Bentur Ohad S, Li Jihong, Jiang Caroline S, Martin Linda H, Kereiakes Dean J, Coller Barry S
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York, United States.
The Rockefeller University Hospital, New York, New York, United States.
TH Open. 2021 Sep 28;5(3):e449-e460. doi: 10.1055/s-0041-1732343. eCollection 2021 Jul.
Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ3 antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ3 antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. Standard light transmission aggregometry (LTA) is difficult to perform during STEMI, so we applied VerifyNow (VN) assays to assess the pharmacodynamics of RUC-4 relative to aspirin and ticagrelor. Blood from healthy volunteers was anticoagulated with phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) or sodium citrate, treated in vitro with RUC-4, aspirin, and/or ticagrelor, and tested with the VN ADP + PGE , iso-TRAP, and base channel (high concentration iso-TRAP + PAR-4 agonist) assays. The results were correlated with both ADP (20 µM)-induced LTA and flow cytometry measurement of receptor occupancy and data from individuals treated in vivo with RUC-4. RUC-4 inhibited all three VN assays, aspirin did not affect the assays, and ticagrelor markedly inhibited the ADP + PGE assay, slightly inhibited the iso-TRAP assay, and did not inhibit the base channel assay. RUC-4's antiplatelet effects were potentiated in citrate compared with PPACK. Cut-off values were determined to correlate the results of the VN iso-TRAP and base channel assays with 80% inhibition of LTA. The VN assays can differentiate the early potent anti-αIIbβ3 effects of RUC-4 from delayed effects of P2Y12 antagonists in the presence of aspirin. These pharmacodynamic assays can help guide the clinical development of RUC-4 and potentially be used to monitor RUC-4's effects in clinical practice.
使用αIIbβ3拮抗剂对ST段抬高型心肌梗死（STEMI）进行院前治疗可改善临床结局，但它们在院前环境中难以应用。RUC-4是一种正在开发用于STEMI院前治疗的新型αIIbβ3拮抗剂，皮下给药后能迅速实现高效的血小板抑制。在STEMI期间难以进行标准的光透射聚集测定（LTA），因此我们应用VerifyNow（VN）检测来评估RUC-4相对于阿司匹林和替格瑞洛的药效学。 来自健康志愿者的血液用苯丙氨酰-脯氨酰-精氨酰氯甲基酮（PPACK）或柠檬酸钠抗凝，在体外分别用RUC-4、阿司匹林和/或替格瑞洛处理，并用VN ADP + PGE 、异-TRAP和基础通道（高浓度异-TRAP + PAR-4激动剂）检测进行测试。结果与ADP（20 µM）诱导的LTA以及受体占有率的流式细胞术测量结果相关，也与体内接受RUC-4治疗的个体的数据相关。 RUC-4抑制了所有三种VN检测，阿司匹林不影响检测，替格瑞洛显著抑制ADP + PGE 检测，轻微抑制异-TRAP检测，不抑制基础通道检测。与PPACK相比，RUC-4在柠檬酸盐中的抗血小板作用增强。确定了截断值，以将VN异-TRAP和基础通道检测的结果与LTA的80%抑制相关联。 VN检测可以在有阿司匹林存在的情况下，将RUC-4早期强效的抗αIIbβ3作用与P2Y12拮抗剂的延迟作用区分开来。这些药效学检测有助于指导RUC-4的临床开发，并有可能用于监测RUC-4在临床实践中的效果。
