摘要
背景:心力衰竭的临床治疗仍然受到有限的疗效和不利的副作用。最近开发的一类药物肌球蛋白运动激活剂直接作用于心肌肌球蛋白,导致产生的力量增加和收缩的延长。先导分子omecamtiv mecarbil现在处于人类3阶段。除了迄今发表的有希望的临床数据外,还有新的体外结果表明奥美卡替米卡必尔对收缩性的作用是依赖于速率的。此外,omecamtiv mecarbil被证明可以激活心脏兰尼碱受体,这种作用可能带有致心律失常的风险。 方法:根据目前有关omecamtiv mecarbil的文献,这些新的研究结果以及药物对心脏耗氧的争议性影响在本文中进行了批判性讨论。 结果:根据良好的临床数据,在治疗相关浓度下,药物的有利变力作用不可能受到这些新结果的影响。然而,在超治疗浓度下,心脏兰尼碱受体的激活可能增加心律失常倾向,并且在更高的起搏频率观察到的收缩期细胞缩短对舒张期的更强的作用可能降低或抵消omecamtiv mecarbil的肌力作用。 结论:进一步研究肯定超治疗浓度的奥美康莫卡必尔应该被设计来描绘这些潜在有害副作用的实际风险
关键词: 心力衰竭,正性肌力药,肌球蛋白激活剂,奥美康唑mecarbil,Ryanodine受体,胞浆Ca2 +。
Current Medicinal Chemistry
Title:Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results
Volume: 25 Issue: 15
关键词: 心力衰竭,正性肌力药,肌球蛋白激活剂,奥美康唑mecarbil,Ryanodine受体,胞浆Ca2 +。
摘要: Background: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition to the promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbil was shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk.
Methods: These new results, together with the controversial effects of the drug on cardiac oxygen consumption, are critically discussed in this review in light of the current literature on omecamtiv mecarbil.
Results: In therapeutically relevant concentrations the beneficial inotropic effect of the agent is not likely affected by these new results - in accordance with the good clinical data. At supratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increase arrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, observed at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtiv mecarbil.
Conclusion: Further studies with definitely supratherapeutical concentrations of omecamtiv mecarbil should be designed to map the actual risk of these potentially harmful side-effects.
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Cite this article as:
Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results, Current Medicinal Chemistry 2018; 25 (15) . https://dx.doi.org/10.2174/0929867325666171222164320
DOI https://dx.doi.org/10.2174/0929867325666171222164320 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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