ## Cardiovascular Effects - Patients should be informed that Celecoxib may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. - Patients should be informed that Celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, and that Celecoxib may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. . ## Gastrointestinal Effects - Patients should be informed that Celecoxib can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis. . ## Hepatic Effects - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur . ## Adverse Skin Reactions - Patients should be informed that Celecoxib is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms. - Patients should be advised to stop Celecoxib immediately if they develop any type of rash and contact their physician as soon as possible. - Patients with prior history of sulfa allergy should not take Celecoxib . ## Weight Gain and Edema - Long-term administration of NSAIDs including Celecoxib has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly. - Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with Celecoxib . ## Anaphylactoid reactions - Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms . ## Effects During Pregnancy - Patients should be informed that in late pregnancy Celecoxib should be avoided because it may cause premature closure of the ductus arterioles ## Preexisting Asthma - Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take Celecoxib. Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking Celecoxib # Precautions with Alcohol - Alcohol-Celecoxib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CELEBREX # Look-Alike Drug Names - Celecoxib - CeleXA Celecoxib - Cerebyx [5] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Celebrex
1235429ba680647a5e7f4ea50f1d7e67be6b542e	wikidoc	Cell type	Cell type A cell type is a distinct morphological or functional form of cell. When a cell switches state from one cell type to another, it undergoes cellular differentiation. Three Domains of life: Eukaryota, bacteria and archaea Eukaryotes: animals, humans, plants and , also algae, and protozoa. Prokaryotes: bacteria and archaea (Special kind of prokaryotes). # Animals ## Humans Different cell types react differently to external stimuli. For instance, the function of PKA differs from cell type to cell type. Calcium, too, has specific cell type actions in humans. A partial list of cell types includes: - Blastomere - Egg - Embryonic stem cell - Erythrocyte - Fibroblast - Hepatocyte - Myoblast - Myotube - Neuron - Oocyte - Osteoblast - Osteoclast - T-Cell - Zygote # Plants A partial list of cell types includes: - Aleurone - Collenchyma - Endodermis - Endosperm - Epidermis - Mesophyll - Meristematic cells - Palisade - Parenchyma - Phloem sieve tube - Pollen generative - Pollen vegetative - Sclerenchyma - Tracheids - Xylem vessel - Zygote de:Zelltyp - ↑ Robert F.Weaver. Posttranslation.In. Molecular Biology. Fourth Edition. Page 600.McGraw-Hill International Edition. ISBN 978-0-07-110216-2	Cell type A cell type is a distinct morphological or functional form of cell. When a cell switches state from one cell type to another, it undergoes cellular differentiation. Three Domains of life: Eukaryota, bacteria and archaea [1] Eukaryotes: animals, humans, plants and , also algae, and protozoa. Prokaryotes: bacteria and archaea (Special kind of prokaryotes). # Animals ## Humans Different cell types react differently to external stimuli. For instance, the function of PKA differs from cell type to cell type. Calcium, too, has specific cell type actions in humans. A partial list of cell types includes: - Blastomere - Egg - Embryonic stem cell - Erythrocyte - Fibroblast - Hepatocyte - Myoblast - Myotube - Neuron - Oocyte - Osteoblast - Osteoclast - T-Cell - Zygote # Plants A partial list of cell types includes: - Aleurone - Collenchyma - Endodermis - Endosperm - Epidermis - Mesophyll - Meristematic cells - Palisade - Parenchyma - Phloem sieve tube - Pollen generative - Pollen vegetative - Sclerenchyma - Tracheids - Xylem vessel - Zygote de:Zelltyp Template:WH Template:WS - ↑ Robert F.Weaver. Posttranslation.In. Molecular Biology. Fourth Edition. Page 600.McGraw-Hill International Edition. ISBN 978-0-07-110216-2	https://www.wikidoc.org/index.php/Cell_type
