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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levosimendan, a novel agent developed for the treatment of acute and decompensated heart failure, exerts potent positive inotropic action and peripheral vasodilatory effects. The mechanism of vasodilation by levosimendan may involve reduction of Ca2+ sensitivity of contractile proteins in vascular smooth muscle, the lowering of intracellular free Ca2+, the potential inhibition of phosphodiesterase (PDE) III, and an opening of K+ channels. Although the importance and relative contribution of each of these mechanisms of vasorelaxation is unclear and may be different in various vessels and dependent on the dose of levosimendan, the important roles of K+-channel opening and Ca2+ desensitization in vascular smooth muscle are obvious, whereas the role of PDE inhibition remains to be defined. This review article briefly discusses the current research data on the mechanism of levosimendan-induced vasodilation with an emphasis on the types of the blood vessels and the K+ channels. It also summarizes the current experimental and clinical knowledge of the use of levosimedan in the treatment of heart failure.
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PMID:Vasodilating mechanisms of levosimendan: involvement of K+ channels. 1745 12

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.
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PMID:Clinical pharmacology of levosimendan. 1759 1

Simendans are novel agents used in the treatment of decompensated heart failure. They sensitize troponin C to calcium and open ATP-sensitive potassium channels and have been shown to reduce cardiac myocyte apoptosis. The aim of the present study was to evaluate whether simendans reduce pulmonary eosinophilia and regulate eosinophil apoptosis. Bronchoalveolar lavage (BAL) eosinophilia was evaluated in ovalbumin-sensitized mice. Effects of simendans on apoptosis in isolated human eosinophils were assessed by relative DNA fragmentation assay, annexin V-binding, and morphological analysis. Dextrosimendan [(+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono]propanedinitrile] reduced ovalbumin-induced BAL-eosinophilia in sensitized mice. Levosimendan [(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile] and dextrosimendan reversed interleukin (IL)-5-afforded survival of human eosinophils by inducing apoptosis in vitro. Even high concentrations of IL-5 were not able to overcome the effect of dextrosimendan. Dextrosimendan further enhanced spontaneous apoptosis as well as that induced by CD95 ligation, without inducing primary necrosis. Dextrosimendan-induced DNA fragmentation was shown to be dependent on caspase and c-Jun NH2-terminal kinase activation, whereas extracellular signal-regulated kinase, p38 mitogen-activated kinase, and ATP-sensitive potassium channels seemed to play no role in its actions. Taken together, our results show that simendans possess antieosinophilic activity and may be useful for the treatment of eosinophilic inflammation.
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PMID:Antieosinophilic activity of simendans. 1762 Apr 56

Levosimendan enhances cardiac contractility by increasing myocyte sensitivity to calcium, and induces vasodilatation. Although studies have evaluated the efficacy of levosimendan in heart failure, it is not clear whether it might produce functional influence on platelet response. In this study, the effect of levosimendan on platelet aggregation was investigated. Platelet function tests were performed in 12 healthy male volunteers. Three concentrations of levosimendan solution were prepared that would result in 10, 25, and 45 ng/ml levosimendan concentrations in the blood similar to that observed after clinical therapeutic intravenous application of 0.05-0.1 microg/kg/min. Each concentration of levosimendan solution and a control diluent without levosimendan were incubated with whole blood at 37 degrees C. After incubation for 15 min, aggregation responses were evaluated with adenosine diphosphate (ADP) (5 and 10 microM) and collagen (2 and 5 microg/ml) in platelet-rich plasma. Preincubation with all dilutions of levosimendan inhibited aggregation of platelets induced by ADP and collagen significantly. Levosimendan also inhibited significantly the secondary wave of platelet aggregation induced by ADP. The results showed that there was a relationship between levosimendan concentration and inhibition of platelet aggregation. In conclusion, this study with an in vitro model showed that levosimendan had a significant inhibitory effect on platelets in clinically relevant doses.
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PMID:Levosimendan has an inhibitory effect on platelet function. 1765 87

Levosimendan, a drug used in the treatment of acute and decompensated heart failure, has positive inotropic and antistunning effects mediated by calcium sensitization of contractile proteins, and vasodilatory and antiischemic effects mediated via the opening of ATP-sensitive potassium channels in vascular smooth-muscle cells. Recently, it also has been shown to act on mitochondrial ATP-sensitive potassium (mitoKATP) channels, an action thought to protect the heart against ischemia-reperfusion damage. This finding has suggested a possible application for levosimendan in clinical situations in which preconditioning would be beneficial (eg, in pre- and perioperative settings in cardiac surgery). The demonstration that levosimendan can prevent or limit myocyte apoptosis via the activation of mitoKATP channels provides a potential mechanism whereby this agent might protect cardiac myocytes during episodes of acute heart failure. This finding may explain why short-term treatment with levosimendan may improve longer-term survival. The present article reviews the literature on the cardioprotective actions of levosimendan, with particular emphasis on its recently recognized effects on mitoKATP channels and the putative preconditioning effects of that action. A therapeutic approach to acute heart failure that includes a cardioprotective strategy could have a clinically meaningful benefit on disease progression beyond alleviation of symptoms.
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PMID:The cardioprotective effects of levosimendan: preclinical and clinical evidence. 1787 52

