Preclinical Toxicologic Evaluation of Misonidazole (NSC-261,037) and Desmethylmisonidazole (NSC-261,036) Given Orally or Intravenously to Rats

摘要

NSC-261,036 and NSC-261,037 were given orally (p.o.) or intravenously (i.v.) to Sprague Dawley rats either as a single dose (p.o. and i.v.) or on a daily basis for up to 20 days (p.o.). The toxic effects, hematologic and blood chemistry changes, histopathologic tissue lesions and LD10, LD50 and LD90 values are included when possible. The toxic effects of these compounds were qualitatively similar, but NSC-261,037 was approximately twice as toxic as NSC-261,036. Further, the i.v. route of administration was approximately twice as toxic as the p.o. route of administration for NSC-261,036. Few clinical signs of toxicity other than an immediate abdominal contraction, tachypnea and lethargy were observed in rats given either compound as a single dose by either route of administration. The majority of deaths occurred during the night following treatment. The most prominent tissue lesions were testicular atrophy and aspermatogenesis, which was evidently reversible. Isolated brain lesions and thymic involution were also detected. The incidence of both the toxic signs and tissue lesions were increased when given orally on a daily basis. At a total dose administered of approximately 46,000 mg/sq m (7,667 mg/kg) and 27,000 mg/sq m (4,500 mg/kg) for NSC-261,036 and NSC-261,037, respectively, regardless of the daily dose level, neurologic symptoms were observed. These symptoms included imbalance, incoordination, tremors and/or convulsions. Upon cessation of drug administration, surviving animals recovered from these symptoms and were apparently normal by day 58. One blood chemistry change worthy of note was an increased blood glucose level in several moribund animals. No pancreatic lesions were detected in any of these rats. Tissue lesions observed in rats given either compound were similar and included the brain, lymphoid tissue and testes. Lesions of the brain were characterized by malacia, glial cell infiltration, gliosis, necrosis, hemorrhage and cavitation. Lymphoid depletion in the spleen and thymic involution were the lymphoid tissue lesions. The most prominent and severe lesions were testicular atrophy and aspermatogenesis. These lesions were detected at all dose levels tested for either compound. All three tissue lesions were reversible upon cessation of drug administration.