Therapeutic activities of 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine and -thymine alone and in combination with acyclovir and vidarabine in mice infected intracerebrally with herpes simplex virus

Abstract

The therapeutic effectiveness of two new antiviral agents, 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine and 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)thymine, was compared with that of acyclovir and vidarabine. In mice inoculated intracerebrally with high 50% lethal doses of herpes simplex virus type 2, nontoxic intraperitoneal or oral treatments with the two new fluorinated antiviral agents were highly effective in reducing mortality. The two drugs were also effective when treatment was begun as late as 48 h after virus inoculation. The relative order of potencies of the drugs when compared on a molar basis or in terms of therapeutic index was 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)thymine much greater than 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine greater than vidarabine approximately to acyclovir. The new pyrimidine analogs were also found to lack immunosuppressive activity in mice. The combination of 1-(2-fluoro-2-deoxy-beta-=D-arabinofuranosyl)-5-iodocytosine and vidarabine was the most effective; significantly greater reduction in mortality was achieved with this combination than with either drug alone. Thirty minutes after intraperitoneal treatment with the fluorinated analogs, the drugs (or their metabolites) were transported to the brains of virus-inoculated and normal mice at levels about one-third to two thirds those in the blood. The levels of 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)thymine in the blood or brain were consistently higher than those found with equivalent intraperitoneal doses of the 5-iodocytosine analog.