Neurotoxic effects of the anti-varicella zoster virus agent 2'-valeryl-6-methoxypurine arabinoside in monkeys and rats dosed orally for 90 days.
The 2'-valerate ester of 6-methoxypurine arabinoside (170U88), a nucleoside analog with anti-varicella zoster virus (VZV) activity, was given to monkeys and rats. In subchronic preclinical toxicity studies, dosing was by gavage to monkeys (distilled water vehicle) and rats (0.5% methylcellulose vehicle) for 90 days. Groups of 5 male and 5 female monkeys (Macaca fascicularis) were given 170U88 at 0, 25, 50, or 100 mg/kg/day. The daily dose was given in two equal portions with 6 hr between doses. Monkeys in the high-dose group lost weight. Food consumption was decreased for mid- and high-dose monkeys and for low-dose female monkeys. Slightly decreased values for erythrocyte and leukocyte counts at the mid- and high dose were fully reversed during an 8-week recovery period. Two high-dose male monkeys and a middose female monkey developed signs of central nervous system toxicity and were necropsied before dosing was complete. These signs were first observed in the fifth week of dosing and included body tremors, incoordination, reduced activity, sleepiness, stupor, and lack of eye tracking. Axonal lesions were observed in histologic sections of sciatic nerve in monkeys at all dose levels. Neither the signs of central nervous system toxicity nor the axonal lesions reversed during the 8-week recovery period. Groups of 14 male and 14 female CD rats (Sprague-Dawley derived) were given single daily doses of 170U88 at 0, 150, 300, or 600 mg/kg. Body weights were decreased at all dose levels and food consumption was decreased for mid- and high-dose rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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Division of Toxicology and Pathology, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
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D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001087:Arabinonucleosides / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000998:Antiviral Agents; D001087:Arabinonucleosides; C075032:2'-valeryl-6-methoxypurine arabinoside