Sakata Chinatsu, Suzuki Ken-Ichi, Morita Yoshiaki, Kawasaki Tomihisa
Project Management, Development, Astellas Pharma Inc., 2-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Eur J Pharmacol. 2017 Mar 5;798:72-76. doi: 10.1016/j.ejphar.2017.01.015. Epub 2017 Jan 14.
Clopidogrel (Plavix, Sanofi-Aventis), the adenosine diphosphate P2Y receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl-induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel.
氯吡格雷（波立维，赛诺菲-安万特公司生产），一种二磷酸腺苷P2Y受体拮抗剂，据报道在预防心血管事件方面有效，并且常与阿司匹林联合使用，尤其是在高危患者中。ASP6537是一种可逆性环氧化酶（COX）-1抑制剂，正在作为一种抗血小板药物进行研究。首先，我们研究了ASP6537抗血小板作用的可逆性及其与布洛芬的相互作用，以比较ASP6537与阿司匹林的可用性。然后，我们使用豚鼠的FeCl诱导血栓形成模型评估了ASP6537与氯吡格雷联合使用时的抗血栓作用。ASP6537具有可逆性抗血小板活性，且未发现与布洛芬有药效学相互作用。当作为单一疗法给药时，ASP6537在≥3mg/kg时具有显著的抗血栓作用，而阿司匹林在100mg/kg时抑制血栓形成。ASP6537与氯吡格雷联合使用时具有显著的相加作用，并且氯吡格雷的联合给药降低了最小抗血栓剂量。我们的研究表明，ASP6537与布洛芬不相互作用，与氯吡格雷联合使用时有明显的相加作用。因此，ASP6537可能是一种有前景的抗血小板药物，可与氯吡格雷联合用于临床。
