Triazolodiazepines are potent antagonists of platelet activating factor (PAF) in vitro and in vivo.

The triazolodiazepines brotizolam, triazolam and alprazolam inhibited PAF-induced human platelet aggregation in vitro (IC50 = 0.54, 7.6 and 13.7 microM, respectively) but showed only a weak or no effect against other aggregating agents (ADP, adrenaline, collagen, serotonin, arachidonic acid). In comparison, flunitrazepam and diazepam, two diazepines without the triazole ring, showed IC50-values of 42 and 260 microM, respectively. Flunitrazepam does not possess the specificity shown by the other compounds. Brotizolam and triazolam also inhibited PAF-induced human neutrophil aggregation in vitro, with IC50-values 0.21 and 6.6 microM, respectively. In anesthetized guinea pigs, brotizolam (2.5 to 10 mg/kg p.o. or 0.1 to 0.5 mg/kg i.v.) or triazolam (20 to 100 mg/kg p.o.) inhibited dose-dependently the intrathoracic accumulation and aggregation of 111Indium labelled platelets induced by an i.v. infusion of PAF (30 ng/kg X min). Brotizolam at doses of 1 to 10 mg/kg p.o. and 0.1 to 0.5 mg/kg i.v. inhibited dose-dependently the reduction in tidal volume (bronchoconstriction), the systemic hypotension and the lethal effect due to i.v. PAF in guinea pigs. Triazolam inhibited these effects of PAF at doses of 50 to 200 mg/kg p.o. PAF-induced systemic hypotension in rats can be reversed by cumulative i.v. doses (0.05 to 1.0 mg/kg) of brotizolam. In conclusion, these results show that triazolodiazepines, like brotizolam and triazolam, are potent inhibitors of PAF-induced effects in vitro and in vivo.