A new PAR1 antagonist, F 16618 exerted a potent antithrombotic activity by intravenous and oral routes, without affecting bleeding time, this activity was potentiated when combined with aspirin or clopidogrel.
The purpose of the present work was the evaluation of the antithrombotic activity of a new PAR1 antagonist, F 16618 in arterio-venous shunt in the rat. Arterial thrombosis was induced by insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. F 16618 was administered either by intravenous route (0.63-2.5 mg/kg) or by oral route (20-80 mg/kg). Oral activity of F 16618 was compared to that of aspirin (20-80 mg/kg) and clopidogrel (0.63-10 mg/kg). Finally, F 16618 was associated to aspirin and/or clopidogrel to test for possible antithrombotic activity and its effects on bleeding time. SFLLR-induced human platelet aggregation was evaluated in the presence of F 16618, demonstrating the anti-aggregant activity of this compound. F 16618 (1.25 mg/kg) significantly delayed the time leading to occlusion by 52 ± 17%, without affecting bleeding time and in absence of hemodynamic effects. F 16618 given orally dose-dependently increased the time to occlusion. The maximal effect was observed at 40 mg/kg (984 ± 95 s versus 644 ± 17 s in vehicle group). Aspirin and clopidogrel also dose-dependently lengthened time to occlusion, but this effect was associated with an increase of bleeding time. F 16618 (20 mg/kg) orally associated with either aspirin (40 mg/kg) or with clopidogrel (1.25 mg/kg) potentiated the antithrombotic effects of both compounds without further increasing of bleeding time. In conclusion, F 16618 exerted a potent antithrombotic activity by intravenous and oral routes, without affecting bleeding time. Furthermore, the antithrombotic activity was potentiated when combined with aspirin or clopidogrel.