Levosimendan and dobutamine are comparable inotropic drugs as regards their hemodynamic effects and clinical outcomes in decompensated heart failure (HF). The aim of this study was to compare the effects of levosimendan and dobutamine treatment on NT-proBNP levels in patients with decompensated HF. Forty-four patients with decompensated HF and ejection fraction <35% received either a 24-h infusion of levosimendan (n=26) or dobutamine (n=18). NT-proBNP was measured at baseline and 12 h, 24 h and 48 h after the initiation of drug infusion. NT-proBNP levels at baseline, 12 h, 24 h and 48 h were 16,879+/-2437, 16,004+/-2635, 12,881+/-2305 and 11,078+/-2092 pg/ml, respectively, in the levosimendan group and 16,031+/-3463, 15,908+/-3806, 12,271+/-3299 and 14,840+/-4009 pg/ml, respectively, in the dobutamine group. NT-proBNP decreased significantly at 24 h in response to both levosimendan and dobutamine treatment (p<0.01 and p<0.05, respectively) with no significant difference among the treatment groups. In the dobutamine group, NT-proBNP increased at 48 h (p=n.s. vs. baseline), in contrast, NT-proBNP reduction continued for up to 48 h in the levosimendan group (p<0.001 vs. baseline). Although not statistically different, a greater percentage of NT-proBNP reduction was observed with levosimendan treatment at both 24 h (-25+/-7% vs. -20+/-10%) and 48 h (-32+/-7% vs. -20+/-11%) compared to dobutamine. Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels at the end of the 24-h infusion. However, compared to dobutamine, levosimendan has better and prolonged effects on NT-proBNP levels in decompensated HF.
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PMID:Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels, but levosimendan has better and prolonged neurohormonal effects than dobutamine. 1850 48

Levosimendan has been used successfully in the treatment of ischaemic cardiac failure and myocardial stunning. There is growing evidence from both human and animal experiments that levosimendan has particularly favourable effects on the right ventricle. We describe a case of life-threatening pulmonary embolus supported by the use of levosimendan.
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PMID:Levosimendan in acute pulmonary embolism. 1793 66

Heart Failure (HF) accounted for 3.4 million ambulatory visits in 2000. Current guidelines from the American Heart Association/American College of Cardiology, the Heart Failure Society of America, and the International Society for Heart & Lung Transplantation recommend aggressive pharmacologic interventions for patients with HF. This may include a combination of diuretics, Angiotensin Converting Enzyme inhibitors, beta-blockers, angiotensin receptor blockers, aldosterone antagonists, and digoxin. Nitrates and hydralazine are also indicated as part of standard therapy in addition to beta-blockers and Angiotensin Converting Enzyme inhibitors, especially but not exclusively, for African Americans with left ventricular (LV) systolic dysfunction. For those with acute decompensated HF, additional treatment options include recombinant human B-type natriuretic peptide, and in the future possible newer agents not yet approved for use in the U.S., such as Levosimendan. Medical devices for use in patients with advanced HF include LV assist devices, cardiac resynchronization therapy, and implantable cardioverter defibrillators. For refractory patients, heart transplantation, the gold-standard surgical intervention for the treatment of refractory HF, may be considered. Newer surgical options such as surgical ventricular restoration may be considered in select patients.
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PMID:Management strategies for stage-D patients with acute heart failure. 1795 41

Levosimendan is emerging as a novel cardioprotective inotrope. Levosimendan augments myocardial contractility by sensitising contractile myofilaments to calcium without increasing myosin adenosine triphosphatase activity or oxygen consumption. Levosimendan activates cellular adenosine triphosphate-dependent potassium channels, a mechanism which is postulated to protect cells from ischaemia in a manner similar to ischaemic preconditioning. Levosimendan may therefore protect the ischaemic myocardium during ischaemia-reperfusion as well as improve the contractile function of the heart. Adenosine triphosphate-dependent potassium channel activation by levosimendan may also be protective in other tissues, such as coronary vascular endothelium, kidney and brain. Clinical trials in patients with decompensated heart failure and myocardial ischaemia show levosimendan to improve haemodynamic performance and potentially improve survival. This paper reviews the known pharmacology of levosimendan, the clinical experience with the drug to date and the potential use of levosimendan as a cardioprotective agent during surgery.
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PMID:Inoprotection: the perioperative role of levosimendan. 1836 Oct 22

Levosimendan (LS), a Ca(2+) sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, chronically instrumented mongrel dogs. Animals received a placebo capsule on day 1, and then LS was administered at single oral doses of 0.025 (day 2), 0.05 (day 4), and 0.1 (day 8) mg/kg. We serially measured plasma LS concentrations, hemodynamic, and left ventricular (LV) systolic and diastolic functional responses periodically until 12 h after oral LS. In both normal and HF, after three incremental dosages of oral LS, the peak plasma LS concentrations (34.6, 66.8, and 123.2 ng/ml in normal and 38.3, 71.5, and 137.4 ng/ml in HF) were achieved within 2 h in proportion to the dose, parallel to an increased LV contractility (normal, from 5.7 mm Hg/ml placebo to 8.2, 10.5, and 12.6 mm Hg/ml; HF, from 3.7 mm Hg/ml placebo to 5.7, 7.1, and 8.7 mm Hg/ml), and decreased time constant of LV relaxation (tau) (normal, from 28.8 ms of placebo to 25.6, 24.7, and 23.5 mm Hg/ml; HF, from 44.7 ms of placebo to 38.9, 36.4, and 34.6 ms). Compared with placebo, total systemic vascular resistance and mean left atrial pressure were significantly reduced after LS. In HF, oral LS caused a dose-dependent increase of LV-arterial coupling and mechanical efficiency. Heart rate increased only after 0.1 mg/kg LS in normal dogs. In conclusion, oral LS produces vasodilatation and dose-dependent augmentation in LV contractility and relaxation both in normal and HF.
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PMID:Orally available levosimendan dose-related positive inotropic and lusitropic effect in conscious chronically instrumented normal and heart failure dogs. 1817 83


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