The toxicology of brotizolam.
Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose.
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001381:Azepines / Q000008:administration & dosage / Q000633:toxicity*; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D005260:Female; D005333:Fetus / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000633:toxicity*; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009128:Muscle Spasticity / Q000139:chemically induced; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000139:chemically induced; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D012472:Salivation / Q000187:drug effects; D013375:Substance Withdrawal Syndrome; D013997:Time Factors
D001381:Azepines; D006993:Hypnotics and Sedatives; C020960:brotizolam