Combination
therapy with
A1110U, an inactivator of the herpes simplex virus (HSV) and the varicella zoster virus
ribonucleotide reductase, and
acyclovir (ACV) was evaluated for treatment of cutaneous herpetic disease in athymic mice infected on the dorsum. In this model,
infection with HSV produces a 'zosteriform-like'
rash that is first visible on day 3 or 4 post-
infection (p.i.) and eventually extends from the anterior mid-line to the dorsal mid-line of the affected flank. In untreated mice, the
infection is fatal at about day 7 p.i. presumably due to central nervous system involvement. Topical treatment of
infections induced by either wild-type (wt) HSV-1 or wt HSV-2 with 3%
A1110U in combination with 5% ACV resulted in synergistic (P less than 0.01) reductions in lesion scores.
Therapy was also synergistic in mice infected with an ACV-resistant
thymidine kinase-deficient mutant and an ACV-resistant TK-altered mutant HSV-1 isolated. Combination
therapy was very effective in reducing lesion scores of mice infected with an ACV-resistant HSV-1
DNA polymerase mutant, but did not result in statistically significant synergy (P = 0.07) because of the enhanced efficacy of
A1110U alone against this virus. These results provide encouragement that the combination of
A1110U and ACV may offer an effective
therapy for topical treatment of cutaneous HSV
infections in humans.