Combination Chemotherapy of Punta Toro Virus Infections in Mice Using Ribavirin and 7-thia-8-oxoguanosine

Abstract

Ribavirin was combined with the immunoenhancing agent 7-thia-8-oxoguanosine (TOGuo) to treat lethal experimental Punta Toro virus infections in mice. Lethal hepatic disease caused by the Adames strain of the virus was treated orally with ribavirin and intraperitoneally with TOGuo, with both treatments starting 24 h after virus inoculation. By themselves, ribavirin (25 mg/kg) and TOGuo (12.5 and 25 mg/kg) protected 80–100% of mice from mortality, but lower doses of each were ineffective. Combinations of the two agents (ribavirin, 25 mg/kg plus TOGuo at 6.25 and 12.5 mg/kg) produced synergistic decreases in hepatic icterus scores, liver and spleen virus titres, and serum alanine aminotransferase and aspartate aminotransferase activities. Lower dosage combinations were not synergistic. Of particular interest was the observation that TOGuo (25 mg/kg) could reverse the lethal toxicity of a high dose of ribavirin (1250 mg/kg) both in Punta Toro virus-infected and uninfected mice. These data suggest that TOGuo increased the therapeutic index of ribavirin by decreasing toxicity and increasing antiviral activity in this model.