Curry Benjamin J, Rikken A O F Sem, Gibson C Michael, Granger Christopher B, van 't Hof Arnoud W J, Ten Berg Jurriën M, Jennings Lisa K
MLM Medical Labs, 140 Collins Street, Memphis, TN, 38117, USA.
St. Antonius Hospital, Nieuwegein, The Netherlands.
J Thromb Thrombolysis. 2023 Nov;56(4):499-510. doi: 10.1007/s11239-023-02867-x. Epub 2023 Aug 10.
Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.
了解血小板抑制剂的药效学作用是开发更有效抗血栓治疗方法的标准。一个例子是急性冠状动脉综合征（ACS）的抗血栓治疗，特别是ST段抬高型心肌梗死（STEMI）患者，尽管使用了阿司匹林和口服P2Y12抑制剂，但仍需要快速起效的强效抗血栓治疗。在本研究中，我们评估了两种处于临床开发阶段的注射用血小板抑制剂（P2Y12拮抗剂塞拉托格雷和糖蛋白IIb-IIIa拮抗剂扎伦非班），它们可能适用于STEMI患者的院前治疗。在代表临床相关血小板抑制水平（IC20-50%、1/2Cmax和Cmax）的抑制剂浓度下评估血小板反应性。采用光透射聚集法（LTA）评估聚集初始速率（初级斜率，PS）和最大聚集（MA）。二磷酸腺苷（ADP）和凝血酶受体激动肽（TRAP）均用作激动剂。当在PPACK或TSC中采集血液时，扎伦非班对血小板聚集的抑制作用相似，而塞拉托格雷在PPACK中的抑制作用更强。在本研究中，使用PPACK抗凝剂时，在所有测试药物浓度下，塞拉托格雷和扎伦非班对ADP反应的PS影响相当。相比之下，以TRAP作为激动剂时，扎伦非班在其Cmax浓度下的效力明显高于塞拉托格雷。在较低剂量下评估MA反应时，塞拉托格雷对ADP反应的MA抑制作用比扎伦非班更强；然而，在代表Cmax的浓度下，两种药物相当。扎伦非班在Cmax剂量下对TRAP反应的MA抑制作用也更强。这些数据表明，扎伦非班在减少血栓形成方面可能比塞拉托格雷提供更大的保护，特别是因为凝血酶是血栓形成事件病理生理学中的早期关键主要激动剂。
