Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.
The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000700:Analgesics / Q000633:toxicity*; D000818:Animals; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009019:Morphinans / Q000633:toxicity*; D009292:Narcotic Antagonists / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000700:Analgesics; D009019:Morphinans; D009292:Narcotic Antagonists; C030122:N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol