Levosimendan: Beyond its simple inotropic effect in heart failure

Modulation of Programmed Forms of Cell Death by Intracoronary Levosimendan During Regional Myocardial Ischemia in Anesthetized Pigs

“…Moreover, it has been proposed that agents which open mitochondrial K ATP channels can protect the myocardium against ischemia and myocardial infarction [11]. One such agent is levosimendan, a novel pharmacological agent widely used in acute heart failure syndromes; it is an effective vascular smooth muscle vasodilator resulting in decreasing vascular resistance, and both preload and afterload of heart [12]. Systemic levosimendan administration has been reported to induce beneficial hemodynamic effects in the presence of stunned or global ischemic myocardium [13].…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…50). While the half-life of levosimendan is short (;1 hour), the active metabolite has a half-life of a few days, and the beneficial effect is observed for considerably longer than what the parent half-life would indicate, suggesting an important role for OR-1896 in the extended duration of activity (Antoniades et al, 2007). In contrast to this, no apparent difference in efficacy has been observed between poor and extensive acetylators despite a difference in exposure to OR-1986 between the two groups (Antila et al, 2004;Kivikko et al, 2011).…”

Evoked Changes in Cardiovascular Function in Rats by Infusion of Levosimendan, OR-1896 [(R)-N-(4-(4-Methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide], OR-1855 [(R)-6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], Dobutamine, and Milrinone: Comparative Effects on Peripheral Resistance, Cardiac Output, dP/dt, Pulse Rate, and Blood Pressure

“…However, their clinical value is limited by the narrow therapeutic index of these agents, associated toxicity including arrhythmias, and only modest efficacy in chronic therapy (Lehmann et al, 2003). In contrast, levosimendan and other calciumsensitizing agents are able to enhance the contractile status of the heart (mechanism recently reviewed in Antoniades et al, 2007) without concomitant elevations in calcium, and thus, they represent a potentially valuable alternative to increasing left ventricular function in the treatment of cardiac dysfunction and heart failure without the cardiovascular risks associated with increased intracellular-free calcium (Lehmann et al, 2003). However, it should be noted that some studies have suggested that levosimendan might actually increase Ca 2ϩ transients (Takahashi and Endoh, 2002), and it has also been suggested that phosphodiesterase 3 (PDE3) inhibitory activity might also contribute to the positive inotropic effects of the compound (Sato et al, 1998), suggesting a complex mechanism of action that might result in clinical benefit versus classic inotropic agents (Endoh and Hori, 2006).…”