Disease relevance of LEVOSIMENDAN

• Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure [1].
• OBJECTIVES: We assessed the effects of levosimendan on left ventricular (LV) function in patients with acute myocardial ischemia and after coronary angioplasty [2].
• CONCLUSIONS: Levosimendan improved the function of stunned myocardium without obvious impairment of diastolic function [2].
• AIMS: To evaluate the safety and efficacy of levosimendan in patients with left ventricular failure complicating acute myocardial infarction [3].
• A higher frequency of ischaemia and/or hypotension was only seen in the highest levosimendan dose group [3].
• Levosimendan infusion in cardiogenic shock following acute myocardial infarction improved cardiovascular hemodynamics without leading to hypotension [4].

Psychiatry related information on LEVOSIMENDAN

• When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time point (time-response curve) or concentration (dose-response curve) [5].

High impact information on LEVOSIMENDAN

• CONCLUSIONS: Levosimendan has inotropic and lusitropic actions in failing human myocardium [6].
• METHODS AND RESULTS: We investigated the influence of levosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with end-stage failing dilated or ischemic cardiomyopathy (n=27) [6].
• In aequorin-loaded muscles, levosimendan 10(-6) mol/L increased average tension by 50% (P<0.02), associated with a nonsignificant increase in aequorin light (16%) [6].
• Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart [7].
• Administration of 0.1 or 0.3 mumol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein [7].

Chemical compound and disease context of LEVOSIMENDAN

• Acidosis inhibits the PIE of levosimendan due to suppression of the increase in Ca(2+) transients in response to the compound [8].
• Cardiogenic shock after primary percutaneous coronary intervention: Effects of levosimendan compared with dobutamine on haemodynamics [9].
• OBJECTIVE: The aim was to study the pharmacodynamic interactions and safety of the co-administration of the calcium sensitizer levosimendan and the calcium antagonist felodipine in patients with coronary heart disease (CHD) and with normal ejection fraction (EF) [10].
• Beneficial outcome after prostaglandin-induced post-partum cardiac arrest using levosimendan and extracorporeal membrane oxygenation [11].
• DATA SOURCES: Articles were identified through searches of MEDLINE (1966-June 2005), International Pharmaceutical Abstracts (1970-June 2005), and EMBASE (1992-June 2005) using the key words levosimendan, simendan, calcium sensitizer, calcium sensitiser, and congestive heart failure [12].

Biological context of LEVOSIMENDAN

• In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca2+, yielding half-maximal uptake rates by the SR vesicles [7].
• Moreover, it was shown that levosimendan was in fast exchange on the NMR time scale with a secondary binding site in the C-domain of both cTnC(C35S) and cTnC(A-Cys) [13].
• Cardiac output increased by 0.7 and 1.61.min-1 (P < 0.05 for both) after 8 and 24 micrograms.kg-1 of levosimendan, respectively [14].
• During administration of levosimendan, cardiac output increased by 32% (P = .002) mainly because of higher stroke volume [15].
• AIMS: Levosimendan, a novel calcium-dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels [15].

Anatomical context of LEVOSIMENDAN

• They received placebo (n = 8), 8 (n = 8) or 24 (n = 7) micrograms.kg-1 of levosimendan after coronary artery bypass operation [14].
• The new myofilament Ca2+ sensitizer levosimendan (LSM) is a positive inotropic and vasodilatory agent [16].
• Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit [17].
• Our results indicate a lowering of [Ca++]i by levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smooth muscle contractile or regulatory proteins themselves [18].
• We hypothesized that levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS [19].

Associations of LEVOSIMENDAN with other chemical compounds

• However, levosimendan produced significantly greater left ventricular ejection fraction and fractional area changes compared with dobutamine and saline placebo [20].
• Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs [21].
• Pimobendan increased hepatic blood flow to a greater degree than levosimendan but did not alter small intestinal perfusion [21].
• In summary, in intact canine ventricular myocardium, levosimendan elicits a dual inotropic effect: at lower concentrations, it induces a PIE by a combination of increases in Ca(2+) transients and Ca(2+) sensitivity, while at higher concentrations it elicits an NIE due to a decrease in Ca(2+) sensitivity [8].
• We investigated the effects of levosimendan on [Ca++]i, and force in porcine coronary arteries, with receptor-mediated (U46619) or KCl stimulation [18].
• In animals receiving milrinone cardiac output was preserved, and in animals receiving levosimendan cardiac output increased by 14% [22].

Gene context of LEVOSIMENDAN

• Levosimendan produced a significant reduction in BNP compared to baseline, at both 48 h (744.1+/-100 vs 1136.3+/-93.7 pg/ml, p=0.04) and 5 days (446+/-119.3 vs 1136.3+/-93.7 pg/ml, p=0.03), while IL-6 values decreased after 5 days (4.8+/-1.3 vs 8.6+/-1.5 pg/ml, p=0.01) [23].
• The CYP3A4 inhibitor intraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan [24].
• Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-alpha, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand [25].
• This raises the possibility that levosimendan may also interact with smooth muscle EF-hand proteins, such as, calmodulin, the regulatory myosin light chains, or S100 proteins [18].
• This randomized, placebo-controlled trial showed that levosimendan administration causes a significant reduction of circulating proinflammatory cytokine interleukin-6 and soluble apoptosis mediators, such as soluble Fas and Fas ligand in patients with decompensated heart failure [26].

Analytical, diagnostic and therapeutic context of LEVOSIMENDAN

• In these same hearts, perfusion with 0.03 mumol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels [7].
• METHODS: Twenty-four patients with an acute coronary syndrome underwent angioplasty followed by double-blinded, randomized treatment with 24 microg/kg of levosimendan (n = 16) or placebo (n = 8) [2].
• The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia [2].
• Thus levosimendan has the potential to treat low cardiac output states after cardiopulmonary bypass surgery [14].
• METHODS AND RESULTS: Levosimendan at different doses (0.1-0.4 microg x kg(-1) x min(-1)) or placebo were administered intravenously for 6h to 504 patients in a randomised, placebo-controlled, double-blind study [3].

References