Antithrombotic activity of F 16618, a new PAR1 antagonist evaluated in extracorporeal arterio-venous shunt in the rat

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.

Graphical abstractA 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.Figure optionsDownload full-size imageDownload as PowerPoint slide