43ba1cd69d1c548c0935eb8837c2c7aa905cb7b6	wikidoc	Cellulite	Cellulite Cellulite describes a condition that occurs in men and women where the skin of the lower limbs, abdomen, and pelvic region becomes dimpled after puberty. The term was first used in the 1920s and began appearing in English language publications in the late 1960s, the earliest reference in Vogue magazine, "Like a swift migrating fish the word cellulite has suddenly crossed the Atlantic." Descriptive names for cellulite include orange peel syndrome, cottage cheese skin, the mattress phenomenon, and hail damage. Synonyms include: adiposis edematosa, dermopanniculosis deformans, status protrusus cutis, and gynoid lipodystrophy. Cellulite is unrelated to cellulitis, which is infection of the skin and its underlying connective tissue. # Occurrence Practically all post-pubescent females display some degree of cellulite. There appears to be a hormonal component to its presentation. It is rarely seen in males. It is seen more commonly in males with androgen-deficient states such as Klinefelter's syndrome, hypogonadism, post-castration states and in those patients receiving estrogen therapy for prostate cancer. The cellulite becomes more severe as the androgen deficiency worsens in these males. Cellulite is not related to being overweight; average and underweight people also get cellulite. # Causes One plausible explanation - which also explains why very few men suffer from cellulite - is based on the composition and behavior of women's fat cells and the connective tissue that holds them in place. Very simply, a woman's connective tissue is very inflexible, so as females gain weight their fat cells expand, and tend to bulge upwards towards the surface of the skin, giving the classic orange-peel appearance of cellulite. In men, not only is there generally less fat on the thighs, but also the outer skin is thicker and thus obscures what is happening to any surplus fat below. The causes are poorly understood, and several changes in metabolism and physiology may cause cellulite or contribute to cellulite. Among these are a disorder of water metabolism, abnormal hyperpolymerization of the connective tissue, and chronic venous insufficiency. ## Hormonal factors Hormones play a dominant role in the formation of cellulite. Estrogen is the most important hormone. It seems to initiate, and aggravate cellulite. Other hormones including insulin, the catecholamines adrenaline and noradrenaline, thyroid hormones, and prolactin have all been shown to participate in the development of cellulite. ## Predisposing factors Several genetic factors have been shown to be necessary for cellulite to develop. Gender, race, biotype, a hormone receptor allele that determines the receptor number and sensitivity, distribution of subcutaneous fat, and predisposition to circulatory insufficiency have all been shown to contribute to cellulite. ## Diet Diet has been shown to affect the development and amount of cellulite. Excessive amounts of fat, carbohydrates, salt, alcohol or too little fiber can all contribute to an increased cellulite. ## Lifestyle Smoking, lack of exercise, tight clothes, high heeled shoes, and sitting or standing in a single position of long periods have all been correlated with an increase in cellulite. A high stress lifestyle will cause an increase in the catecholamine hormones. # Classification ## Grade 1 No clinical symptoms, but histopathology detects underlying anatomical changes. ## Grade 2 The skin shows pallor, lower temperature, and decreased elasticity after compression or muscular contraction. There is no visible "orange peel" roughness to the skin. Additional anatomical changes are detected by histopatholgy. ## Grade 3 Visible "orange peel" roughness to the skin is visible at rest. This is the "canonical" grade of cellulite. Thin granulations in the deep levels of the skin can be detected by palpatation. All Grade 2 signs are present, with further anatomical changes are detectable by histopathology. ## Grade 4 All Grade 3 symptoms are present, with more visible, palpable, and painful lumps present which adhere to deep structures in the skin. The skin has a noticeable dimpled, wavy appearance. Additional histopathologic changes are detected. # Therapy Numerous therapies have been tried. There are no published reports in the scientific literature showing that any of these therapies works. The most beneficial therapy is to control lifestyle factors. Controlling stress and anxiety are of considerable benefit. ## Physical and mechanical methods Iontophoresis, ultrasound, thremotherapy, pressotherapy (pneumatic massaging in the direction of the circulation), lymphatic drainage (massage technique to stimulate lymphatic flow), electrolipophoresis (application of a low frequency electric current) have all been tried. To administer a lymphatic drainage massage, the individual is positioned so that maximum exposure is given to the target area. Several slaps with the open palm are applied to the area for about two minutes, with occasional pauses to rub the area in a circular motion. The resulting heat, along with the vibration of the skin and rhythmic contractions of the gluteus muscles stimulates the draw of fluid into the capillaries. The absorption of fatty acids and subsequent transport of fat causes the "orange peel" roughness to the skin to disappear. This may take several sessions to accomplish. The massage can be effective not only with Grade 3 cellulite but can be used pro-actively for Grade 1 and 2. ## Pharmacological agents Any number of drugs that act on fatty tissue have been tried as therapeutic agents. Certain drugs act on the fatty tissue and connective