Preclinical Toxicologic Evaluation of 5-Isoxazoleacetic Acid, alpha-Amino-3-Chloro-4,5-Dihydro-(NSC 163501), in Dogs, Monkeys, and CDF1 Mice

摘要

Dose-limiting gastrointestinal toxicosis was qualitatively similar in dogs, monkeys, and mice. In dogs and monkeys, anorexia and/or oligodipsia were cardinal signs. Severity of intoxication was indicated by progression to a diarrheal syndrome. Intoxication of the erythron was indicated in the dog and monkey studies. Quantitatively, mice were the most resistant to toxicity, and monkeys were more resistant than dogs. In dogs, fractionation of a single dose to five daily doses resulted in marked cumulative toxicity. Further fractionation to 10 daily doses produced only additive intoxication. Fractionation of a single dose to weekly doses offered some protection from additive toxicity. Similar results were obtained when 5 daily doses were fractionated to three 5-day courses of treatment separated by 9-day rest periods.