Preclinical safety evaluation of the benzodiazepine quazepam.
7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4- benzodiazepine-2-thione (quazepam, Sch 16134, Dormalin) was evaluated for evidence of systemic toxicity, carcinogenicity and reproductive toxicity in several laboratory animal species including the hamster. Mutagenic potential was also assessed in one in vivo and three in vitro assays. In some studies, diazepam was used as a comparative control. Oral LD50 values were greater than 5000 mg/kg in the mouse and rat while i.p. LD50 values were approximately 900 and 2900 mg/kg in the mouse and rat, respectively. Studies in hamsters for 4 weeks at doses up to 500 mg/kg/d and for 51 weeks at doses up to 120 mg/kg/d demonstrated that the liver was the principal target organ in this species with the effects upon the liver related to dose and duration of dosing. Studies in the squirrel monkey for 13 and 52 weeks at doses up to 50 mg/kg/d demonstrated a transient ataxia, hypoactivity and somnolence during the initial two weeks of dosing. No unusual necropsy or microscopic observations were noted in the 13-week study. Male reproductive organs of quazepam-dosed monkeys were reduced in weight after 52 weeks. Moderate to marked impairment of spermatogenesis and higher liver weights with moderate to marked fatty change in both sexes were observed in groups given diazepam. Abrupt withdrawal of quazepam or diazepam after 52 weeks of dosing was associated at all dose levels with excitability, hyperactivity and convulsions. Two quazepam- and all diazepam-dosed monkeys died.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D001569:Benzodiazepines / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D006224:Cricetinae; D004285:Dogs; D004341:Drug Evaluation; D005260:Female; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009153:Mutagens; D011247:Pregnancy; D051381:Rats; D012453:Saimiri; D013045:Species Specificity; D013723:Teratogens
D014151:Anti-Anxiety Agents; D002273:Carcinogens; D009153:Mutagens; D013723:Teratogens; D001569:Benzodiazepines; C025130:quazepam