Didanosine

Abstract

Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest.

Intracellular Metabolism of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine in Combination in the Absence and Presence of Ribavirin

“…The affinities of HIV RT for AZT-TP and ddA-TP are similar (K, values of 0.1 and 0.2 11M, respectively (Hao et al, 1988). The increased level of AZT-TP formed is therefore consistent with the higher antiviral activity of AZT compared to ddl in cell culture (Faulds and Brogden, 1992;Cox et al, 1994). The results obtained here for the levels of AZT-TP and ddA-TP formed in CEM cells agree well with previous data on the phosphorylation of AZT and ddl in peripheral blood mononuclear cells (Gao et al, 1993).…”

“…In the case of AZT, the thymidine salvage pathway is responsible for the phosphorylation, whereas ddl is phosphorylated by a more complex pathway involving deoxyadenosine-metabolizing enzymes (summarized in Fig. 1) (Furman et al, 1986;Faulds and Brogden, 1992;Sommadossi, 1993). The synergistic mechanism of the combination of AZT and ddl is, however, unknown.…”

Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs

“…The rate-limiting step after incorporation of a single nucleotide is the release of the DNA from the enzyme (26). 2 In each panel, the solid line represents the best fit of the data to a burst equation, from which the burst amplitude, A, the observed rate of incorporation, k obsd , and the observed steadystate rate, k ss , were obtained.…”

High performance liquid chromatography analysis of 9‐(2′,3′‐dideoxy‐2′β‐fluoro‐D‐threo‐penta furanosyl) adenine and its metabolite in human plasma using solid‐phase extraction on a polyfluorinated reversed stationary phase

“…1) possess in vitro activity and potency against HIV (Jeri and James, 1995) that is similar to that of 2',3'-dideoxy inosine (ddI) (Jeri and James, 1995;Marquez et al, 1990;Faulds and Brogden, 1992).…”