Efficacy of 5-vinyl-1-beta-D-arabinofuranosyluracil (VaraU) against herpes simplex virus type 2 strains in cell cultures and against experimental herpes encephalitis in mice: comparison with acyclovir and foscarnet.

Abstract

The sensitivity of different herpes simplex virus type 2 (HSV-2) strains to inhibition by 5-vinyl-1-beta-D-arabinofuranosyluracil (VaraU) was evaluated in comparison to 9-(2-hydroxyethoxymethyl)guanine (ACV; acyclovir) and trisodiumphosphonoformate (Na3PFA; foscarnet), using a plaque inhibition assay in primary rabbit testes (PRT) cells as well as in human embryonic lung fibroblast (HELF) cell cultures. The order of decreasing activity found was ACV much greater than VaraU greater than Na3PFA in PRT cells and ACV greater than VaraU much greater than Na3PFA in HELF cells, with 50% inhibition doses (ID50) of 1.8, 8.8, and greater than 110 microM for the three drugs in HELF cells, respectively. After 72hr of drug treatment, inhibition of HELF cell proliferation by VaraU (ID50, greater than 1000 microM) was less than that by ACV and Na3PFA, resulting in high selectivity indexes of greater than 100 against HSV-2 for VaraU and ACV. Their in vivo efficacy was assessed in a mouse encephalitis model. Using a treatment schedule of three daily intraperitoneal (ip) doses over a period of 5 days, only the survival times of mice were considerably prolonged by VaraU (150 or 300 mg/kg per day; P less than 0.05 or P less than 0.001, respectively). In contrast, ACV treatment (150 mg/kg per day) led to a nearly complete prevention of encephalitis and death (P less than 0.001). Similar therapy results with VaraU application through the drinking water were obtained using only one-sixth of the high ip dose (approximately 50 mg/kg per day) but over a prolonged period of treatment. Under similar conditions no therapeutic effect of oral Na3PFA was observed.