acyclovir and hypoxanthine-arabinoside

Seven 6-alkoxypurine arabinosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). The simplest of the series, 6-methoxypurine arabinoside (ara-M), was the most potent, with 50% inhibitory concentrations ranging from 0.5 to 3 microM against eight strains of VZV. This activity was selective. The ability of ara-M to inhibit the growth of a variety of human cell lines was at least 30-fold less (50% effective concentration, greater than 100 microM) than its ability to inhibit the virus. Enzyme studies suggested the molecular basis for these results. Of the seven 6-alkoxypurine arabinosides, ara-M was the most efficient substrate for VZV-encoded thymidine kinase as well as the most potent antiviral agent. In contrast, it was not detectably phosphorylated by any of the three major mammalian nucleoside kinases. Upon direct comparison, ara-M was appreciably more potent against VZV than either acyclovir or adenine arabinoside (ara-A). However, in the presence of an adenosine deaminase inhibitor, the arabinosides of adenine and 6-methoxypurine were equipotent but not equally selective; the adenine congener had a much less favorable in vitro chemotherapeutic index. Again, this result correlated with data from enzyme studies in that ara-A, unlike ara-M, was a substrate for two mammalian nucleoside kinases. Unlike acyclovir and ara-A, ara-M had no appreciable activity against other viruses of the herpes group. The potency and selectivity of ara-M as an anti-VZV agent in vitro justify its further study.

Topics: Acyclovir; Antiviral Agents; Arabinonucleosides; Cell Survival; Cells, Cultured; Herpesvirus 3, Human; Humans; Kinetics; Thymidine Kinase; Vidarabine

The effects of double and triple combinations of acyclovir (ACV), adenine arabinoside (ara-A), arabinosyl hypoxanthine, or interferon on herpes simplex virus type 2 in mouse embryo fibroblasts were measured. These in vitro data were compared with results obtained in mice infected intravaginally with herpes simplex virus type 2 and treated intraperitoneally with low- and high-dose combinations of ACV, ara-A, or polyriboinosinic-polyribocytidylic acid(poly-L-lysine)carboxymethylcellulose complex [poly IC(LC)], an interferon inducer. Although all double combinations and one triple combination evoked synergistic reactions in vitro, results did not necessarily predict in vivo observations. In vivo synergy was observed when combinations of ACV and ara-A and low doses of ara-A-ACV-poly IC(LC) were used. However, toxicity was seen with full-dose nucleoside-poly IC(LC) doublets. The full-dose ACV-ara-A combination completely prevented progression beyond vaginitis, with all animals surviving. The ara-A-ACV results observed in mice, together with in vivo data of others, suggest that this combination might prove clinically useful for certain herpes simplex virus type 2 infections.

Topics: Acyclovir; Animals; Antiviral Agents; Arabinonucleosides; Carboxymethylcellulose Sodium; Culture Techniques; Drug Combinations; Female; Herpes Genitalis; Interferons; Male; Mice; Mice, Inbred BALB C; Poly I-C; Polylysine; Simplexvirus; Vidarabine