Safety assessment of brotizolam.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was submitted to a comprehensive range of safety assessment tests. Acute (single dose) toxicity was very low, while in subacute and chronic studies in rodents, signs of toxicity were first seen at doses of 400 mg/kg or more. Histopathological changes were only seen in the 1 1/2-year study. Ataxia, salivation, and diarrhea were observed in a 4-week intravenous study in dogs, and ataxia, increased feed intake, muscular spasms, increased liver weight, and lipid depletion of the adrenal cortex in two oral studies in monkeys. Reproductive studies in the rat and the rabbit revealed no disturbances in fertility, nor were any embryotoxic or teratogenic effects detected in doses of up to 30 mg/kg. Only at 400 mg/kg was litter mortality increased. Local tolerance tests in rabbits indicated good compatibility of brotizolam when administered intramuscularly, intra-arterially, or intravenously. No signs of any genotoxic action could be detected. A carcinogenicity study in mice showed no evidence of any oncogenic effect, while in rats, although the incidence of certain tumors appeared somewhat higher in the high-dose group, this could be explained by the range of biological variation within the strain, a possible modulating effect on the immune system due to the stress of a very high dose, and a functional effect on the thyroid. These studies thus demonstrate that brotizolam has a remarkably wide therapeutic range.(ABSTRACT TRUNCATED AT 250 WORDS)