Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is effective when used as part of combination therapy to treat HIV-1-infected individuals and as monotherapy for prevention of mother-to-child HIV-1 transmission. Nevirapine pharmacokinetics are characterised by rapid absorption and distribution, followed by prolonged elimination. Nevirapine is generally well tolerated. The most common toxicity is rash, which is usually mild and self-limiting. The primary route of nevirapine elimination is through metabolism by the cytochrome P450 enzyme system. Nevirapine elimination accelerates during long term administration because of autoinduction of the enzymes involved in its elimination pathway. The recommended regimen for adults is nevirapine 200mg once daily for 2 weeks, followed by 200mg twice daily. Nevirapine elimination is prolonged in pregnant women during labour and in newborns. A regimen of a single 200mg oral dose administered to the mother during labour and a single 2 mg/kg dose administered to the newborn at 48 to 72 hours after birth maintains serum nevirapine concentrations above 100 microg/L (10 times the in vitro 50% inhibitory concentration against wild-type HIV-1) throughout the first week of life. This limited regimen has been shown to be extremely well tolerated and to reduce mother-to-child transmission by nearly 50% in mothers and infants receiving no other antiretrovirals. There are few data describing the safety and pharmacokinetics of nevirapine during long term use in pregnancy. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. Children should receive 4 mg/kg once daily for the first 2 weeks of therapy, followed by 7 mg/kg doses twice daily if below the age of 8 years or 4 mg/kg twice daily if older than 8 years. Alternatively, children may receive 150 mg/m2 across all ages, once daily for the first 2 weeks of therapy followed by the same dose twice daily.
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PMID:Nevirapine: pharmacokinetic considerations in children and pregnant women. 1106 14

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has the most common treatment limiting side effect of rash. Severe rash has been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men. In a multicenter, retrospective cohort study of all patients who received nevirapine over a 5-year period, severe rash was noted in 9 of 95 women and 3 of 263 men (risk ratio [RR], 8.31; 95% confidence interval [CI], 2.3-30.0; P=.005). Women were more likely to discontinue nevirapine therapy because of rash (RR, 4.5; 95% CI, 1. 9-10.5; P=.0005). After adjusting for age and baseline CD4 cell count in multivariate analysis, women had a 7-fold increase in risk for severe rash and were 3.5 times more likely to discontinue nevirapine therapy. In women of reproductive age for whom contraception may occur, nevirapine remains the NNRTI of choice. Recognition of sex differences in this severe adverse event will be important in prescribing nevirapine.
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PMID:Sex differences in nevirapine rash. 1171 1

The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing. Although administration of oral zidovudine during labor may not provide equivalent serum drug exposure as with continuous intravenous infusion, the clinical relevance of the difference is unknown. Nevirapine is well absorbed during labor, and sufficient drug for prophylaxis against perinatal transmission crosses the placenta if an oral dose is administered to the mother at least 1 hour before delivery. Placental transfer of reverse transcriptase inhibitors is good, whereas preliminary data suggest that protease inhibitors do not cross the placenta well. The use of antiretrovirals during pregnancy is becoming increasingly common, although their safety, toxicity, and teratogencity in pregnancy have not been well described. Normal growth and development have a profound impact on the pharmacokinetics of antiretrovirals in newborns and infants. Washout elimination of transplacentally acquired drug is slow. The pattern of increase in drug clearance over time will depend on the specific elimination pathway for the agent. Dosing regimens must take into account developmental changes in clearance and appropriate scaling for size. Adherence to antiretroviral regimens is a critical factor in determining the success of prophylactic and therapeutic regimens and is made difficult by the inability of infants to swallow pills and capsules.
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PMID:Antiretroviral pharmacology in pregnant women and their newborns. 1113 16

Nevirapine is a non-nucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of HIV infection. Severe rash, including the Stevens-Johnson syndrome (SJS), is the major toxicity of nevirapine and is described in the package labeling with a prominent, boxed warning. Though physicians treating large populations of patients with HIV are well aware of this complication, only one other report of nevirapine-associated SJS has been documented in the dermatology literature. We describe 2 cases of SJS related to nevirapine use and review the literature on this newly recognized association.
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PMID:Stevens-Johnson syndrome caused by the antiretroviral drug nevirapine. 1117 14

The capacity of three clinically available nonnucleoside reverse transcriptase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 (CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevirapine, and efavirenz produced negligible inhibition of phenacetin O-deethylation (CYP1A2) or dextromethorphan O-demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upon initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP-mediated drug biotransformation. However, the model does not incorporate interactions attributable to enzyme induction.
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PMID:Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. 1122 65

