We have developed a
gastrointestinal hemorrhage model in mice and thereby assessed 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 aggregation in mice and produced an ED50 value of 0.02 mg/kg. ED50 values of cyclo(RGDT)2,
aspirin and
ticlopidine were 0.48, 0.74 and 13.3 mg/kg, respectively. 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 to 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, primarily based on the criteria used in the TIMI trial. All compounds tested induced
gastrointestinal hemorrhage in a dose-dependent manner. Minimum hemorrhagic doses, MHDs, of
SM-20302, cyclo (RGDT)2,
aspirin and
ticlopidine 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
hemorrhage model may be useful for the evaluation of the
bleeding complications of
antiplatelet agents and that
SM-20302 may have a wider therapeutic window than nonspecific
integrin inhibitor and conventional
antiplatelet agents.