Reverse transcriptase inhibitors nevirapine

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. 

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

Nonnucleoside reverse transcriptase inhibitors (del-avirdine, efavirenz, nevirapine)... 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used to treat HIV-infected patients that causes mild to severe skin rash and even Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in a substantial proportion (16%) of patients. Nevirapine also induces hepatotoxicity. These adverse clinical symptoms may also occur in non-HIV subjects taking the drug as postoperative prophylaxis [15]. 

Pharmacology Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against HIV-1. 

Many of the drugs likely to be taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYP450 and have been shown to interact with protease inhibitors. Delavirdine is an inhibitor of CYP3A4 but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. 

Three non-nucleoside reverse transcriptase inhibitors (NNRTI) are currently used efavirenz (EFV), nevirapine (NVP) and delavirdine (DLV). The last NNRTI is not registered in Europe. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine mesylate efavirenz nevirapine... 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used in the treatment of AIDS. Elimination of nevirapine from the body occurs via P-glycoprotein, and it is extensively metabolized by the CYPs (88). In... 

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. 

Nevirapine is a member of the dipyridodiazepinone class of chemicals and is a nonnucleoside reverse transcriptase inhibitor that induces a conformational change in HIV-1 reverse transcriptase. Although the conformational change is at a distance from its active site, it disrupts its catalytic activity. It blocks both RNA-dependent and DNA-dependent DNA polymerase activity but does not affect the activity of the template or nucleoside triphosphate. Nevirapine does not inhibit HIV-2 reverse transcriptase or human DNA polymerases a, (3 or y. The resistance to the drug results from site-directed mutagenesis at codons 103 or 181, and also at 100, 106, 108, 188 and 190 of viral reverse transcriptase. The development of resistance to one nonnucleoside reverse transcriptase implies that HIV will also be resistant to the rest of the drugs in this class. 

Manfredi R, Calza L, Chiodo F. An extremely different dysmetabohc profile between the two available nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. J Acquir Immune Defic Syndr 2005 38(2) 236-8. 

More recently, RTIs that are chemically distinct from zidovudine and other NRTIs have also been developed (see Table 34-3). These agents are known as nonnucleoside reverse transcriptase inhibitors (NNR-TIs), and include drugs such as delavirdine (Rescrip-tor), efavirenz (Sustiva), and nevirapine (Viramune).32 These drugs also inhibit the reverse transcriptase enzyme, but act at a different site on the enzyme than do their NRTI counterparts. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Nevirapine (BI-RG-587) ATC Use JOS AGO 1 antiviral, anti-AIDS therapeutic, reverse transcriptase inhibitor... 

Abstract Non-nucleoside reverse transcriptase inhibitors, such as nevirapine, TIBO, HEPT, and efavirenz, are very specific to HIV-1 reverse transcriptase and have few side... 

Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002 185(5) 599-607. 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (1). Concerns about the adverse effects of nevirapine have delayed its implementation in preventing perinatal HIV. Decision analysis has been used to compare three strategies a single dose of nevirapine, a short course of zidovudine, and no intervention (2). The... 

In a review of the medical records of HIV-positive patients who had taken nevirapine, delavirdine, or both, the frequency of skin reactions was determined, as were the consequences of rechallenge with the same or the alternative agent (17). The overall incidence of rash attributed to the use of one of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was 37%. While rash due to delavirdine was more common (8/20 versus 25/69), the rash due to nevirapine was more severe and necessitated more frequent hospitalization. Rash recurred in six of eight patients who were rechallenged with the same agent and in seven of 10 who were switched to the alternative agent. The conclusion was drawn that there is little value in attempting to re-treat patients who have had skin reactions to NNRTIs, except possibly those with limited treatment options. 

The non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) include delavirdine, efavirenz, and nevirapine (all rINNs). The pharmaceutical chemistry and uses of the first- and second-generation NNRTIs have been reviewed (1). 

Krogstad P, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudoime A, Khoury M, Mendez H, Nachman S, Wiznia A, BaUow A, Aweeka F, Rosenblatt HM, Perdue L, Frasia A, Jeremy R, Anderson M, Japour A, Fields C, Farnsworth A, Lewis R, Schnittman S, GigUotti M, Maldonaldo S, Lane B, Hernandez JE, et al Pediatric AIDS CUnical Trials Group 377 Study Team. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nehinavir, or ritonavir for pretreated children mfected with human immnnodeficiency virus type 1. Qin imect Dis 2002 34(7) 991-1001. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

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