of nevirapine and its major metabolite.

(Analysis of 1291 patients started on nevirapine based combination regimens in India; rash in 6.6% and hepatitis in 3.2%, but no deaths from liver injury except 4 with lactic acidosis on stavudine).

A cohort study of nevirapine tolerance in clinical practice: French Aquitaine Cohort, 1997-1999.

Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial. At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for patients taking racemic methadone (37%; n = 11) and (R)-methadone (44%; n = 9). AUC changes ranged from mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine. Due to extensive variability, the adjustments must be tailored to the individual patient's needs.

Synthesis of nevirapine and its major ..

(Review of hepatotoxicity of nevirapine; some of the risk factors identified may not apply to antiretroviral experienced patients).

(Retrospective review of 136 patients treated with regimens including nonnucleoside reverse transcriptase inhibitors, 48% had ALT elevations which were >5 times ULN in 20%; risk factors were alcohol use, HCV infection and 4 drug regimens; 3 of 17 patients with ALT elevations on nevirapine redeveloped ALT elevations on restarting; 2 patient had jaundice, but had HCV coinfection and were exposed to other hepatotoxins).

a common pain killer, is often used for acetaminophen, its active ..

A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay was recently developed to quantitate the phase I metabolites of nevirapine (). The present analyses applied this assay to specimens from two prior studies to characterize plasma nevirapine phase I metabolite profiles in two different situations, one involving a single 200-mg oral dose of nevirapine given to 10 HIV-negative African Americans and the other at steady state with a 200-mg oral dose twice daily in 10 HIV-infected Cambodians. We also compare metabolite profiles between these situations.

drug itself and its major metabolite desmethylamiodarone ..

Despite its widespread use, there remain gaps in understanding of nevirapine metabolism and disposition. Its pharmacokinetic characteristics include a long plasma half-life after single-dose administration which decreases with repeated doses due to autoinduction of its biotransformation (, –). Nevirapine is 60% bound to plasma proteins, and elimination occurs mainly through oxidative metabolism. Five metabolites, including hydroxyl metabolites at positions 2, 3, 8, and 12 () and 4-carboxynevirapine derived from the 12-hydroxy metabolite, have been identified. In vitro microsome data suggest that CYP3A is involved in 2-hydroxynevirapine formation and CYP2B6 is involved in 3-hydroxynevirapine formation (). Several CYPs are involved in the other pathways (, ). These metabolites are eliminated in the urine as conjugates, mainly glucuronides (). Relatively little is known regarding nevirapine biotransformation and metabolite disposition following a single dose and at steady state, in part due to the lack of a direct and sensitive assay (, ).

amanitins are cyclic octapeptides that stop protein synthesis

In resource-limited settings, the nonnucleoside HIV-1 reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) is among WHO-recommended components of first-line antiretroviral therapy. At the time of this study, nevirapine in combination with two nucleoside reverse transcriptase inhibitors, such as stavudine or zidovudine, and together with lamivudine was the preferred regimen for treatment-naïve patients, in part because of the availability of a WHO-prequalified, low-cost, generic, fixed-dose combination (, ). In addition, single-dose nevirapine administered to pregnant, HIV-infected women at delivery has been widely prescribed to prevent mother-to-child transmission (–). Despite its major therapeutic benefits, treatment with nevirapine may cause severe hepatotoxicity and/or skin rash in some patients. Molecular mechanisms of nevirapine toxicity are incompletely understood, but a causal role of metabolites has been suggested (, ).