pd-0348292 and Disease-Models--Animal

The clinical use of venous stents is increasing dramatically. Although antiplatelet agents are required for arterial stent patency, optimal thrombo-prophylaxis after venous stenting remains undefined. To address this issue, PD0348292, a direct Factor Xa inhibitor, was compared with antiplatelet therapy in a porcine venous stent model.. Four hours before stent deployment, pigs (n=5 to 6 per group) received oral PD0348292 at 0.4, 0.9, 4.3 mg/kg, or 0.4 mg/kg plus aspirin (325 mg). Aspirin, clopidogrel (75 mg), aspirin plus clopidogrel, or vehicle (n=10) were administered daily for 2 days before the procedure. Two hours after stent placement, thrombi were quantified by autologous (111)In-platelet content and weights. Thrombus weight and platelet deposition were significantly reduced by PD0348292 at 0.4 (49+/-79 mg and 110+/-145x10(6)/cm2), 0.9 (5+/-6 mg and 107+/-128x10(6)/cm2), 4.3 mg/kg (0+/-0 mg and 87+/-125x10(6)/cm2), and PD348292 plus aspirin (20+/-40 mg and 157+/-70x10(6)/cm2) compared with vehicle (402+/-226 mg; 584+/-454x10(6)/cm2). Despite prolonging bleeding times and inhibiting platelet aggregation, neither aspirin (567+/-683 mg and 533+/-622x10(6)/cm2), clopidogrel (404+/-349 mg and 178+/-101x10(6)/cm2), nor aspirin plus clopidogrel (247+/-261 mg and 231+/-266x10(6)/cm2) significantly decreased stent thrombosis.. PD0348292 completely inhibited thrombosis after venous stenting. Platelet accretion in these venous thrombi appear to involve pathways distinct from arachidonate metabolism or ADP P2Y12 receptor activation.

Topics: Administration, Oral; Angioplasty; Animals; Antithrombin III; Aspirin; Clopidogrel; Constriction, Pathologic; Disease Models, Animal; Drug Therapy, Combination; Female; Iliac Vein; Preoperative Care; Probability; Pyridones; Pyrrolidines; Random Allocation; Reference Values; Stents; Ticlopidine; Treatment Outcome; Vascular Patency; Venous Thrombosis

Topics: Animals; Anticoagulants; Blood Coagulation; Disease Models, Animal; Factor Xa Inhibitors; Humans; Pyridones; Pyrrolidines; Sus scrofa; Thrombosis

The objective of this study was to determine if orally-administered PD0348292, a direct specific factor Xa inhibitor, inhibits thrombosis following porcine carotid arterial injury comparably to aspirin or clopidogrel alone or in combination. We further sought to determine whether the antithrombotic efficacy in vivo could be predicted using an ex-vivo perfusion chamber. Oral treatments included: PD0348292 (0.4, 0.9, or 4.3 mg/kg); PD0348292 (0.4 mg/kg) plus aspirin (325 mg); aspirin; clopidogrel (75 mg); aspirin plus clopidogrel; or vehicle (n = 6-10/group). Aspirin and clopidogrel were administered 27 and four hours pre-injury and PD0348292 or vehicle was administered four hours pre-injury. Both carotid arteries were crush-injured, and thrombus was measured by detection of (111)In-platelets over 30 minutes. Prior to injury, the antithrombotic efficacy was assessed by ex-vivo perfusion chamber platelet deposition. PD0348292 produced dose-dependent prothrombin time (0.9- to 2.9-fold) and aPTT (1.4- to 2.5-fold) prolongations. Bleeding times were significantly prolonged in each active drug group compared to vehicle, but were not significantly different between drug groups. PD0348292 significantly inhibited arterial platelet deposition (x10(6)/cm(2)) at 4.3(549 +/- 1,066), 0.9 (399 +/- 162) and 0.4 mg/kg (531 +/- 470) compared to vehicle (2,242 +/- 1,443). Aspirin (992 +/- 973), clopidogrel (537 +/- 483), clopidogrel plus aspirin (228 +/- 66) or PD0348292 plus aspirin (558 +/- 317) also significantly inhibited platelet deposition, although these values were not significantly different than with any dose of PD348292. Perfusion chamber platelet deposition correlated significantly with in-vivo anti-thrombotic response. In conclusion, PD0348292 inhibited arterial thrombosis comparable to aspirin plus clopidogrel. Perfusion chamber methodology may be useful in predicting in-vivo antithrombotic efficacy.

Topics: Administration, Oral; Animals; Aspirin; Bleeding Time; Blood Coagulation; Carotid Artery Injuries; Carotid Artery Thrombosis; Clopidogrel; Disease Models, Animal; Factor Xa Inhibitors; Female; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridones; Pyrrolidines; Sus scrofa; Thrombosis; Ticlopidine