NRTIs Abacavir

Abacavir NRTI 300 mg bid Rash, hypersensitivit y reaction, nausea Do not rechallenge after hypersensitivity reaction... 

The efficacy and safety of abacavir (NRTI) and efavirenz (NNRTI) plus background therapy have been retrospectively evaluated in 50 patients, who had previously been treated with HAART (3). There was some immunological benefit, albeit limited, in most of the patients. Adverse effects were not mentioned in detail, but the dropout rate during the first 4 weeks of treatment was high, owing to skin rashes and hypersensitivity reactions. 

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

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... 

Triple NRTI therapy is recommended only when a first-line or alternative first-line therapy with either an NNRTI-based or Pi-based regimen cannot be used. Abacavir plus zidovudine plus lamivudine is the only regimen approved by the DHHS. The following triple nucleoside therapy combinations have shown poor or limited efficacy, and should be avoided abacavir plus tenofovir plus lamivudine (or emtricitabine), and didanosine plus tenofovir plus lamivudine (or emtricitabine). 

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. 

Abacavir (Ziagen) [AntIretroviral/NRTI] WARNING Aller ... 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

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. 

NRTIs and 1 PI 2 NRTIs and INNRTI 2 NRTIs and 1 PI with ritonavir 2 NRTIs and abacavir... 

Lamivudine is the best-tolerated NRTI. Its most common adverse effects include headache, malaise, fatigue, and insomnia. Pancreatitis is rare. Gastrointestinal complaints are common with lamivudine-zidovudine therapy but are probably mainly due to the zidovudine component. Lamivudine resistance sometimes occurs early in treatment. Cross-resistance to zal-citabine, didanosine, and abacavir can occur simultaneously. Withdrawal of lamivudine in patients infected with both hepatitis B virus and HIV can cause a flare-up of hepatitis symptoms. 

NRTIs) abacavir sulfate didanosine (ddl) lamivudine (3TC) stavudine (d4T) zalcitabine (ddC) zidovudine (AZT)... 

Other effects associated with NRTIs include pancreatitis, CNS toxicity (headache, irritability, insomnia), and gastrointestinal disturbances (nausea, diarrhea). Abacavir can cause an allergic (hypersensitivity) reaction that produces symptoms such as fever, joint and muscle pain, skin rashes, abdominal pain, nausea, diarrhea, and vomiting.32 In severe cases, this reaction can progress to anaphylactic shock and possibly death. 

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. 

In contrast to earlier NRTIs, abacavir is a guanosine analog. It is well absorbed following oral administration (83%), is unaffected by food, and is about 50% bound to plasma proteins. In singledose studies, the elimination half-life was 1.5 hours. Cerebrospinal fluid levels are approximately one-third those of plasma. The drug is metabolized by alcohol dehydrogenase and glucuronosyltransferase to inactive metabolites that are eliminated primarily in the urine. 

A number of currently prescribed NRTIs are shown in Figure A.44. Compounds A.155 through A.158 are all analogues of pyrimidine nucleosides. Compounds A.159 and A.160 are both purine nucleoside analogues. Abacavir (Ziagen, A.160) is inactive until it is metabolized to carbovir (A.161) in vivo. The seven drugs in Figure A.44 were approved in the United States over a span of more than 25 years. Zidovudine reached the market first in 1987, and emtricitabine was the last to be approved in 2003. The steady release... 

Nevirapine = Viramune] (dipyridodiazepinone) [NRTIs in clinical use Abacavir (ABC) Adefovir dipivoxil (9-[2-Phosphonomethoxy)ethyl] -adenine PMEA) AZT Didanosine (= 2, 3 -Dideoxyinosine) Lamivudine Stavudine Zalcitabine (2, 3 -Dideoxycytidine]... 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

Zidovudine monotherapy was the only available treatment for HIV disease before the 1990s, and was used until 1992. Zidovudine monotherapy has been proven to be efficacious for both the treatment of HAD as well as for HIV-associated minor cognitive/motor disorder (MCMD) (Arendt et al., 1992 Sidtis et al., 1993 Tozzi et al., 1993). Unfortunately, the beneficial effect of zidovudine was transient and an addition of a second NRTI such as dideoxyinosine (ddl), lamivudine (3TC), or dideoxycytidine (ddC), may not further improve psychomotor performance. Stavudine was shown to improve motor performance even after pretreatment with zidovndine (Arendt et al., 2001). A study in 1998, using abacavir versns placebo showed no nenrologic deterioration in the abacavir group as compared with the placebo group (Lanier et al., 2001). However, there was no benefit when abacavir was added to a stable ART, despite good proven CNS penetration. 

