Add time:07/25/2019         Source:sciencedirect.com

Doxapram HCl (3,3-diphenyl-1-ethyl-4-[β-morpholinoethyl]-2-pyrrolidinone hydrochloride monohydrate: Dopram®: AHR-619), a new respiratory stimulant, was studied in several species to characterize its toxicity and assess its safety.The intravenous LD50 in mice, rats, dogs, and cats was approximately 75 mg/kg; the intraperitoneal LD50 was about twice as great; and the subcutaneous and oral LD50's were three to four times the intravenous value. Sex differences were not apparent in mice. Newborn rats appeared more suceptible than older animals, whereas newborn dogs did not.One-month subchronic studies were conducted as follows: rats, by intubation, at 40, 80, or 160 mg/kg/day; rats, intravenously, at 20 mg/kg/day; dogs, by capsule, at 2.5, 5, 10, 20, 50, or 125 mg/kg/day; dogs, intravenously at 2.5, 5, 10, or 20 mg/kg/day. Respiratory stimulation, pressor activity, and tachycardia were observed in dogs at lower does; hyperactivity, hyperthermia, emesis, salivation, lacrimation, defecation, urination, diarrhea, tremors, opisthotonus, and convulsions were observed at high doses. Deaths occurred in dogs at 50 mg/kg/day and above. Hypoxia was observed histologically in the brain at doses of 20 mg/kg/day and above, apparently the result of hyperventilation. Hemograms, blood chemical values, and urinalyses were normal.Reproductive and teratologic studies in rats gave results that were within normal limits. Tissue irritation was produced by subcutaneous injection in rabbits but not by intramuscular injection. Liver triglycerides were elevated in dogs and rats, apparently as a result of sympathetic stimulation by the compound.

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