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 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.
Horisawa
S
S
Sumitomo Pharmaceuticals Co., Ltd. Research Center, Osaka, Japan. horisawa@sumitomopharm.co.jp
Kaneko
M
M
Sakurama
T
T
D000284:Administration, Oral; D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001792:Blood Platelets / Q000502:physiology; D004195:Disease Models, Animal; D006471:Gastrointestinal Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*
D001555:Benzene Derivatives; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C112851:SM 20302