Nevirapine is an antiretroviral agent belonging to the class of non-nucleoside reverse transcriptase inhibitors. We describe a fast, simple isocratic reversed-phase high-performance liquid chromatography method with a 30-mm long column for assaying nevirapine in human serum. After deproteinization of 200 microl serum samples with 50% trichloroacetic acid, the supernatant was injected into a reversed-phase C18 column, using 10 mM phosphate buffer (pH 5)-acetonitrile (82:18, v/v) as the mobile phase. Peak detection was performed at 240 nm. Nevirapine retention time was 2 min. The method was validated over 0.1-10 microg/ml and the assay was linear over this concentration range (r2>0.998). Within- and between-day precisions were less than 5.4%. The lower limit of quantification was 0.1 microg/ml. Nevirapine in human serum samples was stable for 2 days at 20-25 degrees C, 15 days at 4 degrees C and 3 months at -20 degrees C.
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PMID:Simple and rapid determination of nevirapine in human serum by reversed-phase high-performance liquid chromatography. 1123 94

Patients taking a triple combination of AZT, ddI, and nevirapine appear to have better surrogate markers than those taking the double combination of AZT and ddI, according to 241 AIDS Clinical Trials Group (ACTG) researchers. The triple combination resulted in a 40 percent increase in T-cells over baseline, which persisted through 40 weeks of the study. The triple combination also produced greater decreases in the viral load. Although the trial was not designed to evaluate clinical endpoints, there appeared to be no difference in clinical endpoints except in patients with fewer than 50 T-cells or where there was a trend toward fewer clinical endpoints with the triple combination. Nevirapine, an investigational nonnucleoside reverse transcriptase, is available only through clinical trials.
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PMID:Triple combination superior to double combination. 1136 10

The results of the AIDS Clinical Trials Group (ACTG) 076 protocol have proved that antiviral medications, specifically zidovudine (ZDV; AZT), can reduce HIV transmission from mother to fetus. However, AZT therapy is not a viable option for many women--women who are at a late stage in disease progression, have had ZDV therapy prior to pregnancy, are unable to tolerate ZDV, or cannot afford ZDV. In response, the Pediatric AIDS Clinical Trials Group is developing other trials that might offer evidence of reduction of perinatal transmission. Nevirapine is a non-nucleoside HIV reverse transcriptase inhibitor. In studies of adults and children older than three months, nevirapine has demonstrated an ability to reduce HIV viral burden although it is an unlikely candidate for long-term therapy because HIV develops resistance to it in four weeks. Nevirapine may be useful in preventing perinatal transmission since fifty to seventy percent of vertical transmission is believed to occur during labor and delivery. The ACTG has established nine ACTG 250 (nevirapine) sites in the United States and Puerto Rico. It is imperative for clinicians to provide a thorough, non-directive, and culturally appropriate presentation of information about the complex research studies. The discussions should cover data about perinatal transmission, with and without ZDV use; possible benefits of the trial; unknown long-term adverse outcomes for the woman and her infant; information about study protocol, including the existence of placebo arms; and notice of the rights of the woman to withdraw without compromising her or her infant's health care at the clinic. Clinicians must negotiate a balance between providing appropriate clinical care and enrolling the number of participants that will secure not only the current trial but also future trials.
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PMID:Nevirapine: ethical dilemmas and care for HIV-infected mothers. 1136 87

An antiviral drugs advisory committee unanimously recommended accelerated approval for nevirapine (Viramune) for combination therapy with other anti-HIV drugs. Nevirapine, produced by Boehringer Ingelheim Parmaceuticals, is the first non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by the Food and Drug Administration (FDA). Studies have shown that best results were seen when patients started using the drug at the same time they began using previously untried nucleoside analogs. In April, an expanded access program was initiated to make Viramune available to adult and pediatric patients with progressive, symptomatic disease.
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PMID:Nevirapine recommended for approval. 1136 50

The Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee recommended the accelerated approval of nevirapine, a nonnucleoside reverse transcriptase inhibitor. The recommendation was based on immunologic and virologic data obtained in several trials. Nevirapine must be given in combination with nucleoside analogs. Combining protease inhibitors with nevirapine is being considered, but more data on its safety is necessary. HIV becomes resistant to nevirapine, but curiously, some patients sustain their reduction in HIV RNA. Several adult nevirapine trials are summarized. Pediatric studies have shown interesting results, such as effective entry of the drug into both plasma and cerebrospinal fluid, decreased viral load, and antibody seroreversion. The primary side effect of nevirapine is rash, which may be fatal in some patients.
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PMID:Nevirapine: new drug, new class, new questions. 1136 50


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