Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease.
Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease.
复制标题
DOI：
10.1161/atvbaha.115.306777
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Kuliopulos A
中科院分区：
文献类型：
--
作者：
Gurbel PA;Bliden KP;Turner SE;Tantry US;Gesheff MG;Barr TP;Covic L;Kuliopulos A
肽素是一种膜系结的、穿透细胞的脂肽，其作用目标是其同源受体的细胞质表面。在这里，我们报告了人类首次使用蛋白酶激活受体-1型肽肽，其目的是作为一种抗血小板药物，以防止经皮冠状动脉介入治疗的缺血性并发症。31例冠心病或多重冠心病危险因素患者连续静脉滴注PZ-128 (0.01 ~ 2 mg/kg) 1 ~ 2小时。在基线和给药后0.5、1、2、6、24小时和7至10天评估安全性、抗血小板疗效和药代动力学。PZ-128对蛋白酶激活受体1激动剂SFLLRN （8 μmol/L）刺激血小板聚集的抑制作用呈剂量依赖性，在0.3 mg/kg时抑制20% ~ 40%，在0.5 mg/kg时抑制40% ~ 60%，在1 ~ 2 mg/kg时抑制≥80% ~ 100%。服用阿司匹林0.5和1 mg/kg剂量组的亚组在30分钟至2小时内对SFLLRN的最终聚集有65%至100%的抑制，在6小时内有95%至100%的抑制。0.5 mg/kg PZ-128的抑制作用是可逆的，24小时后SFLLRN聚集恢复50%。PZ-128对AYPGKF、ADP或胶原诱导的聚集无显著影响，表明所观察到的影响是蛋白酶激活受体-1特异性的。血浆半衰期为1.3 ~ 1.8小时，尿液中检测不到PZ-128。对出血、凝血、临床化学或心电图参数没有影响。PZ-128是一种很有前景的抗血小板药物，通过一种新的细胞内机制，提供快速、特异性、剂量依赖性和可逆的血小板蛋白酶活化受体-1抑制。URL: http://www.clinicaltrials.gov。唯一标识符：NCT01806077。
Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report the first human use of a protease-activated receptor-1–based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications of percutaneous coronary interventions. PZ-128 was administered by 1 to 2 hours continuous intravenous infusion (0.01–2 mg/kg) to 31 subjects with coronary artery disease or multiple coronary artery disease risk factors. Safety, antiplatelet efficacy, and pharmacokinetics were assessed at baseline and 0.5, 1, 2, 6, 24 hours, and 7 to 10 days postdosing. The inhibitory effects of PZ-128 on platelet aggregation stimulated by the protease-activated receptor-1 agonist SFLLRN (8 μmol/L) at 30 minutes to 6 hours were dose dependent with 20% to 40% inhibition at 0.3 mg/kg, 40% to 60% at 0.5 mg/kg, and ≥80% to 100% at 1 to 2 mg/kg. The subgroup receiving aspirin in the 0.5 and 1-mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours and 95% to 100% inhibition by 6 hours. The inhibitory effects of 0.5 mg/kg PZ-128 were reversible with 50% recovery of aggregation to SFLLRN by 24 hours. There were no significant effects of PZ-128 on aggregation induced by AYPGKF, ADP, or collagen, indicating that the observed effects were specific to protease-activated receptor-1. The plasma half-life was 1.3 to 1.8 hours, and PZ-128 was nondetectable in urine. There were no effects on bleeding, coagulation, clinical chemistry, or ECG parameters. PZ-128 is a promising antiplatelet agent that provides rapid, specific, dose dependent, and reversible inhibition of platelet protease-activated receptor-1 through a novel intracellular mechanism. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.