abacavir and Heart-Diseases

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes.

Topics: Aldehydes; Animals; Anti-HIV Agents; Biotransformation; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Heart Diseases; Humans

Abacavir (ABC) is a guanosine nucleoside reverse transcriptase inhibitor (NRTI) with potent antiretroviral activity. Since NRTIs exhibit tissue-specific inhibition of mitochondrial DNA (mtDNA) synthesis, the ability of ABC to inhibit mtDNA synthesis in vivo was evaluated. Inbred wild-type (WT) and transgenic mice (TG) treated with ABC (3.125 mg/d p. o., 35 days) were used to define mitochondrial oxidative stress and cardiac function. Chosen TGs exhibited overexpression of HIV-1 viral proteins (NL4-3Deltagag/pol, non-replication competent), hemizygous depletion or overexpression of mitochondrial superoxide dismutase (SOD2(+/-) knock-out (KO) or MnSOD OX, respectively), overexpression of mitochondrially targeted catalase (MCAT), or double "knockout" deletion of aldehyde dehydrogenase activity (ALDH2 KO). Impact on mtDNA synthesis was assessed by comparing changes in mtDNA abundance between ABC-treated and vehicle-treated WTs and TGs. No changes in mtDNA abundance occurred from ABC treatment in any mice, suggesting no inhibition of mtDNA synthesis. Left ventricle (LV) mass and LV end-diastolic dimension (LVEDD) were defined echocardiographically and remained unchanged as well. These results indicate that treatment with ABC has no visible cardiotoxicity in these adult mice exposed for 5 weeks compared to findings with other antiretroviral NRTI studies and support some claims for its relative safety.

Topics: Animals; Anti-HIV Agents; Dideoxynucleosides; DNA, Mitochondrial; Echocardiography; Heart; Heart Diseases; Heart Ventricles; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mitochondria, Heart; Oxidative Stress; Superoxide Dismutase

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Fat Distribution; Cognition; Cyclopropanes; Diabetes Mellitus; Dideoxynucleosides; Ginkgo biloba; Growth Hormone-Releasing Hormone; Heart Diseases; Humans; Nitriles; Pyridazines; Pyrimidines

Topics: Anti-HIV Agents; Clinical Trials as Topic; Didanosine; Dideoxynucleosides; Heart Diseases; Humans; Multicenter Studies as Topic; Risk Factors

Topics: Anti-HIV Agents; Australia; Didanosine; Dideoxynucleosides; Europe; Heart Diseases; HIV Infections; HIV-1; Humans; Myocardial Infarction; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors