A Na+ channel agonist: a potential cardiotonic agent with a novel mechanism?
A Na+ channel agonist: a potential cardiotonic agent with a novel mechanism?
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DOI：
10.1038/sj.bjp.0705970
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发表时间：
2004-11
影响因子：
7.3
通讯作者：
M. Endoh
中科院分区：
文献类型：
--
作者：
M. Endoh
强心药对于改善急性充血性心力衰竭(CHF)和慢性充血性心力衰竭(CHF)加重期的收缩功能障碍是必不可少的。近220年来，洋地黄一直被用于治疗慢性充血性心力衰竭，尽管其安全性、致心律失常和药代动力学方面存在缺陷。虽然静脉输注儿茶酚胺可改善急性充血性心力衰竭患者的收缩功能障碍，但由于持续给药，儿茶酚胺也是致心律失常的，存在能量缺陷和药物耐受性。自20世纪80年代初以来，人们已经做出了广泛的努力来开发新的强心剂来取代洋地黄和儿茶酚胺(Farah等人，1984)。由于这些努力，选择性磷酸二酯酶(PDE)III抑制剂，包括氨力农、米力农、依莫西蒙和奥普利酮，具有肌丝钙敏化作用的新型药物，如左西孟丹和吡莫本丹(除了对PDE III的抑制作用外)，以及一种口服用儿茶酚胺衍生物，地诺帕明，已进入临床应用(Endoh，2002；2003)。这些新型药物已被证明通过改善血流动力学参数和运动能力来改善CHF患者的生活质量(QOL)，但它们并未改善慢性CHF患者的预后。大规模临床试验表明，其中一些药物甚至缩短了患者的寿命，这从接受这些药物治疗的患者与接受安慰剂治疗的患者相比心源性猝死的发生率增加中可以看出(例如，Packer等人，1991年)。基于这些大规模临床试验的结果，慢性充血性心力衰竭的药物治疗已经发生了巨大的范式转变：从正性肌力疗法转向心脏保护疗法，而没有仔细审查导致意外结果的机制，包括强心剂的作用机制、所用药物的剂量、给药方法(连续或间歇)以及与洋地黄联合给药的影响。
Cardiotonic agents are essential for improvement of contractile dysfunction in acute congestive heart failure (CHF) and in aggravating phase of chronic CHF. For almost 220 years, digitalis has been used for the treatment of chronic CHF in spite of its narrow safety margin, arrhythmogenicity and pharmacokinetic drawbacks. While catecholamines have been infused intravenously to improve contractile dysfunction in acute CHF, they are also arrhythmogenic and suffer from energetic disadvantages and drug tolerance by continuous administration. Since the early 1980s, extensive efforts have been made to develop novel cardiotonic agents to replace digitalis and catecholamines (Farah et al., 1984). As a result of these efforts, selective phosphodiesterase (PDE) III inhibitors, including amrinone, milrinone, enoximon and olprinone, novel agents such as levosimendan and pimobendan that have myofilament Ca2+ sensitizing action (in addition to PDE III inhibition), and an orally useful catecholamine derivative, denopamine, have become clinically available (Endoh, 2002; 2003). These novel agents have been shown to elicit beneficial effects to improve the quality of life (QOL) of CHF patients by ameliorating hemodynamic parameters and exercise capacity, but they have failed to improve the prognosis of chronic CHF patients. Large-scale clinical trials have revealed that some of them even abbreviated the lifespan of patients as seen in the increasing incidence of cardiac sudden death in those being treated with these agents compared with those who received a placebo (eg, Packer et al., 1991). A large paradigm shift of pharmacological treatment of chronic CHF has occurred based on the result of these large-scale clinical trials: from inotropic to cardioprotective therapies without scrutinizing the mechanisms underlying the unexpected outcome, including the mechanisms of action of cardiotonic agents, the doses of agents employed, the methods of administration (continuous or intermittent) and the influence of coadministration with digitalis.