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 toxicitystudies, dosing was by gavage to monkeys (distilled water vehicle)and rats (0.5% methylcellulose vehicle) for 90 days. Groupsof 5 male and 5 female monkeys (Macaca fascicularis) were given170U88 at 0, 25, 50, or 100 mg/kg/day. The daily dose was givenin two equal portions with 6 hr between doses. Monkeys in thehigh-dose group lost weight. Food consumption was decreasedfor mid- and high-dose monkeys and for low-dose female monkeys.Slightly decreased values for erythrocyte and leukocyte countsat the mid- and high dose were fully reversed during an 8-weekrecovery period. Two high-dose male monkeys and a middose femalemonkey developed signs of central nervous system toxicity andwere necropsied before dosing was complete. These signs werefirst observed in the fifth week of dosing and included bodytremors, incoordination, reduced activity, sleepiness, stupor,and lack of eye tracking. Axonal lesions were observed in histologicsections of sciatic nerve in monkeys at all dose levels. Neitherthe signs of central nervous system toxicity nor the axonallesions reversed during the 8- week recovery period. Groupsof 14 male and 14 female CD rats (Sprague-Dawley derived) weregiven single daily doses of 170U88 at 0, 150, 300, or 600 mg/kg.Body weights were decreased at all dose levels and food consumptionwas decreased for mid- and high-dose rats. Small increases invalues for erythrocyte count, hemoglobin, and packed cell volumeand small decreases in values for glucose, serum protein, andserum albumin were limited to high-dose rats and reversed duringa 4- week recovery period. High-dose rats also had reversibleliver lesions consisting of necrosis of individual hepatocytes,megalocytosis, occasional mitotic figures, and biliary stasis.Clinical and morphologic indications of central nervous systemtoxicity in the rats consisted of altered exploratory behaviorat the high dose and groups of small vacuoles in cerebellarwhite matter at all dose levels. Cerebellar vacuolation wasobserved in rats examined at the end of the exposure periodand also in rats examined after the 4-week postdose recoveryperiod. Signs interpreted as peripheral nervous system toxicitywere limited to rats in the high-dose group and consisted ofhindquarter weakness, slow righting and placing reflexes, andataxia. Again, these findings did not reverse during the recoveryperiod. Thus, signs of both central and peripheral nervous systemtoxicity were observed in both monkeys and rats. These neurotoxiceffects resulted in the decision to stop further developmentof 170U88.