Physical dependence capacity of brotizolam in rhesus monkeys. 2nd communication: primary dependence and barbital substitution.
The degree of physical dependence induced by oral administration of 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), triazolam, diazepam and nitrazepam in rhesus monkeys was evaluated in primary dependence studies. Substitution tests were performed in barbital-dependent animals. In the primary dependence studies, two dosages of each compound were administered for four weeks to compare the effects on motocoordination and development of body weight as well as the withdrawal symptoms after interruption of these chronic administrations. Taking into account the therapeutically effective doses in man, brotizolam and triazolam were tested at doses of 2 X 2 and 2 X 3 mg/kg/d. For comparison, 2 X 10 and 2 X 15 mg/kg/d of diazepam and nitrazepam were administered. Brotizolam and triazolam had a shorter duration of action than diazepam and nitrazepam. During chronic administration of brotizolam, triazolam and diazepam all animals gained body weight. Motocoordination was impaired by these compounds to a comparable degree. Nitrazepam, in contrast, was less compatible. It induced a decrease in body weight and a more pronounced disturbance of motocoordination. Only triazolam evoked effects indicating development of tolerance. Compared with the reference compounds, brotizolam induced the weakest degree of physical dependence. In the substitution tests about 2 mg/kg brotizolam, 0.6 mg/kg triazolam, 4.5 mg/kg diazepam and doses of less than 1 mg/kg nitrazepam were equipotent, suppressing withdrawal symptoms of barbital. These results demonstrate that relatively high doses of brotizolam were necessary to substitute barbital. The data obtained in rhesus monkeys are compared with the therapeutic doses in humans and discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001381:Azepines; D001462:Barbital / Q000494:pharmacology*; D001463:Barbiturates / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D006993:Hypnotics and Sedatives; D008253:Macaca mulatta; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control; D019966:Substance-Related Disorders / Q000503:physiopathology; D014229:Triazolam / Q000494:pharmacology
D001381:Azepines; D001463:Barbiturates; D006993:Hypnotics and Sedatives; D014229:Triazolam; D001462:Barbital; C020960:brotizolam; D003975:Diazepam