Antiherpesvirus Activity in Human Sera and Urines after Administration of Adenine Arabinoside

Abstract

A B S T R A C T The minimum inhibitory concentration (MIC) of adenine arabinoside (ara-A) in rabbit kidney microtiter tissue cultures (RK-13) to a prototype strain of herpes simplex virus, type 1 (E115) based upon inhibition of cytopathic effects is 1.5 ,ug/ml. In this system, the MIC of arabinosylhypoxanthine (araHx), the major in vivo metabolic derivative of ara-A, is 75 4g/ml. 1142In vitro checkerboard studies in RK-13 cells confirmed that ara-A and ara-Hx in combination had antiviral effects which are synergistic. The total of the fractional MIC of ara-A plus ara-Hx in combination also varies inversely with residual HSV-1 in microtiter wells. Because virus adsorption is complete at 2 h before specimens to be tested are added in this assay, and because human interferon is not measured in rabbit cells, the antiviral assay is not affected by the presence of type-specific antiherpesvirus antibody or human interferon.Antiviral activity (AVA) was assayed as ara-A equivalents in sera and urines from 10 patients with serious herpesvirus infections who received 2.5-20 mg/kg daily of ara-A by intramuscular or intravenous routes. When a dosage schedule of 10 mg/kg per day or more was used, sustained concentrations of AVA that ranged from 0.8 to 14.4 ,ug/ml were found. When an inhibitor of adenosine deaminase (covidarabine) was not added to the specimens, mean serum concentrations were =3.0 jig/ml (10 mg/kg per day, i.v.), and 4.1 ,ug/ml (20 mg/kg per day). However, in a single patient given 20 mg/kg of ara-A daily with covidarabine immediately added to the sera, the mean concentration of AVA was 12.9 ,ug/ml. Urines contained even higher AVA. Assays of 19 sera were performed both by microbiologic assay for AVA and by high pressure liquid chromatography for ara-A and ara-Hx. AVA was greater by microbiologic assay, and was greater than that which could be accounted for by stoichiometric chromatographic measures of ara-A and ara-Hx. These results with sera of treated patients are consistent both with the in vitro synergy ofara-A and ara-Hx found by checkerboard titrations, and with the beneficial responses to ara-A of patients with herpesvirus infections reported here and elsewhere.J. Clin. Invest.

Effect of antiviral agents on replication of herpes simplex virus type 1 in brain cultures

“…The differences in virus susceptibilities may not reflect differences in just individual cell lines but also in host-cell metabolism (24). Analysis of Ara-A breakdown in cell culture media revealed rapid deamination of Ara-A to hypoxanthine arabinoside, which is less active than Ara-A (3,5,13,24). In HSV-1-treated brain cell aggregates, there was a dramatic decrease in titer at 24 h after infection with a gradual dose-dependent increase after that time.…”

Plasma levels and urinary excretion of vidarabine after repeated dosing

“…The results of metabolism in children and infants have not been reported. Bryson et al l and Champney et al 2 have described microbiologic assays for vidarabine and its hypoxanthine metabolite, which may help in new studies.…”

Antiviral Agents

“…The primary metabolite is hypoxanthine arabinoside (Ara-Hx), which has 30 to 50 times less activity than Ara-A.28 Ara-Hx, however, seems to enhance the activity of Ara-A. 13 Ara-A also inhibits S-adenosylhomocysteine hydrolase in vitro and in red blood cells from patients treated with Ara-A. S-adenosylhomocysteine hydrolase is an enzyme involved in transmethylation.…”