tissue and on the microcirculation. They can be used topically, systemically, or transdermally. These include the methyxanthines (theobromine, theophylline, aminophylline, caffeine), which act through phosphodiesterase inhibition, and pentoxifylline which improves micro-circulation; the adrenergic beta-agonists isoproterenol and adrenaline; the adrenergic alpha-agonists yohimbine, piperoxan, phentolamine and dihydroergotamine; the methyIxanthine enhancers Coenzyme A and the amino acid l-carnitine; the drugs with connective tissue activity sillicium and Asiatic centella; and the microcirculation active drugs Indian chestnut, ginkgo biloba, and rutin. These drugs are administered orally, as topically applied ointments, and by trans dermal injection. None of them has been reported in the scientific literature as having a significant effect on cellulite. # Cosmetic concern While harmless, the dimpled appearance is a cause of concern for some people. The cosmetics industry claims to offer many of what it calls remedies. There are no supplements that have been approved as effective for reducing cellulite. Syneron, the first cosmetic laser manufacturer to receive FDA clearance for treating cellulite, combine mechanical, light, heat, and radio frequency energy, also known as ELOS, to the skin and claim success after a few applications of their product. Radio frequency in the cosmetic industry is used to heat the skin in a non-invasive (medical) cosmetic procedure to heat the fat tissue underneath the skin. That procedure regenerates the collagen in the area and makes the skin look younger and more vital. Other cosmetic procedures such as Mesotherapy and Endermologie have produced inconclusive results. While each has been FDA approved to temporarily reduce the appearance of cellulite, effectiveness varies by procedure. All methods require continual follow-up to maintain reduced levels of cellulite. "No statistical difference existed" in morphologic assessment of the body after 12 weeks of randomised control trial with Endermologie (Collis N et al. 1999 Sep;104(4):1110-4 Plast Reconstr Surg) Liposuction, which extracts fat from under the skin, is not effective for cellulite reduction and may exacerbate the cosmetic problem. Dieting does not get rid of the dimpled appearance, but a balanced diet and exercise may help to reduce the fat content within the distorted cells, reducing their contribution to the dimpling. ## Feminist criticism Feminists claim that the idea that cellulite is an undesirable condition that needs to be treated is harmful to women, since this is a natural occurrence in the bodies of most post pubescent women and "treating" cellulite would be no different from "treating" pubic hair or enlarged breasts. They claim it is another example of the phenomenon of women being pressured to have a more pre-pubescent childish appearance.	Cellulite Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Cellulite describes a condition that occurs in men and women where the skin of the lower limbs, abdomen, and pelvic region becomes dimpled after puberty.[1] The term was first used in the 1920s and began appearing in English language publications in the late 1960s, the earliest reference in Vogue magazine, "Like a swift migrating fish the word cellulite has suddenly crossed the Atlantic."[2] Descriptive names for cellulite include orange peel syndrome, cottage cheese skin, the mattress phenomenon, and hail damage. Synonyms include: adiposis edematosa, dermopanniculosis deformans, status protrusus cutis, and gynoid lipodystrophy. Cellulite is unrelated to cellulitis, which is infection of the skin and its underlying connective tissue. # Occurrence Practically all post-pubescent females display some degree of cellulite. There appears to be a hormonal component to its presentation. It is rarely seen in males.[1] It is seen more commonly in males with androgen-deficient states such as Klinefelter's syndrome, hypogonadism, post-castration states and in those patients receiving estrogen therapy for prostate cancer. The cellulite becomes more severe as the androgen deficiency worsens in these males. Cellulite is not related to being overweight; average and underweight people also get cellulite.[1] # Causes One plausible explanation - which also explains why very few men suffer from cellulite - is based on the composition and behavior of women's fat cells and the connective tissue that holds them in place. Very simply, a woman's connective tissue is very inflexible, so as females gain weight their fat cells expand, and tend to bulge upwards towards the surface of the skin, giving the classic orange-peel appearance of cellulite. In men, not only is there generally less fat on the thighs, but also the outer skin is thicker and thus obscures what is happening to any surplus fat below. The causes are poorly understood, and several changes in metabolism and physiology may cause cellulite or contribute to cellulite. Among these are a disorder of water metabolism, abnormal hyperpolymerization of the connective tissue, and chronic venous insufficiency.