S. Horisawa et al., SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist, exhibits a wide therapeutic window in a newly developed hemorrhage model in mice, THROMB HAEM, 82(6), 1999, pp. 1743-1748
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
.