Copegus
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Copegus
RibavirinSystematic (IUPAC) name1--1H-1,2,4-triazole-3-carboxamideIdentifiersCAS number36791-04-5ATC codeJ05AB04PubChem5064DrugBankAPRD00081ChemSpider34439Chemical dataFormulaC8H12N4O5 Mol. mass244.206Synonyms1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamidePharmacokinetic dataBioavailability45% oral (without food), about 76% with fatty mealMetabolismMetabolized to 5'phosphates, de-riboside, and deriboside carboxylic acidHalf life12 days - Multiple Dose; 120-170 hours - Single DoseExcretion10% fecal, remainder in urine (30% unchanged, remainder metabolites)Therapeutic considerationsPregnancy cat.US: X; AU: XLegal statusEthical U.S. pharmaceutical; Not DEA-controlled.RoutesLiquid for inhalation; oral capsule and tabletRibavirin (brand names: Copegus, Rebetol, Ribasphere, Vilona and Virazole) is an anti-viral drug indicated for severe RSV infection (individually), hepatitis C infection (used in conjunction with peginterferon alfa-2b) and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides. In this form it interferes with RNA metabolism required for viral replication. How it exactly affects viral replication is unknown; many mechanisms have been proposed for this (see Mechanisms of Action, below) but none of these has been proven to date. Multiple mechanisms may be responsible for its actions.The primary observed serious adverse side-effect of ribavirin is hemolytic anemia, which may worsen preexisting cardiac disease. The mechanism for this effect is unknown. It is dose-dependent and may sometimes be compensated by decreasing dose. Ribavirin is also a teratogen in some animals species and thus poses a theoretical reproductive risk in humans, remaining a hazard as long as the drug is present, which can be as long as 6 months after a course of the drug has ended.// UsesIt is active against a number of DNA and RNA viruses. It is a member of the nucleoside antimetabolite drugs that interfere with duplication of viral genetic material. Though not effective against all viruses, ribavirin is remarkable as a small molecule for its wide range of activity, including important activities against influenzas, flaviviruses and agents of many viral hemorrhagic fevers.In the U.K. & the U.S. the oral (capsule or tablet) form of ribavirin is used in the treatment of hepatitis C, in combination with pegylated interferon drugs.The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children. However, its efficacy has been called into question by multiple studies, and most institutions no longer use it. It is still used in some cases.In Mexico, ribavirin ("ribavirina") has been sold for use against influenza. Studies have been mixed, but the derivative viramidine may have more promise.It has been used (in combination with ketamine, midazolam, and amantadine) in treatment of rabies. MarketingOral ribavirin, as Rebetol, was marketed in the U.S. until 2005 by Schering Plough with royalty payments for licensing made to Valeant Pharmaceuticals International (see History below). It was also marketed as Copegas tablets by Roche Pharmaceuticals under a separate license to Valeant Pharmaceuticals International. After concluding patent disputes over generic ribavirin availability in 2003, Three Rivers Pharmaceuticals, LLC in conjunction with Par Pharmaceutical, was approved in 2005 to market ribavirin as Ribosphere capsules. Generic ribavirin (200 mg, no brand name) became available in 2005 from Sandoz, Teva Pharmaceutical Industries, and Warrick Pharmaceuticals, which is the generic arm of Schering Plough. These products are expected to displace the brand name products paying license fees to Valeant Pharmaceuticals International. The only present FDA-approved indication for these products is in conjunction with interferon against chronic hepatitis C with hepatic damage.In Mexico, oral ribavirin has been available since the 1980s as an over-the-counter drug ("ribavirina," ICN pharmaceuticals Spanish tradename Vilona), for treating influenza. In this form it was occasionally brought into the U.S. for HIV/AIDS patients. However, ribavirin has proven to have little if any clinical usefulness against HIV, and it can greatly increase blood levels and also toxicity of the HIV antiviral didanosine (ddI, Videx). Other interactions with nucleoside antivirals for HIV should be considered when HIV/AIDS patients use ribavirin to treat hepatitis C (see "aidsinfo" external link). HistoryRibavirin (originally also known as Virazole) is a synthetic chemical not found in nature. It was first synthesized in 1970 (Lau, 2002-- see hepcassoc.org external link below) at ICN Pharmaceuticals, Inc. (later Valeant Pharmaceuticals International) by chemist Joseph T. Witkowski, under the direction of laboratory director Roland K. Robins. (Robins , a purine chemist, had earlier been the inventor of the highly successful purine-analogue pharmaceutical allopurinol). Ribavirin was discovered as part of a systematic ICN search of antiviral and antitumor activity in synthetic nucleosides. This was inspired in part by discovery (in the 1960s) of antiviral activity from naturally-occurring purine-like nucleoside antibiotics like showdomycin, coformycin, and pyrazomycin. These agents had too much toxicity