Reverse transcriptase inhibitors hepatitis

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Adefovir dipivoxii is an orally-administered nucleotide analog reverse transcriptase inhibitor. However it is used for treatment of hepatitis B and failed as a treatment for HIV. 

Emtricitabine is a nucleoside reverse transcriptase inhibitor, launched for the treatment of HIV infection. It is also currently in phase III for the treatment of hepatitis B virus (HBV) infection (Fig. 35) [98]. 

Erickson DA, Mather G, Trager WE, Levy RH, Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999 27(12) 1488-1495. 

The resolution of racemic FTC butyrate (34) was required for the synthesis of the antiviral drug emtricitabine (Emtriva) (Scheme 7.15) a nucleoside reverse transcriptase inhibitor targeted for treatment of human immunodeficiency virus (HIV) and hepatitis infections [35]. The racemic FTC butyrate ester (34) was treated with immobilized cholesterol esterase, which cleaved the required isomer to the corresponding alcohol (-) 35 with 91% and 52% conversion [36]. The product was isolated as the hydrochloride salt to give 31% yield (98% ) from the 8 kg demonstration. The esterase was immobilized by precipitation onto an accurel polypropylene support using acetone followed by cross linking with glutaralde-... 

Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin. 

Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours in some patients. Quinupristin and dalfopristin are not metabolized by cytochrome P450 enzymes but significantly inhibit CYP 3 A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleo- side reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary. 

In 2001, tenofovir disoproxil fumarate 61, a prodrug of tenofovir was approved for treatment of HIV, subsequently being preregistered in the USA for treatment of hepatitis B. Emtricitabine 62, a reverse transcriptase inhibitor, was approved in 2003 for HIV. What is of import is that these compounds are now part of fixed dose combination therapies for treatment of HIV, either two drug (tenofovir disoproxil fumarate/emtricitabine) or three drug Atripla (tenofovir disoproxil fumarate/emtricitabine/efavirenz) formulations. Thus, even 50 + years after Bergmann s discovery of bioactive arabinose nucleosides, small molecules synthesised as result of his discoveries are still in clinical use and others are in clinical trials for treatment of viral diseases. 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RIBAVIRIN 1. t side-effects, risk of lactic acidosis, peripheral neuropathy, pancreatitis, hepatic decompensation, mitochondrial toxicity and anaemia with didanosine and stavudine 2.1 efficacy of lamivudine 1. Additive side-effects t intracellular activation of didanosine and stavudine 2. J intracellular activation of lamivudine 1. Not recommended. Use with extreme caution monitor lactate, LFTs and amylase closely. Stop co-administration if peripheral neuropathy occurs. Stavudine and didanosine carry a higher risk 2. Monitor HIV RNA levels if they T, review treatment combination... 

An example of the use of a terpene as a chiral auxiliary is provided by the synthesis of the anti-viral reverse transcriptase inhibitor Lamivudine (148). The nucleoside analog is marketed by Biochem Pharma (now Shire Pharmaceuticals) and Glaxo Wellcome (now GlaxoSmithKline) for the treatment of HIV and hepatitis B virus infection. In the... 

Adverse reactions early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose need not be altered. More serious Eire anaemia and neutropenia which develop more commonly when the dose is high, and with advanced disease. A toxic myopathy (not easily distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors). 

Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life (14 h plasma t 6 h). In combination with zidovudine, lamivudine appears to reduce viral load effectively and to be well tolerated, although bone marrow suppression may be produced. Rarely, pancreatitis may occur. Lamivudine has also been used for treatment of chronic hepatitis B infection, but resistant strains of virus have been reported. 

Use of St. John s Wort is complicated by the lack of standardisation of the ingredients. Those who wish to take St. John s Wort should be made aware that it may cause dry mouth, dizziness, sedation, gastrointestinal disturbance and confusion. Importantly also, it induces hepatic P450 errzymes (CYP 1A2 and CYP 3A4) with the result that the plasma concentration and therapeutic efficacy of warfarin, oral contraceptives, some anticonvulsants, antipsychotics and HTV protease/reverse transcriptase inhibitors are reduced. Concomitant use of tr5 to-phan and St John s Wort may cause serotonergic effects including nausea and agitation. 

Adefovir is an adenine analogue reverse transcriptase inhibitor. While it has activity against both HIV and hepatitis B, its use in HIV infection is limited by nephrotoxicity due to the high doses needed (1). The dose used for treatment of hepatitis B is about one-tenth that needed to treat HIV infection, so patients with hepatitis B must have co-infection with HIV ruled out before treatment is started. 

Lamivudine (3TC) is a nucleoside analogue reverse transcriptase inhibitor that has been widely used against HIV infection which also has antiviral effects against hepatitis B (1). 

Stavudine is a nucleoside analogue reverse transcriptase inhibitor. Its most important adverse effects are peripheral neuropathy and increases in hepatic transaminases, both of which usually resolve on withdrawal. 

Trade names Hepsera (Gilead) Preveon Indications HIV infection, Hepatitis B infection Category Antiretroviral Nucleotide analog reverse transcriptase inhibitor Half-life 16-18 hours... 

Pancreatic dysfunction, heralded by large increases in serum amylase and lipase, is associated with the use of several reverse-transcriptase inhibitors (RTIs). Didanosine appears to be the worst offender, and pancreatitis is the most characteristic adverse effect of this particular NRTI. Conditions enhancing susceptibility to drug-induced pancreatic dysfunction include hypertriglyceridemia, hypercalcemia, and history of excessive ethanol use. Liver dysfunction including hepatitis may occur with the antitu-bercular drugs, isoniazid, and pyrazinamide. Cholestasis is associated with the estolate form of erythromycin. 

Zalcitabine (2, 3 dideoxycytidine ddC) is a synthetic cytosine analog reverse-transcriptase inhibitor. It is active against HIV-I, HIV-2, and hepatitis B virus (HBV). The in vitro ICjo of zalcitabine against HIV-1 ranges from 2 nM in monocytes-macrophage cell lines to 0.5 pM in human peripheral blood mononuclear cells. Zalcitabine has considerably more antiretroviral activity in monocytes-macrophage cell lines than other nucleoside analogs, but the potential clinical utility of this observation is uncertain. 

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