Development of new drugs for the treatment of congestive heart failure

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The congestive heart failure (CHF) affects approximately 10 million adults worldwide and is the most common reason for hospital admission in patients over the age of 65. The incidence of mortality is high. Between 10-50% of patients with the CHF die annually. The therapy of the disease has not yet been settled and the concept for the treatment is shifting between two notions. The purpose of the treatment is twofold : 1) unloading to the cardiac pump ; 2) increase in myocardial contractility. Although the drugs that act by the latter mechanism have been shown to improve the quality of life (QOL) of the patients by improving the hemodynamic parameters and the exercise capacity, the long-term treatment with these agents has failed to show a beneficial effect on the survival of the patients but even shortened the life-span of the patients with CHF compared with placebo. Thus the focus of the treatment has currently been shifted more to the former. It has to be noted, however, that all of t … More he existing positive inotropic agents, such as digitalis, catecholamines and PDEIII inhibitors act through an increase in intracellular Ca^<2+> mobilization : combined application of these agents could readily result in Ca^<2+> overload in myocardial cells that leads to various types of arrhythmias, an increase in myocardial oxygen consumption, myocardial cell injury and death. In addition under pathological condition after myocardial ischemia such as stunned myocardium, these cardiotonic agents lose their effectiveness to increase myocardial contractility. Since Ca^<2+> sensitizers overcome these drawbacks of pre-existing agents, they have high potential for the treatment of CHF.In this study it is clearly shown that a Ca^<2+> sensitizer Org 30029 elicits a positive inotropic effect even under acidosis or in the presence of butanedione monoxime (BDM). Furthermore the mechanism of actions of newer Ca^<2+> sensitizers, including levosimendan, SCHOOO13 and MCI-154 has been elucidated ; all of these agents act through a dual mechanism, Ca^<2+> sensitization and PDEIII inhibition, in the basic study in animal models. Clinical studies with the first and third compounds have been launched. The second agent is unique in that even in animal models it has no chronotropic action, which could be an important property of cardiotonic agents. Novel effective therapeutic agents for application in the patients with CHF could be developed from the family of compounds that increase myofibrillar Ca^<2+> sensitivity. Less