to be clinically useful (and the antiviral activity of them may be incidental), but they served as the starting point for pharmaceutical chemists interested in antivirals and antimetabolic chemotherapeutic agents.In 1972 it was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity. Ribavirin protected mice against mortality from both A and B strains of influenza, and ICN originally planned to market it as an anti-influenza drug. Results in human trials against experimental influenza infection were mixed, however, and the FDA ultimately did not approve this indication for ribavirin use in humans, thereby causing a severe financial shock to ICN.Although ICN was allowed in 1980 to market ribavirin, in inhalant form, for RSV infection in children, the U.S. market for this indication was small. By the time oral ribavirin was finally approved by the FDA as part of a combination treatment (with interferon) for hepatitis C in 1998, the original ICN patents on ribavirin itself had expired, and (notwithstanding subsequent patent disputes) ribavirin had become essentially a generic drug. Future: Other Viral ActivitiesExperimental data indicate that ribavirin may have useful activity against many viruses of interest, including avian influenza, hepatitis B, polio, measles, Canine distemper and smallpox. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers, including Lassa fever, Crimean-Congo hemorrhagic fever, and Hantavirus infection. Ribavirin is active in a hamster model of yellow fever, a finding which is not surprising, given the familial relationship of yellow fever and hepatitis C viruses as flaviviridae. Ribavirin is active against other important flaviviridae such as West Nile virus and dengue fever.Ribavirin's present generic status is expected to slow research into new uses, however. ChemistryPhysically ribavirin is similar to the sugar D-ribose from which it is derived. It is freely soluble in water, and is re-crystallized as fine silvery needles from boiling methanol. It is only sparingly soluble in anhydrous ethanol.Classically ribavirin is prepared from natural D-ribose by blocking the 2', 3' and 5' OH groups with benzyl groups, then derivatizing the 1' OH with an acetyl group which acts as a suitable leaving group upon nucleophilic attack. The ribose 1' carbon attack is accomplished with 1,2,4 triazole-3-carboxymethyl ester, which directly attaches the 1' nitrogen of the triazole to the 1' carbon of the ribose, in the proper 1-β-D isomeric position. The bulky benzyl groups hinder attack at the other sugar carbons. Following purification of this intermediate, treatment with ammonia in methanolic conditions then simultaneously deblocks the ribose hydroxyls, and converts the triazole carboxymethyl ester to the carboxamide. Following this step, ribavirin may be recovered in good quantity by cooling and crystallization. DerivativesRibavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2' nitrogen of the triazole with a carbon (which becomes the 5' carbon in an imidazole), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5' imidazole riboside derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin. Note that two natural products were already known with this imidazole riboside structure: substitution at the 5' carbon with OH results in pyrazomycin/pyrazofurin, an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has only modest antiviral properties.Derivatization of the triazole 5' carbon, or replacement of it with a nitrogen (i.e., the 1,2,4,5 tetrazole 3-carboxamide) also results in substantial loss of activity, as does alkyl derivatization of the 3' carboxamide nitrogen.The 2' deoxyribose version of ribavirin (the DNA nucleoside analogue) is not active as an antiviral, suggesting strongly that ribavirin requires RNA-dependent enzymes for its antiviral activity.Antiviral activity is retained for acetate and phosphate derivation of the ribose hydroxyls, including the triphosphate and 3', 5' cyclic phosphates, but these compounds are no more active than the parent molecule, reflecting the high efficiency of esterase and kinase activity in the body. Vi
Roche announced final results from the REPEAT study, which demonstrated that treatment with once-weekly PEGASYS(R) (peginterferon alfa-2a) and daily COPEGUS(TM) (ribavirin) for 72 weeks is a promising treatment option for patients whose infection did not respond to previous treatment with another pegylated interferon (Peg- Intron(R)Chugai Pharmaceutical has said that the antiviral ribavirin, trade name Copegus, obtained an approval for combination therapy with the chronic hepatitis C treatment drug Pegasys.Roche announced results from the LATINO study, the largest prospective study to evaluate the response of Latino whites infected with genotype 1 hepatitis C virus (HCV) to combination
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Important Drug Warning Update to PEGASYS and COPEGUS Package Inserts -- Dear Healthcare Professional Letter; COPEGUS Prescribing Information and COPEGUS Medication Guide
Roche U.S. Pharmaceuticals : Our Products : Copegus
1 COPEGUS (ribavirin, USP) TABLETS R x only COPEGUS (ribavirin) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone ...
COPEGUS (ribavirin, USP) TABLETS
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