In a multicenter trial, 128 chUdren were randomly assigned to one of three regimens zidovudine + lamivudine (n — 36), zidovudine + abacavir (n = 45), or lamivudine + abacavir (n — 47) (12). The children who were free of symptoms (n — 55) were also randomized to nelfinavir or placebo, while those with more advanced disease received open-label nelfinavir (n — 73). All 13 episodes of diarrhea occurred in those taking nelfinavir. Nelfinavir did not affect serum cholesterol or triglyceride concentrations and there were no cases of lipodystrophy. There were 24 serious adverse events six were in the symptom-free children (all taking nelfinavir), but all were attributed to the NRTIs. 

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 ... 

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. 

Three NRTI medications are Abacavir (Ziagen, ABC), Abacavir, and Lamivudine (Epzicom). 

Mechanisms Abacavir is a guanosine analog with mechanisms similar to those of other NRTIs. 

NRTIs are faulty version reverse transcriptase. Reproduction of HIV is stalled when HIV uses NRTI instead of the normal reverse transcriptase. Dmgs within this category include Abacavir (Ziagen, ABC), Abacavir, Lamivudine (Epzicom), Abacavir, Lamivudine, Zidovudine (Trizivir), Didanosine (Videx, ddl, Videx EC), Emtricitabine (Emtriva, FTC, Coviracil), Emtricitabine, Tenofovir DF (Truvada), Lamivudine (Epivir, 3TC), Lamivudine, Zidovudine (Combivir), Stavudine (Zerit, d4T), Tenofovir DF (Viread, TDF), Zalcitabine (Hivid, ddC), and Zidovudine (Retrovir, AZT, AZV). 

Nucleoside reverse Iranscriplase inhibilors (NRTI) Abacavir 1.54 0.63 h Chronic Lactic acidosis, mitochondrial toxicity, hepatotoxicity. Diarrhea, nausea, vomiting hypersensitivity (fatal reactions reported) perioral paresthesias. 

NRTIs are water soluble, and are mainly eliminated by the kidneys (di-danosine, lamivudine, stavudine, and zalcitabine) or undergo hepatie glu-curonidation (abacavir, zidovudine). The few important interactions with these drugs primarily involve altered renal clearance. For zidovudine (and possibly abacavir) some interactions occur via altered glucuronidation, but the clinical relevance of these are less clear (e.g. rifampicin , (p.792)). Cytochrome P450-mediated interactions are not important for this class of drugs. 

Some combinations of NRTIs are potentially antagonistic (stavudine with zidovudine, lamivudine with zalcitabine) and some are expected to result in additive toxicity (didanosine with stavudine or zalcitabine, and possibly stavudine with zalcitabine). Some do not appear to result in additional benefits (emtricitabine with lamivudine), and some are considered inferior to other combinations (stavudine with lamivudine, zidovudine with zalcitabine or didanosine). None of these combinations are recommended. Combinations that are specifically recommended (with other antiretrovirals) include lamivudine with abacavir, didanosine or zidovudine, or didanosine with emtricitabine. Sole use of all triple NRTI regimens should generally be avoided, with the possible exception of abacavir or tenofovir , (p.806) with zidovudine and lamivudine. 

A single 300-mg dose of zidovudine was given with abacavir 600 mg to 13 mV-positive subjects. The pharmaeokinetics of abacavir were not significantly affected. The zidovudine maximum plasma level deereased by 20%, but the AUC was unchanged. This ehange is not thought to be elin-ically significant and so no dose alteration would seem neeessaty on eon-current use. These results were eonfirmed in a steady-state study in which 79 mV-positive subjects received 8 weeks of treatment with abacavir 600 mg to 1.8 g daily, in divided doses, and zidovudine 600 mg daily, in divided doses. The triple NRTI eombination of abacavir, lamivudine and zidovudine may also be considered if protease inhibitors or NNRTIs cannot be used. ... 

Buffered didanosine decreases the AUC of indinavir, and the drugs shouid be given one hour apart. Buffered didanosine interacts simiiarly with atazanavir. Tipranavir with low-dose ritonavir modestly reduced the AUC of abacavir and zidovudine, and such combinations are not recommended in the UK. The changes in pharmacokinetics seen when giving other combinations of protease inhibitors with NRTIs do not appear to be clinically significant. Protease inhibitors do not affect the intracellular activation of NRTIs. 

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