Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a photochemically induced thrombosis model in guinea pigs

SM-20302, a synthetic inhibitor of the fibrinogen receptor of platelets, ha s been shown to inhibit the platelet aggregation induced by various stimuli . In the present study, we performed ex vivo platelet aggregation studies b y using heparinized platelet-rich plasma (PRP) as well as citrated PRP and compared the antiaggregatory activity with the in vivo antithrombotic effic acy of SM-20302. The oral administration of SM-20302 (0.3-10 mg/kg) to guin ea pigs completely inhibited the ADP-induced ex vivo platelet aggregation i n citrated PRP. In heparinized PRP, SM-20302 (1-10 mg/kg) showed a dose-dep endent inhibition of ex vivo platelet aggregation, and it exhibited complet e inhibition at a dose of 3 and 10 mg/kg, respectively. The concentration o f ionized calcium in the citrated samples was approximately 35 times lower than that in heparinized samples. Chelation of ionized calcium caused an en hancement of the antiaggregatory activity of SM-20302 in guinea pig heparin ized PRP in vitro. And addition of CaCl2 to citrated PRP reversed the enhan cement. Citrate therefore appeared to enhance the inhibitory activity of SM -20302 by lowering the ionized calcium levels. We also examined the in vivo efficacy of SM-20302 in a photochemically induced femoral artery thrombosi s model in guinea pigs. The photochemical in jury of the endothelium of fem oral artery resulted in a progressive decline in the blood flow. The oral a dministration of SM-20302 (0.1-3 mg/kg) produced a dose-dependent maintenan ce of the femoral artery patency and significantly prolonged the time to oc clusive thrombus formation at a dose of 1 and 3 mg/kg, respectively. These results suggest that SM-20302 may be an orally active antithrombotic agent, and its in vivo antithrombotic efficacy appeared to correlate well with th e ex vivo platelet inhibition in PRP prepared from heparinized blood but no t in PRP anticoagulated with citrate. (C) 1999 Elsevier Science Ltd. All ri ghts reserved.