Li Ruizhi, Grosser Tilo, Diamond Scott L
a Institute for Medicine and Engineering, University of Pennsylvania , Philadelphia , PA , USA.
b Institute for Translational Medicine and Therapeutics, University of Pennsylvania , Philadelphia , PA , USA.
Platelets. 2017 Jul;28(5):457-462. doi: 10.1080/09537104.2016.1268254. Epub 2017 Jan 19.
Platelets present a number of intracellular and transmembrane targets subject to pharmacological modulation, either for cardiovascular disease reduction or as an unintended drug response. Microfluidic devices allow human blood to clot on a defined surface under controlled hemodynamic and pharmacological conditions. The potencies of a number of antiplatelet and anticancer drugs have been tested with respect to platelet deposition on collagen under flow. Inhibitors of cyclooxygenase-1 (COX-1) reduce platelet deposition, either when added ex vivo to blood or ingested orally by patients prior to testing. Some individuals display a functional "aspirin-insensitivity" in microfluidic assay. When certain nonsteroidal anti-inflammatory drugs (NSAIDs) are taken orally, they block COX-1 acetylation by aspirin with concomitant reduction of aspirin efficacy against platelets in microfluidic assay. Both P2Y and P2Y inhibitors reduce platelet deposition under flow, as do NO donors and iloprost that target the guanylate cyclase and the prostacyclin receptor, respectively. In a microfluidic assay of 37 kinase inhibitors, dasatinib had potent antiplatelet activity, while bosutinib was less potent. Dasatinib and bosutinib have known profiles against numerous kinases, revealing overlapping and nonoverlapping activities relevant to their unique actions against platelets. Also, dasatinib caused a marked and specific inhibition of GPVI signaling induced by convulxin, consistent with a dasatinib-associated bleeding risk. Microfluidic devices facilitate drug library screening, dose-response testing, and drug-drug interaction studies. Kinase inhibitors developed as anticancer agents may present antiplatelet activities that are detectable by microfluidic assay and potentially linked to bleeding risks.
血小板存在许多细胞内和跨膜靶点，这些靶点可进行药理学调节，用于降低心血管疾病或作为意外的药物反应。微流控装置可使人体血液在可控的血流动力学和药理学条件下在特定表面凝结。已经针对多种抗血小板和抗癌药物在流动状态下对胶原蛋白上血小板沉积的效力进行了测试。环氧合酶-1（COX-1）抑制剂可减少血小板沉积，无论是离体添加到血液中还是患者在测试前口服摄入。在微流控试验中，一些个体表现出功能性的“阿司匹林不敏感性”。当口服某些非甾体抗炎药（NSAIDs）时，它们会阻断阿司匹林对COX-1的乙酰化作用，同时降低阿司匹林在微流控试验中对血小板的疗效。P2Y和P2Y抑制剂均可减少流动状态下的血小板沉积，分别靶向鸟苷酸环化酶和前列环素受体的一氧化氮供体和伊洛前列素也有同样效果。在一项对37种激酶抑制剂的微流控试验中，达沙替尼具有强大的抗血小板活性，而博舒替尼的活性较弱。达沙替尼和博舒替尼对多种激酶具有已知的作用谱，揭示了与其对血小板的独特作用相关的重叠和非重叠活性。此外，达沙替尼对convulxin诱导的糖蛋白VI（GPVI）信号传导有显著且特异性的抑制作用，这与达沙替尼相关的出血风险一致。微流控装置有助于药物文库筛选、剂量反应测试和药物相互作用研究。作为抗癌药物开发的激酶抑制剂可能具有可通过微流控试验检测到的抗血小板活性，并可能与出血风险相关。