[1] ## Hormonal factors Hormones play a dominant role in the formation of cellulite. Estrogen is the most important hormone. It seems to initiate, and aggravate cellulite. Other hormones including insulin, the catecholamines adrenaline and noradrenaline, thyroid hormones, and prolactin have all been shown to participate in the development of cellulite.[1] ## Predisposing factors Several genetic factors have been shown to be necessary for cellulite to develop. Gender, race, biotype[3], a hormone receptor allele that determines the receptor number and sensitivity, distribution of subcutaneous fat, and predisposition to circulatory insufficiency have all been shown to contribute to cellulite.[1] ## Diet Diet has been shown to affect the development and amount of cellulite. Excessive amounts of fat, carbohydrates, salt, alcohol or too little fiber can all contribute to an increased cellulite.[1] ## Lifestyle Smoking, lack of exercise, tight clothes, high heeled shoes, and sitting or standing in a single position of long periods have all been correlated with an increase in cellulite. A high stress lifestyle will cause an increase in the catecholamine hormones.[1] # Classification ## Grade 1 No clinical symptoms, but histopathology detects underlying anatomical changes.[1] ## Grade 2 The skin shows pallor, lower temperature, and decreased elasticity after compression or muscular contraction. There is no visible "orange peel" roughness to the skin. Additional anatomical changes are detected by histopatholgy.[1] ## Grade 3 Visible "orange peel" roughness to the skin is visible at rest. This is the "canonical" grade of cellulite. Thin granulations in the deep levels of the skin can be detected by palpatation. All Grade 2 signs are present, with further anatomical changes are detectable by histopathology.[1] ## Grade 4 All Grade 3 symptoms are present, with more visible, palpable, and painful lumps present which adhere to deep structures in the skin. The skin has a noticeable dimpled, wavy appearance. Additional histopathologic changes are detected.[1] # Therapy Numerous therapies have been tried. There are no published reports in the scientific literature showing that any of these therapies works. The most beneficial therapy is to control lifestyle factors. Controlling stress and anxiety are of considerable benefit. ## Physical and mechanical methods Iontophoresis, ultrasound, thremotherapy, pressotherapy (pneumatic massaging in the direction of the circulation), lymphatic drainage (massage technique to stimulate lymphatic flow), electrolipophoresis (application of a low frequency electric current) have all been tried.[1] To administer a lymphatic drainage massage, the individual is positioned so that maximum exposure is given to the target area. Several slaps with the open palm are applied to the area for about two minutes, with occasional pauses to rub the area in a circular motion. The resulting heat, along with the vibration of the skin and rhythmic contractions of the gluteus muscles stimulates the draw of fluid into the capillaries. The absorption of fatty acids and subsequent transport of fat causes the "orange peel" roughness to the skin to disappear. This may take several sessions to accomplish. The massage can be effective not only with Grade 3 cellulite but can be used pro-actively for Grade 1 and 2. ## Pharmacological agents Any number of drugs that act on fatty tissue have been tried as therapeutic agents. Certain drugs act on the fatty tissue and connective tissue and on the microcirculation. They can be used topically, systemically, or transdermally. These include the methyxanthines (theobromine, theophylline, aminophylline, caffeine), which act through phosphodiesterase inhibition, and pentoxifylline which improves micro-circulation; the adrenergic beta-agonists isoproterenol and adrenaline; the adrenergic alpha-agonists yohimbine, piperoxan, phentolamine and dihydroergotamine; the methyIxanthine enhancers Coenzyme A and the amino acid l-carnitine; the drugs with connective tissue activity sillicium and Asiatic centella; and the microcirculation active drugs Indian chestnut, ginkgo biloba, and rutin. These drugs are administered orally, as topically applied ointments, and by trans dermal injection. None of them has been reported in the scientific literature as having a significant effect on cellulite. # Cosmetic concern While harmless, the dimpled appearance is a cause of concern for some people. The cosmetics industry claims to offer many of what it calls remedies. There are no supplements that have been approved as effective for reducing cellulite. Syneron, the first cosmetic laser manufacturer to receive FDA clearance for treating cellulite, combine mechanical, light, heat, and radio frequency energy, also known as ELOS, to the skin and claim success after a few