Abacavir Nucleoside reverse transcriptase inhibitors

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

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. 

Cross-resistance In clinical trials, patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. Consider the potential for cross-resistance between abacavir and other NRTIs when choosing new therapeutic regimens in therapy-experienced patients. 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

After oral administration, abacavir is rapidly absorbed, and its bioavailability is about 83%. Food does not interfere with its absorption, and it is metabolized by alcohol dehydrogenase to 5 -carboxylic acid derivative and to S -glucuronidc by glucuronidation. Abacavir does not affect the cytochrome P-450 system. In combination with other antiretroviral drugs, abacavir is indicated for the treatment of HIV-1 infection. It is more potent than other nucleoside reverse transcriptase inhibitors in reducing HIV plasma concentration and increasing CD4+ count. 

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. 

METHADONE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS 1 efficacy of methadone when co-administered with abacavir Uncertain possibly enzyme induction Monitor for opioid withdrawal and consider increasing dose... 

ABACAVIR TIPRANAVIR + RITONAVIR Possible 1 efficacy risk of treatment failure of abacavir 1 plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors... 

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of medications approved for the management of HIV infection. They are structural analogues of nucleic acids. They undergo intracellular phosphorylation to a triphosphate metabolite and it is this metabolite that is pharmacologically active against reverse transcriptase. Drugs in this class include abacavir, adefovir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. 

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. 

The lipophilic effect of cyclopropyl explains why abacavir, a nucleoside reverse transcriptase inhibitor, has an improved absorption in the CNS compared to diaminop-urine dioxolane (DAPD) (Figure 20.14). ... 

Abacavir is an antiretroviral/nucleoside reverse transcriptase inhibitor. It is used in the treatment of HIV-1 in combination with other antiretroviral agents. Abacavir is converted inside cells to an active metabolite, carbovir 5 -triphosphate, which is a potent inhibitor of the HIV-1 reverse transcriptase. 

Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, Lafon S, Pearce G, Steel H (2001) Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 23 1603-1614... 

Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against the human immunodeficiency virus (HTV). The most important adverse effect... 

Combination of 16 ARVs seven HIV protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, and saquinavir), seven nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine), and two nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine)... 

The association between the use of abacavir and an increased risk of myocardial infarction has been confirmed in a prospective nationwide cohort study that included 2952 Danish HIV-infected patients taking highly active antiretroviral therapy (HAART) from 1995 to 2005 [87 =]. Hospitalization rates for myocardial infarction were 2.4 per 1000 person-years (95% Cl = 1.7, 3.4) for abacavir non-users and 5.7 per 1000 person-years (95% Cl = 4.1, 7.9) for abacavir users. The risk of myocardial infarction increased after abacavir was started (unadjusted IRR = 2.22 95% Cl = 1.31, 3.76 IRR adjusted for confounders = 2.00 95% Cl = 1.10, 3.64 IRR adjusted for propensity score = 2.00 95% Cl = 1.07, 3.76). This effect was also observed among patients who started to take abacavir within 2 years after the start of HAART and among patients who started to take abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. 

Veldkamp, A.I. Sparidans, R.W. Hoetelmans, R.M.W. Beijnen, J.H. Quantitative determination of abacavir (1592U89), a novel nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection, J.Chromatogr.B, 1999, 736, 123-128. 

The nucleoside analogue reverse transcriptase inhibitors (NRTIs) include abacavir, didanosine, lamivudine, stavu-dine, tenofovir, zalcitabine, and zidovudine (all rINNs). The following abbreviations have been used and may still be encountered in published papers ... 

FIGURE 50-3 Intracellular activation of nucleoside analog reverse transcriptase inhibitors. Drugs and phosphory-lated anabolites are abbreviated the enzymes responsible for each conversion are spelled out. The active antiretroviral anabolite for each drug is shown in the blue box. Key ZDV, zidovudine d4T, stavudine ddC, dideoxycytidine FTC, emtricitabine 3TC, lamivudine ABC, abacavir ddl, didanosine DF, disoproxil fumarate MP, monophosphate DP, diphosphate TP, triphosphate AMP, adenosine monophosphate CMP, cytosine monophosphate dCMP, deoxycytosine monophosphate IMP, inosine 5 -monophosphate PRPP, phosphoribosyl pyrophosphate NDR, nucleoside diphosphate. 

Nucleoside Analogue HIV Reverse Transcriptase Inhibitors as Drugs for the Treatment of HIV and Hepatitis B Zidovudine, Didanosine, Stavudine, Lamivudine, Abacavir, Emtricitabine and Entecavir... 

Compounds featuring this typical functionalized cyclopentane unit are the platelet aggregation inhibitor compound (1) of AstraZeneca, the HCV NS3 NS4A protease inhibitor (2) claimed by Tibotec for the treatment of Hepatitis C, and a Neuraminidase (Sialidase) inhibitor (3) discovered by Biocryst for the treatment of influenza (Figure 4.6). Likewise, the widely used nucleoside analog reverse transcriptase inhibitor Abacavir (4), administered against HIV, produced by GlaxoSmithKline, as well as Medivir s beta-secretase 1 (BACE 1) inhibitor (5) for the treatment of Alzheimer s dementia can be probably derived from this hydroformylation protocol. 

Rezk, N.L. Tidwell, R.R. Kashuba, A.D.M. Simultaneous determination of six HIV nucleoside analogue reverse transcriptase inhibitors and nevirapine by hquid chromatography with ultraviolet absorbance detection, J.Chromatogr.B, 2003, 791, 137-147. [plasma LOQ 10 ng/mL zalcitabine lamivudine didanosine stavudine zidovudine abacavir hexobarbital is internal standard SPE]... 

The enantiopure A-Ts cyclopentene carboxamide 35, obtained by a [2+2] cycloaddition and an enzymatic resolution, could also be a platform to synthesize the antiviral agent ( )-abacavir 38 (Scheme 41.8), which is a nucleoside analog reverse transcriptase inhibitor used in combination... 

Azabicyclo[2.2.1]hept-5-en-3-one is now well established as a very versatile synthon for the production of carbocyclic nucleosides [31] (Scheme 10). A recent example is its use in the s3mthesis of the potent reverse transcriptase inhibitor abacavir. Such compounds, where the ribose oxygen of the nucleoside has been replaced by a methylene, have become very valuable as chemotherapeutic agents in the fight against viral infections such as HIV or herpes. 

Abacavir is a guanidine analogue that inhibits HIV reverse transcriptase. In vitro, its potency is similar to that of zidovudine, protease inhibitors, and dual nucleoside combinations. There is evidence that abacavir is effective in reducing viral load and increasing the CD4 count in HIV-infected patients. Viral resistance is not rapidly selected for, but cross-resistance has been shown to other analogues of cytosine and guanidine (didanosine, lamivudine, and zalcitabine). 

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