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

摘要

Dogs given desmethylmisonidazole (NSC-261,036) in 1.5% mannitol intravenously at doses of 167 mg/kg/day and 112.5 mg/kg/day for 20 days developed peripheral nerve lesions as a consequence of peripheral neurotoxicity of the compound. The histopathologic findings were those of a distal axonopathy. Female dogs proved more susceptible than male dogs. Orally administered for 20 days, the drug caused peripheral nerve lesions only at the dose of 167 mg/kg/day. The toxic effect again was greater in the female than in the male partner. No effect was seen in dogs treated orally for 20 days with 85t mg/kg/day or in dogs receiving single injections of 1,800 mg/kg or 900 mg/kg. Misonidazole (NSC-261,037), which had been found to be twice as toxic as its derivative, caused only a single, minimal lesion in a female dog receiving 85 mg/kg/day for 20 days, a dose held to be equitoxic to the high dose of NSC-261,036 (167 mg/kg/day). Neither compound given orally for 20 days caused lesions in peripheral nerve of rats selected for study. The doses ranged to 750 mg/kg/day for NSC-261,036 and 570 mg/kg/day for NSC-261,037. It is concluded that in rats the clinical signs and symptoms of severe neurotoxicity are of central origin caused by central nervous system involvement. Likewise, the neurologic symptoms of dogs, their inability to stand, rigor, incoordination, rapid eye movements and convulsions are of central origin, separate and independent of the peripheral nerve involvement.