Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levosimendan has been reported to increase cardiac Ca(2+) sensitivity, thereby not enhancing intracellular Ca(2+) or diastolic tension. This may be advantageous for the treatment of heart failure patients. Therefore, the present study investigates the mode of action of levosimendan in both failing and nonfailing (NF) human myocardium. The effects of levosimendan on contractile force, Ca(2+) transient (fura 2), and the force-frequency relationship (0.5-3 Hz) were studied in left ventricular terminally failing [dilated cardiomyopathy (DCM; n = 18)] and nonfailing (NF) myocardium (donor hearts, n = 6). Levosimendan (0.03-10 micromol/l) increased contractile force in NF (EC(50): 0.38 micromol/l). In left ventricular failing myocardium, levosimendan only increased force after prestimulation with isoprenaline (0.1 micromol/l, EC(50) levosimendan: 0.062 micromol/l) or after elevation of the extracellular Ca(2+) concentration from 1.8 to 3.2 mmol/l. After application of isoprenaline, levosimendan shortened relaxation and contraction kinetics. Levosimendan did not change the systolic Ca(2+) transient but it improved the force-frequency relationship in DCM. In conclusion, levosimendan improves contraction in failing human myocardium under conditions with already increased intracellular Ca(2+).
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PMID:Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium. 1174 56

Levosimendan is a new calcium sensitizer developed for the short-term intravenous treatment of congestive heart failure. The aims of the present open-label, nonrandomized study were to determine the tolerability, hemodynamic effects, and the basic pharmacokinetics of levosimendan and its metabolites during an extended continuous infusion of levosimendan. Twenty-four patients with New York Heart Association (NYHA) III-IV heart failure in two groups of 12 patients were exposed to either 0.05 microg/kg/min or 0.1 microg/kg/min of levosimendan for 7 days. Heart rate and blood pressure were measured, and blood samples for the determination of plasma concentrations of the parent drug and its metabolites were drawn daily during the infusion and the 10 to 15 days' follow-up. The 7-day infusion was well tolerated and no premature discontinuations occurred. Both systolic and diastolic blood pressure decreased maximally by 6 mmHg in the lower and by 11 mmHg in the higher levosimendan dose groups during the infusion period (p < 0.05 for both groups). The mean heart rate values increased maximally by 18 and 26 beats/min in the lower and higher levosimendan dose groups, respectively (p < 0.001 for both groups). The hemodynamic effects peaked at the end of the infusion period and thereafter slowly declined during the follow-up. After the recommended infusion period of 24 hours, the mean heart rate increase was only 2 and 6 beats/min in the lower and higher levosimendan dose groups, respectively. The elimination half-life of levosimendan was approximately 1 hour and of the metabolites 70 to 80 hours. It can be concluded that levosimendan, even administered considerably longer than the recommended 24 hours, was well tolerated. The 7-day infusion induced a prolonged increase in heart rate and a minor decrease in blood pressure. The long-lasting effects are probably explained by the active metabolite.
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PMID:Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. 1180 23

Levosimendan is a new inotropic and vasodilator agent. The inotropic effect is mediated by calcium concentration-dependent conformational changes in troponin C during systole leading to sensitization of the contractile apparatus to calcium ions. The vasodilator effect is mediated by opening potassium channels on vascular smooth muscle. It has a complex pharmacokinetic profile, with a long-acting metabolite that has hemodynamic effects persisting for approximately 1 week. Although it is absorbed orally, it has been developed only for intravenous use thus far. The hemodynamic effects are not reduced and may be enhanced in the presence of beta-blockers, possibly an important attribute when dealing with exacerbation of heart failure caused by or in the presence of beta-blockers. More patients with heart failure have participated in randomized controlled trials of levosimendan than of any other intravenous inotropic agent. Experience with its use after cardiac surgery is limited. Preliminary observations suggest that hemodynamic changes are associated with symptomatic benefit and a reduction in morbidity and mortality in patients with severe heart failure caused by left ventricular systolic dysfunction, compared with placebo in one study and dobutamine in another. Levosimendan may be the first inotropic agent that it is both safe and effective in altering clinical outcomes relevant for patients. Part of this benefit may be achieved because levosimendan allows other inotropic agents that may have adverse effects on patient outcome to be avoided. Further research is required to confirm whether levosimendan reduces mortality and morbidity compared with a placebo and when administered repetitively. If it does, it may become routine therapy for the treatment of severe heart failure.
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PMID:Levosimendan: a new era for inodilator therapy for heart failure? 1201 75

Levosimendan is one of the first agents of a new class of drugs known as calcium sensitizers. These drugs are believed to increase cardiac contractility by sensitizing cardiac myofibrils to calcium, and may therefore be of clinical benefit in the treatment of low-cardiac output states, particularly congestive heart failure. In addition to sensitizing troponin to intracellular calcium, levosimendan has been shown to inhibit phosphodiesterase III, which may contribute to its positive inotropic effect, and open adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)), which may produce vasodilation. Unlike currently available intravenous inotropes, levosimendan does not increase myocardial oxygen utilization, has not been shown to be proarrhythmic, and has been used effectively in the presence of beta-blocking medications. Levosimendan also has not been shown to impair ventricular relaxation, which was an initial concern with this class of drugs. Clinical studies of levosimendan have demonstrated short-term hemodynamic benefits of levosimendan over both placebo and dobutamine. While large-scale, long-term morbidity and mortality data are scarce, the Levosimendan Infusion versus Dobutamine in severe low-output heart failure (LIDO) study suggested a mortality benefit of levosimendan over dobutamine up to 180 days after treatment. Clinical studies comparing levosimendan with other positive inotropes, namely milrinone, are lacking. Levosimendan treatment appears to be well-tolerated, with the primary adverse events being headache and hypotension. No clinically significant drug-drug interactions have been reported with levosimendan to date. The clinical future of levosimendan will depend on the results of larger, ongoing clinical trials.
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PMID:Levosimendan: a unique approach to the treatment of heart failure. 1214 86

Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.
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PMID:Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan? 1255 10

The congestive heart failure is a pathological process characterized by the incapacity of the heart to maintain an adequate cardiac perfusion for the tissue metabolism, and that can be secondary to diverse causes, that give as result, alterations in the lusitropism, inotropism or in the cronotropism. Over 4.6 persons per hundred in the United States alone carry this diagnosis, and it is the cause of death in several hundred thousand patients each year, with a 35% mortality over 5 years. In the last years, have existed important advances in the pharmacological treatment of this disease in it's terminal stages. The increase in the knowledge on the physiopathology of the heart failure, has taken place for the use of new schemes of treatment, where it excels the use of vasoactive amines, Angiotensin Converting Enzyme Inhibitors, angiotensin II receptor AT1 antagonists, etc; nevertheless we whereupon that most of these drugs that at the present display a favorable answer to the disease, has the disadvantage of increasing the consumption of oxygen by the own myocardium tissue. Levosimendan has a better profile of security than its predecessors (amrinone and milrinone), improves the haemodynamics parameters of special significant form in the cardiac output, the systolic pressure of the pulmonary artery and the telediastolic pressure of the left ventricle, without significantly increasing the consumption of oxygen by the myocardium. Levosimendan is a new and relevant calcium sensitizer developed for the short-term intravenous treatment of congestive heart failure.
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PMID:[Levosimendan: a new option in the pharmacologic management of cardiac insufficiency]. 1266 17

There are 2 studies which have investigated the hemodynamic efficacy of levosimendan compared to dobutamine in congestive heart failure patients. The first is a dose finding comparative 24-h infusion trial which included 95 NYHA II-III patients to different doses of levosimendan and 20 patients to dobutamine administered as a continuous, open-label infusion of 6 microg/kg/min. Efficacy and safety of levosimendan in severe low-output heart failure a randomized, double-blind comparison to dobutamine study compared the short- and long-term efficacy and safety of a single 24-hour infusion of levosimendan (n=103) with dobutamine (n=100) in hospitalised patients in acute heart failure. This double-blind, parallel-group, randomised trial showed that, irrespective of the aetiology of the heart failure, levosimendan produced significantly greater improvement in major determinants of cardiac function in heart failure patients compared to dobutamine. Levosimendan produced significantly greater haemodynamic improvements than dobutamine by significantly reduced mortality at 31 days compared with dobutamine; this reduction was maintained at 180 days. Levosimendan significantly increased the number of days alive and out of hospital, compared with dobutamine. It was better tolerated than dobutamine and fewer patients receiving levosimendan experienced arrhythmias and myocardial ischaemia, compared with dobutamine. Levosimendan produced haemodynamic responses that were unaffected by concomitant use of beta blockers.
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PMID:Levosimendan compared with dobutamine in low output patients. 1276 17

Levosimendan is a new agent for the treatment of acute heart failure. Levosimendan acts via complementary mechanisms; it enhances contractility by sensitising cardiac myofilaments to calcium and dilates blood vessels by opening ATP-dependent potassium channels. In contrast to traditional inotropes (beta-agonists or phosphodiesterase inhibitors), levosimendan does not raise myocyte calcium levels and is therefore less likely to elicit arrhythmias or to impair diastolic relaxation. The clinical efficacy of levosimendan is supported by four key clinical studies, including more than 900 patients hospitalised for cardiac decompensation due to acutely worsened chronic heart failure or to heart failure following myocardial infarction. When given as short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. At 31 days post-treatment, mortality rates were halved in decompensated chronic heart failure patients who received levosimendan, compared with those on dobutamine--an advantage sustained at 180 days. Similar survival gains were observed among acute failure patients treated with levosimendan following myocardial infarction. With its substantial haemodynamic and survival benefits, levosimendan is well suited to be part of routine management for patients with acutely decompensated heart failure.
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PMID:Levosimendan: a new dual-action drug in the treatment of acute heart failure. 1284 47

For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-III (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented.
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PMID:The role of Ca++-sensitizers for the treatment of heart failure. 1450 45

Levosimendan is a novel calcium sensitizing agent in development for the treatment of acute and chronic heart failure. The agent increases myocardial force without increasing myocyte calcium concentrations, thus reducing the possibility for myocardial necrosis. In addition, the agent also causes vasodilation of coronary and peripheral vessels to improve coronary blood flow and reduce afterload. The short half-life is a benefit for intravenous administration but could be problematic for the drug's use in chronic heart failure. The risk of the development of arrhythmias from levosimendan appears small secondary to an increase in the QTc interval of 15 msec but needs to be evaluated in light of the ability of levosimendan to open adenosine triphosphate (ATP)-sensitive potassium channels. In addition, the agent has not been studied in patients with additional risks for torsades de pointes. Levosimendan has been shown to have beneficial survival effects in several populations; its use improves patient outcomes relative to the standard of care and has the potential to reduce hospital costs associated with heart failure.
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PMID:Levosimendan: implications for clinicians. 1451 89


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