Abstract 526: Oral And Intravenous Anti-thrombotic Activities Of F 16618, A New Selective Par1 Antagonist With Minor Risk Of Bleeding
F 16618 is a new phenyl-pentadienoyl derivative which competitively antagonizes PAR1 giving a prevention in vitro against human platelet aggregation. The main goal of the present study was to investigate the anti-thrombotic effects of F 16618 in two models of platelet aggregation-induced arterial thrombosis: an arteriovenous shunt in anesthetized rats and a photochemical-induced carotid artery thrombosis in anesthetized guinea-pigs. Firstly, a shunt was placed between the right jugular vein and the left carotid artery using polyethylene catheters. The kinetics of thrombus formation were assessed by a thermic probe fixed in the middle of the shunt. F 16618 was administered by gavage 15 min before anesthesia. F 16618 dose-dependently increased the occlusion time from 10 to 80 mg/kg, p.o. The first effective dose was 20 mg/kg and the maximal response was found at 40 mg/kg (54 ± 14 %, P < 0.001 vs. vehicle). In addition, 29 % of the shunts remained open 20 min after unclamping in presence of F 16618 (40 mg/kg, n = 7). Similarly, a high dose of F 16618 administered i.v. significantly delayed the occlusion time (29 ± 8 %, P < 0.05) without any significant effect on the tail bleeding time (358 ± 26 sec in the presence of F 16618 vs 397 ± 38 sec in the presence of vehicle). Secondly, the intravenous activity of F 16618 (from 40 μg/kg to 630 μg/kg) was investigated in a model based on the photochemical reaction between Rose Bengal and trans-illuminated green light to induce a transluminal thrombus in a guinea-pig carotid artery. F 16618 was administered as bolus over 2 min before Rose Bengal administration, followed by a constant infusion over 15 min immediately after the source of light was turned on. F 16618 at 80 μg/kg only tended to increase the occlusion time (29 ± 36 % vs. vehicle). From the dose of 160 μg/kg, F 16618 significantly prolonged this occlusion time and the maximal effect was obtained with 320 μg/kg (bolus and infusion, 112 ± 36 %, P < 0.001 vs. vehicle). Collectively, the results demonstrate that F 16618, a new PAR1 antagonist, dose-dependently prevents platelet-induced arterial thrombosis with minor risk of bleeding by both single intravenous or oral administration.