applications of their product. Radio frequency in the cosmetic industry is used to heat the skin in a non-invasive (medical) cosmetic procedure to heat the fat tissue underneath the skin. That procedure regenerates the collagen in the area and makes the skin look younger and more vital. Other cosmetic procedures such as Mesotherapy and Endermologie have produced inconclusive results. While each has been FDA approved to temporarily reduce the appearance of cellulite, effectiveness varies by procedure. All methods require continual follow-up to maintain reduced levels of cellulite. "No statistical difference existed" in morphologic assessment of the body after 12 weeks of randomised control trial with Endermologie (Collis N et al. 1999 Sep;104(4):1110-4 Plast Reconstr Surg) Liposuction, which extracts fat from under the skin, is not effective for cellulite reduction and may exacerbate the cosmetic problem. Dieting does not get rid of the dimpled appearance, but a balanced diet and exercise may help to reduce the fat content within the distorted cells, reducing their contribution to the dimpling. ## Feminist criticism Feminists claim that the idea that cellulite is an undesirable condition that needs to be treated is harmful to women, since this is a natural occurrence in the bodies of most post pubescent women and "treating" cellulite would be no different from "treating" pubic hair or enlarged breasts. They claim it is another example of the phenomenon of women being pressured to have a more pre-pubescent childish appearance. # External links - Medline National Library of Medicine MedLine Plus definition of cellulite, October 2006. # Notes - ↑ Jump up to: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Ana Beatris R Rossi, André Luiz Vergnanini; Cellulite: a review, Journal of the European Academy of Dermatology and Venereology; 14 (4), 251–262,(2000). - ↑ Vogue 15 Apr 1968 110/1 - ↑ A population within a species that has distinct genetic variation. da:Appelsinhud de:Orangenschalenhaut fi:Selluliitti it:Cellulite nl:Sinaasappelhuid no:Appelsinhud sv:Cellulit Template:Jb1 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Cellulite
83e6b1071e14368a8a06b76e75b594ed5afcd73a	wikidoc	Cellulose	Cellulose Cellulose is an organic compound with the formula (C6H10O5)n. It is a structural polysaccharide derived from beta-glucose. Cellulose is the primary structural component of green plants. The primary cell wall of green plants is made of cellulose; acetic acid bacteria are also known to synthesize cellulose, as well as many forms of algae, and the oomycetes. Cellulose was discovered and isolated in the mid-nineteenth century by the French chemist Anselme Payen and, as of the year 2006, the estimated annual production of 1.5x109 tonnes. Some animals, particularly ruminants and termites, can digest cellulose with the help of symbiotic micro-organisms (see methanogen). Cellulose is not digestible by humans and is often referred to as 'dietary fiber' or 'roughage', acting as a hydrophilic bulking agent for feces. # Commercial products Cellulose is the major constituent of paper and textiles made from cotton, linen, and other plant fibers. Cellulose can be converted into cellophane, clear rolling papers made from Viscose film, rayon, and more recently cellulose has been used to make Modal, a bio-based textile derived from beechwood cellulose. Cellulose is used within the laboratory as the stationary phase for thin layer chromatography, and cotton linters, is used in the manufacture of nitrocellulose, historically used in smokeless gunpowder. Rayon is an important fiber made out of cellulose and has been used for textiles since the beginning of the 20th century. ## Cellulose source and energy crops The major combustible component of non-food energy crops is cellulose, with lignin second. Non-food energy crops are preferred to edible energy crops (which have a large starch component) because they don´t cause inflation of food prices. Typical non-food energy crops include Switchgrass, Miscanthus, Salix (Willow) and Populus (Poplar) species. # Structure Cellulose is derived from (β-glucose), which condense through β(1→4)-glycosidic bonds. This linkage motif contrasts with that for α(1→4)-glycosidic bonds present in starch and other carbohydrates. Cellulose is a straight chain polymer: unlike starch, no coiling occurs, and the molecule adopts an extended rod-like conformation. In microfibrils, the multiple hydroxyl groups on the glucose residues hydrogen bond with each other, holding the chains firmly together and contributing to their high tensile strength. This strength is important in cell walls, where they are meshed into a carbohydrate matrix, conferring rigidity to plant cells. In contrast to starch, cellulose is also much more crystalline. Whereas starch undergoes a crystalline to amorphous transition at 60 -70 °C in water (as in cooking), cellulose requires 320 °C and 25 MPa to become amorphous in water. # Assaying