SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist, exhibits a wide therapeutic window in a newly developed hemorrhage model in mice

We have developed a gastrointestinal hemorrhage model in mice and thereby a ssessed the potential risk of bleeding following administration of SM-20302 , a nonpeptide GPIIb/IIIa receptor antagonist. First, SM-20302 selectively inhibited the interaction between human platelets and fibrinogen in vitro. Second, SM-20302 dose-dependently inhibited ADP-induced ex vivo platelet ag gregation in mice and produced an ED50 value of 0.02 mg/kg. EDS, values of cyclo(RGDT)(2), aspirin and ticlopidine were 0.48, 0.74 and 13.3 mg/kg, res pectively. Finally, the bleeding risk of SM-20302 was examined in our newly developed hemorrhage model. Gastrointestinal hemorrhage was assessed 24 h later when the antiplatelet agents tested were administered to mice prior t o the oral dosing of 0.1 N hydrochloric acid in 90% ethanol. The resulting hemorrhage was classified into three grades, major, minor or no bleeding, p rimarily based on the criteria used in the TIMI trial. All compounds tested induced gastrointestinal hemorrhage in a dose-dependent manner. Minimum he morrhagic doses, MHDs, of SM-20302, cycle (RGDT)(2), aspirin and ticlopidin e were 3, 3, 1 and 100 mg/kg, respectively. The potential risk of bleeding was assessed by the ratio of MHD to ED50 value. MHD/ED50 values of SM-20302 , cyclo(RGDT)(2), aspirin and ticlopidine were calculated to be 150, 6.3, 1 .4 and 7.5, respectively. These results suggest that this experimental hemo rrhage model may be useful for the evaluation of the bleeding complications of antiplatelet agents and that SM-20302 may have a wider therapeutic wind ow than nonspecific integrin inhibitor and conventional antiplatelet agents .