Abstract 8694: Phosphodiesterase 3 Inhibitor Prevents Thrombotic Diseases Without Affecting Hemostatic Function

Abstract

Introduction: Conventional anti-platelet therapy is associated with increased risk of bleeding. Recently, the results of the second Cilostazol Stroke Prevention Study (CSPS 2) showed similar efficacy but fewer hemorrhagic events with the phosphodiesterase (PDE)3 inhibitor cilostazol vs. aspirin. Hypothesis: We hypothesized that PDE3 inhibition reduces thrombus formation without affecting hemostasis, and leads to beneficial effects in experimental cerebral infarction and peripheral artery disease (PAD) models Methods: We used a cilostazol analog, K-134, as a more potent and selective PDE3 inhibitor. To evaluate the anti-thrombus activity of K-134, we measured mortality rate in a pulmonary embolism model established by collagen infusion into mice via the tail vein 10 min after oral administration of K-134. We also studied its influence on tail vein bleeding times. To investigate whether K-134 can ameliorate other thrombotic diseases, we established a rat cerebral infarction model by photochemically induced thrombosis-mediated occlusion of middle cerebral arteries and a PAD model by laurate injection-mediated peripheral arterial injury. Pathological signs in the areas of necrosis in the hind legs in the PAD model were classified as Grade 0 to 5. Results: K-134 decreased mortality in the mouse pulmonary embolism model when orally administered at 3, 10, and 30 mg/kg ( n = 29-30, P < 0.01 vs. control, ED50 = 2.1 mg/kg) but did not prolong bleeding time even at 100 mg/kg compared to control ( n = 30, 98 ± 6 vs. 84 ± 7 s., not significant). In contrast, warfarin prolonged bleeding time ( n = 29-30, 139 ± 7 vs. 84 ± 7 s., P < 0.01). Preoperative administration of K-134 at 30 mg/kg reduced brain infarct size compared to control in the rat cerebral infarction model ( n = 12, 87.5 ± 5.6 vs. 126.8 ± 7.5 mm 3 , P < 0.01). Furthermore, 30 mg/kg K-134 inhibited the progression of lesions compared with controls in the PAD model ( n = 12-15, mean grade of pathological sign: 2.3 ± 0.2 vs. 3.5 ± 0.3, P < 0.05). Conclusion: PDE3 inhibition is an attractive approach for the secondary prevention of cerebral infarction and treatment of peripheral arterial disease.