cellulose Given a cellulose-containing material, the portion that does not dissolve in a 17.5% solution of sodium hydroxide at 20 °C is α cellulose, which is true cellulose. Acidification of the extract precipitates β cellulose. The portion that dissolves in base but does not precipitate with acid is γ cellulose. Cellulose can be assayed using a method described by Updegraff in 1969, where the fiber is dissolved in acetic and nitric acid, and allowed to react with anthrone in sulfuric acid. The resulting coloured compound is assayed spectrophotometrically at a wavelength of approximately 635 nm. In addition, cellulose is represented by the difference between acid detergent fiber (ADF) and acid detergent lignin(ADL). # Biosynthesis In vascular plants cellulose is synthesized at the plasma membrane by rosette terminal complexes (RTC's). The RTC's are hexameric protein structures, approximately 25 nm in diameter that contain the cellulose synthase enzymes that synthesise the individual cellulose chains. The RTC's contain at least three different cellulose synthases, encoded by CesA genes, in an unknown stoichiometry. Separate sets of CesA genes are involved in primary and secondary cell wall biosynthesis. Cellulose synthase utilizes UDP-D-glucose precursors to generate microcrystalline cellulose. Cellulose synthesis requires chain initiation and elongation, and the two processes are separate. CesA glucosyltransferase initiates cellulose polymerization using a steroid primer, 'sitosterol-beta-glucoside' and UDP-glucose. A cellulase may function to cleave the primer from the mature chain. # Breakdown (cellulolysis) Cellulolysis is the process relating to or causing the hydrolysis of cellulose (i.e. cellulolytic bacteria, fungi or enzymes). Mammals do not have the ability to break down cellulose directly. Typically, this ability is possessed only by certain bacteria (which have specific enzymes) like Cellulomonas etc., and which are often the flora on the gut walls of ruminants like cows and sheep, or by fungi, which in nature are responsible for cycling of nutrients. The enzymes utilized to cleave the glycosidic linkage in cellulose are glycoside hydrolases including endo-acting cellulases and exo-acting glucosidases. Such enzymes are usually secreted as part of multienzyme complexes that may include dockerins and cellulose binding modules, referred to in some cases as cellulosomes. Many cellulolytic bacteria, fungi or enzymes break down cellulose into shorter linked chains known as cellodextrins. # Derivatives The hydroxyl groups of cellulose can be partially or fully reacted with various reagents to afford derivatives with useful properties. Cellulose esters and cellulose ethers are the most important commercial materials. In principle, though not always in current industrial practice, cellulosic polymers are renewable resources. Among the esters are cellulose acetate and cellulose triacetate, which are film- and fiber-forming materials that find a variety of uses. The inorganic ester nitrocellulose was initially used as an explosive and was an early film forming material. Ether derivatives include - Ethylcellulose, a water-insoluble commercial thermoplastic used in coatings, inks, binders, and controlled-release drug tablets; - Methylcellulose; - Hydroxypropyl cellulose; - Carboxymethyl cellulose; - Hydroxypropyl methyl cellulose, E464, used as a viscosity modifier, gelling agent, foaming agent and binding agent; - Hydroxyethyl methyl cellulose, used in production of cellulose films.	Cellulose Cellulose is an organic compound with the formula (C6H10O5)n. It is a structural polysaccharide derived from beta-glucose.[1][2] Cellulose is the primary structural component of green plants. The primary cell wall of green plants is made of cellulose; acetic acid bacteria are also known to synthesize cellulose, as well as many forms of algae, and the oomycetes. Cellulose was discovered and isolated in the mid-nineteenth century by the French chemist Anselme Payen[3][1] and, as of the year 2006, the estimated annual production of 1.5x109 tonnes.[4] Some animals, particularly ruminants and termites, can digest cellulose with the help of symbiotic micro-organisms (see methanogen). Cellulose is not digestible by humans and is often referred to as 'dietary fiber' or 'roughage', acting as a hydrophilic bulking agent for feces. # Commercial products Cellulose is the major constituent of paper and textiles made from cotton, linen, and other plant fibers. Cellulose can be converted into cellophane, clear rolling papers made from Viscose film, rayon, and more recently cellulose has been used to make Modal, a bio-based textile derived from beechwood cellulose. Cellulose is used within the laboratory as the stationary phase for thin layer chromatography, and cotton linters, is used in the manufacture of nitrocellulose, historically used in smokeless gunpowder. Rayon is an important fiber made out of cellulose and has been