Pollesello P, Papp Z, Papp J Gy
Critical Care Proprietary Products, Orion Pharma, Espoo, Finland.
Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, Hungary.
Int J Cardiol. 2016 Jan 15;203:543-8. doi: 10.1016/j.ijcard.2015.10.240. Epub 2015 Nov 2.
The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.
几十年来，一直有关于使用正性肌力药物来纠正充血性心力衰竭患者血流动力学功能障碍的描述。诸如强心苷、儿茶酚胺、磷酸二酯酶抑制剂和钙敏化剂等药物相继被提出。然而，这一治疗领域中新化学实体的数量出奇地少，目前的药物选择有限。新型正性肌力药物研发中的一个范式转变是将重点从“钙动员剂”转向“钙敏化剂”。这样做旨在开发更安全的正性肌力药物，避免因细胞内钙水平升高而引发的并发症。然而，在过去30年里，只有三种这样的钙敏化剂得到了充分研发。此外，其中两种药物，左西孟旦和匹莫苯丹，除了具有正性肌力作用外，还有多个分子靶点和其他药理作用，如外周血管舒张。最近，奥米卡替麦卡比尔被报道，据信它具有纯粹的正性肌力作用，没有多效性效应。当比较这三种钙敏化剂的临床数据时，似乎由于在治疗诸如急性充血性心力衰竭等复杂综合征过程中的附加效应，不纯的正性肌力药物比更纯的正性肌力药物更具优势。本综述旨在回答钙敏化本身是否是为心力衰竭患者带来所需临床益处的充分策略这一问题。本综述谨献给海莫·海卡拉，这个具有挑战性领域中一位真诚且热情的创新者。
