Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
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DOI：
10.1016/s0140-6736(11)61219-1
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发表时间：
2011-08-20
期刊：
影响因子：
168.9
通讯作者：
Wolff, Andrew A.
中科院分区：
文献类型：
--
作者：
Teerlink, John R.;Clarke, Cyril P.;Wolff, Andrew A.
背景
收缩功能下降是全球数百万心力衰竭患者发病机制的核心，但与机制相关的不良反应限制了现有的正性肌力治疗。本研究验证了一个假设，即选择性心肌肌球蛋白激活剂奥美卡替麦考比尔（omecamtiv mecarbil）将增强人类的心脏功能。
方法
在这项剂量递增的交叉研究中，34名健康男性每周接受一次为期6小时的奥美卡替麦考比尔或安慰剂双盲静脉输注，持续4周。每个序列包括三个递增的奥美卡替麦考比尔剂量（范围从每小时0.005到1.0毫克/千克），并将安慰剂输注随机纳入序列。在每次输注前、输注期间和输注后获取生命体征、血液样本、心电图（ECG）和超声心动图。主要目的是确定最大耐受剂量（至少8名参与者所能耐受的最高输注速率）以及奥美卡替麦考比尔的血浆浓度；次要目的是评估药效学和药代动力学特征、安全性和耐受性。本研究在ClinicalTrials.gov注册，编号为NCT01380223。
结果
奥美卡替麦考比尔的最大耐受剂量为每小时0.5毫克/千克。奥美卡替麦考比尔输注导致收缩期射血时间呈剂量相关和浓度相关的增加（在最大耐受剂量下，较基线的平均增加量为85[标准差5]毫秒），这是药物作用最敏感的指标（按剂量计算，r² = 0.99），同时伴有每搏输出量（15[2]毫升）、缩短分数（8%[1]）和射血分数（7%[1]）的增加；所有P值（此处似乎不完整）
Background Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.Methods In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0.005 to 1.0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.Findings The maximum tolerated dose of omecamtiv mecarbil was 0.5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0.99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p