used for textiles since the beginning of the 20th century. ## Cellulose source and energy crops The major combustible component of non-food energy crops is cellulose, with lignin second. Non-food energy crops are preferred to edible energy crops (which have a large starch component) because they don´t cause inflation of food prices. Typical non-food energy crops include Switchgrass, Miscanthus, Salix (Willow) and Populus (Poplar) species. # Structure Cellulose is derived from (β-glucose), which condense through β(1→4)-glycosidic bonds. This linkage motif contrasts with that for α(1→4)-glycosidic bonds present in starch and other carbohydrates. Cellulose is a straight chain polymer: unlike starch, no coiling occurs, and the molecule adopts an extended rod-like conformation. In microfibrils, the multiple hydroxyl groups on the glucose residues hydrogen bond with each other, holding the chains firmly together and contributing to their high tensile strength. This strength is important in cell walls, where they are meshed into a carbohydrate matrix, conferring rigidity to plant cells. In contrast to starch, cellulose is also much more crystalline. Whereas starch undergoes a crystalline to amorphous transition at 60 -70 °C in water (as in cooking), cellulose requires 320 °C and 25 MPa to become amorphous in water.[5] # Assaying cellulose Given a cellulose-containing material, the portion that does not dissolve in a 17.5% solution of sodium hydroxide at 20 °C is α cellulose, which is true cellulose. Acidification of the extract precipitates β cellulose. The portion that dissolves in base but does not precipitate with acid is γ cellulose. Cellulose can be assayed using a method described by Updegraff in 1969, where the fiber is dissolved in acetic and nitric acid, and allowed to react with anthrone in sulfuric acid. The resulting coloured compound is assayed spectrophotometrically at a wavelength of approximately 635 nm. In addition, cellulose is represented by the difference between acid detergent fiber (ADF) and acid detergent lignin(ADL). # Biosynthesis In vascular plants cellulose is synthesized at the plasma membrane by rosette terminal complexes (RTC's). The RTC's are hexameric protein structures, approximately 25 nm in diameter that contain the cellulose synthase enzymes that synthesise the individual cellulose chains.[6] The RTC's contain at least three different cellulose synthases, encoded by CesA genes, in an unknown stoichiometry.[7] Separate sets of CesA genes are involved in primary and secondary cell wall biosynthesis. Cellulose synthase utilizes UDP-D-glucose precursors to generate microcrystalline cellulose. Cellulose synthesis requires chain initiation and elongation, and the two processes are separate. CesA glucosyltransferase initiates cellulose polymerization using a steroid primer, 'sitosterol-beta-glucoside' and UDP-glucose.[8] A cellulase may function to cleave the primer from the mature chain. # Breakdown (cellulolysis) Cellulolysis is the process relating to or causing the hydrolysis of cellulose (i.e. cellulolytic bacteria, fungi or enzymes). Mammals do not have the ability to break down cellulose directly. Typically, this ability is possessed only by certain bacteria (which have specific enzymes) like Cellulomonas etc., and which are often the flora on the gut walls of ruminants like cows and sheep, or by fungi, which in nature are responsible for cycling of nutrients. The enzymes utilized to cleave the glycosidic linkage in cellulose are glycoside hydrolases including endo-acting cellulases and exo-acting glucosidases. Such enzymes are usually secreted as part of multienzyme complexes that may include dockerins and cellulose binding modules, referred to in some cases as cellulosomes. Many cellulolytic bacteria, fungi or enzymes break down cellulose into shorter linked chains known as cellodextrins. # Derivatives The hydroxyl groups of cellulose can be partially or fully reacted with various reagents to afford derivatives with useful properties. Cellulose esters and cellulose ethers are the most important commercial materials. In principle, though not always in current industrial practice, cellulosic polymers are renewable resources. Among the esters are cellulose acetate and cellulose triacetate, which are film- and fiber-forming materials that find a variety of uses. The inorganic ester nitrocellulose was initially used as an explosive and was an early film forming material. Ether derivatives include - Ethylcellulose, a water-insoluble commercial thermoplastic used in coatings, inks, binders, and controlled-release drug tablets; - Methylcellulose; - Hydroxypropyl cellulose; - Carboxymethyl cellulose; - Hydroxypropyl methyl cellulose, E464, used as a viscosity modifier, gelling agent, foaming agent and binding agent; - Hydroxyethyl methyl cellulose, used in production of cellulose films.	https://www.wikidoc.org/index.php/Cellulose

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