The Antiplatelet and Antithrombotic Effects of PF‐253, a Potent and Selective PDE5 Inhibitor, in the Rabbit Folts Model of Arterial Thrombosis

The objective of this study was to test the antiplatelet and antithrombotic efficacy of PF‐253, a potent and selective PDE5 inhibitor, in a Folts model of thrombosis adapted to the rabbit. The major efficacy endpoints were cyclic flow reductions (CFRs), induced by mechanical crushing and stenosis of the vessel. CFRs and blood flow were monitored for a 30 minute period before each rabbit received intravenous vehicle (n=7), aspirin at 5 mg/kg (n=6), PF‐253 at 0.5 mg/kg (n=6), or the combination of aspirin and PF‐253 at the same doses (n=5). CFRs in each control period averaged 6.1 ± 0.6, 8.3 ± 1.0, 7.8 ± 0.7, and 7.0 ± 0.9 compared to 5.9 ± 0.7, 2.3 ±0.9, 3.2 ±0.4 and 2.6 ± 0.7 in the vehicle, aspirin, PF‐253 and aspirin plus PF‐253‐treated groups, respectively. Each of the 3 treatments significantly reduced the number of CFRs compared to its own baseline (p < 0.05). Consistent with the inhibition of CFRs, mean carotid blood flow was also higher in the treatment groups. Carotid blood flow averaged 5.6 ± 0.4, 5.5 ± 0.3, 5.2 ± 0.2, and 5.8 ± 0.2 mL/min in the control period compared to 5.4 ± 0.5, 8.4 ± 0.6, 6.4 ± 0.3, and 7.2 ± 0.7 mL/min in the vehicle, aspirin (p < 0.05), PF‐253 (p < 0.05) and aspirin and PF‐253‐treated groups (p NS). Cuticle bleeding times were unchanged in the vehicle group and significantly increased 2.1 (±0.5)‐, 2.5 (±0.4)‐, and 2.6 (±0.7)‐fold in the 3 treatment groups. Taken together, these results confirm antiplatelet and antithrombotic activity of PF‐253, and support the therapeutic potential of PDE5 inhibitors for thrombotic disease.