Zidovudine and lamivudine triphosphate concentration thresholds were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The significantly elevated triphosphate concentrations in women and individuals with low baseline CD4 cell counts, groups that historically experience high rates of serious NRTI toxicities, provide a hypothesis for the pathogenesis of these events.

These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.

The synthesis and the chemical/biological properties of N-hydroxysaccharin (1) (2-hydroxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide), a nitroxyl prodrug, are described. When treated with 0.1 M aqueous NaOH, 1 liberated nitroxyl (HN=O), a known inhibitor of aldehyde dehydrogenase (AlDH), in a time-dependent manner. Nitroxyl was measured gas chromatographically as its dimerization/dehydration product N2O. Under these conditions, Piloty's acid (benzenesulfohydroxamic acid) also gave rise to HNO. However, whereas Piloty's acid liberated finite quantities of nitroxyl when incubated in physiological phosphate buffer, pH 7.4, formation of nitroxyl from 1 was minimal. This was reflected in the differential inhibition of yeast AlDH (IC50 = 48 and > 1000 microM) and the differential relaxation of preconstricted rabbit aortic rings in vitro (EC50 = 1.03 and 14.0 microM) by Piloty's acid and 1, respectively. The O-acetyl derivative of 1, viz., N-acetoxysaccharin (13a), was much less active in both assays. It is concluded that N-hydroxysaccharin (1) is relatively stable at physiological pH and liberates nitroxyl appreciably only at elevated pH's. As a consequence, neither 1 nor its O-methyl (8a) and O-benzyl (8b) derivatives were effective AlDH inhibitors in vivo when administered to rats at 1.0 mmol/kg.