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A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine nucleoside from enzymatic deamination to the more weakly active metabolite, hypoxanthine arabinoside. Comparing the combination to vidarabine alone, a significant increase (10-fold) of the antiviral activity of the combined drugs was observed against herpes and vaccinia viruses in tissue culture and subcutaneously, against cranial herpesvirus infections in mice. Several other investigators have also recently reported several-fold enhancement of vidarabine activity by newly described deaminase inhibitors. They observed that plaque formation by several large DNA-containing viruses (herpes, vaccinia, varicella zoster) and an RNA-containing oncogenic virus was markedly prevented by the combination compared to vidarabine alone. In animals, enhanced protection (increased survivors) and/or highly significant increase in the life span of dying mice treated with the 2-drug combination, was also observed compared to vidarabine administered singly. These observations in animals clearly indicate that combination studies with vidarabine (Vira-ATM) and co-vidarabine (deaminase inhibitor) deserve serious consideration as future therapy for systemic virus infections in man including herpesvirus encephalitis.

The susceptibility of herpes simplex type 1 and type 2 viruses to 9-fl-Darabinofuranosyladenine (ara-A) was tested in intracerebrally infected mice. Subcutaneously administered ara-A resulted in markedly equivalent and reproducible chemotherapeutic activity against both serotypes of herpes simplex viruses. Administration of ara-A by several different intermittent dosage regimens -showed that change in pattern of response in terms of survivors appears to be influenced more by total amount of drug administered than by schedule or duration of drug treatment. In general, surviving drug-treated, virus-infected animals survived rechallenge with 1,000 LD50 of the respective homologous virus inoculated intracerebrally on the 21st day after the initial virus inoculation. A neutralization test performed in vitro-in vivo confirmed the identity of the two distinct serotypes of herpes simplex virus employed. The data indicate that the genital form of herpes simplex virus (type 2) is as sensitive as the oral-mouth form (type 1) to the significant therapeutic activity of ara-A. Herpes simplex virus (HSV), designatedHerpesvirus hominis by Andrewes (2), is an ubiquitous organism which causes fever blisters and a variety of clinical disorders, including infection of the genital organs in both sexes. Genital strains of HSV are serologically and immunologically different from the mouth and eye strains (4, 9, 16). The genital form is called HSV type 2, and the serotype from the mouth and eyes is type 1. The antigenic and biological differences among HSV strains were recently reviewed by Nahmias and Dowdle (10). Moreover, the two viruses differ from each other in several biological ways (1,(10)(11)(12)15). Recently, interest in the type 2 virus has increased because of reports suggesting its possible etiological role in causing cervical carcinogenesis (6,13,16,17).In a recent summary of a series of papers, 9-,8-D-arabinofuranosyladenine (ara-A) was reported to be markedly effective in vitro and in vivo against several deoxyribonucleic acid (DNA) viruses, including HSV (19). Although in these reports (3,7,(20)(21)(22)

A series of simple carbobenzoxy peptides showed high and consistent antiviral chemotherapeutic activity in cell culture. In general, greatest activity was found against the measles-distemper or herpesvirus groups, or both, but various representatives of the series had quantitatively and qualitatively different antiviral activities. Several of the compounds, showing the highest antimeasles activity, were investigated extensively. In human cell culture plaque assays, these compounds were active against measles virus at levels of from 15 to 500 μg/ml. At single doses of about 250 to 500 mg/kg, orally in three animal species, significant serum levels of drugs were detected in virus cell culture assays. The mode of action appeared to be therapeutic, as an effect was seen in cell systems infected for at least 24 hr before treatment.