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At least 271 records · Page 15Linked to original sources
PubMed2006

Pharmacologic treatment of heart failure due to ventricular dysfunction by myocardial stunning: potential role of levosimendan.

The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. Myocardial stunning is mainly due to calcium overload in the cytosol of myocardial cells, the loss of myofilaments and their reduced sensitivity to calcium. Enhanced immune activation with inflammatory phenomena also plays an important role in the pathophysiology of cardiac dysfunction. Increasing evidence has shown that the myocardial ATP-dependent potassium channel (K(ATP)) plays an important role in many myocardial cell functions and that it is involved in ischemia-reperfusion injury and myocardial stunning. K(ATP) is thus considered a therapeutic target in this setting. Currently used inotropic drugs improve contractility by increasing intracellular concentrations of free calcium, but they increase myocardial consumption of energy and even produce arrhythmia; therefore, in this clinical context, they do not seem to be 'pathophysiologically correct' drugs. Levosimendan, a new calcium-sensitizing agent, increases contractility by enhancing the sensitivity of myofilaments to calcium by binding to the C cardiac troponin in cardiac muscle in a calcium-dependent way. Levosimendan also exerts a coronary and systemic vasodilatory effect through its K(ATP) channel-opening properties and may exert other cardioprotective actions through this mechanism. Levosimendan produces positive hemodynamic effects without increasing myocardial oxygen demand or causing arrhythmias. Intravenous levosimendan is generally well tolerated and has been approved by several European countries, and recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe decompensated heart failure in adults. Randomized, double-blind trials have shown that levosimendan is not only more clinically and hemodynamically effective but also that it significantly reduces morbidity and mortality when compared with dobutamine or placebo. Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.

Adenosine Triphosphate↗
PubMed2005

Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure.

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditional inotropes, levosimendan seems also to be safe in terms of morbidity and mortality.

Administration, Oral↗
PubMed2005

Anti-inflammatory and anti-apoptotic effects of levosimendan in decompensated heart failure: a novel mechanism of drug-induced improvement in contractile performance of the failing heart.

Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. 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. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.

Animals↗
PubMed2002

Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure.

OBJECTIVE: Levosimendan is a new calcium sensitizer with additional vasodilatory properties developed for the short-term intravenous treatment of congestive heart failure. The aims of the present study were to determine the pharmacokinetics and hemodynamic effects of levosimendan and its metabolites during and after a 24-hour levosimendan infusion. METHODS: The study was an open-label, non-randomized, phase II study in 2 centers. Twelve patients with NYHA III-IV heart failure received 0.2 microg/kg/min continuous infusion of levosimendan for 24 hours. Blood samples for the determination of plasma concentrations of the parent drug and the metabolites were drawn repeatedly during the infusion and the 2-week follow-up period. Heart rate from Holter recordings and blood pressure were measured. RESULTS: The elimination half-life of levosimendan was 1.3 hours and that of the metabolites 75-78 hours. The mean maximum increase in heart rate of 10 bpm (p < 0.005) and the mean maximum decreases in systolic and diastolic blood pressure of 12 mmHg and 8 mmHg (p < 0.05 for both), respectively, were observed during the first day after stopping levosimendan infusion. The hemodynamic effects slowly declined during the follow-up, and after 1 week no statistically significant differences compared with baseline were observed. No increase in ventricular arrhythmias was seen. CONCLUSION: A 24-hour infusion of levosimendan induces hemodynamic effects lasting several days after stopping the infusion. The prolongation of the effects beyond the infusion period is most likely due to an active metabolite with a long half-life.

Blood Pressure↗
PubMed2004

Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery.

Following cardiac surgery, low-output syndrome is relatively common. Since this condition can lead to serious consequences, this postsurgical, low-output state should be reversed whenever possible. Patients with low-output syndrome need drug and fluid management aimed at enhancing cardiac contractility and at facilitating optimal myocardial loading. The objective of this pilot study was to evaluate whether benefits of levosimendan, a new calcium-sensitizing agent approved for treatment of patients with acute exacerbation of chronic heart failure, could be extended to patients with low-output syndrome following cardiac surgery. For this study, each patient was given levosimendan as a loading dose of 12 microg/kg over 10 minutes, followed by a continuous infusion of 0.1 microg/kg/min for 12 hours. Of 11 postsurgical patients with severely impaired cardiac output and hemodynamic compromise, 8 patients (73%) showed evidence of combined hemodynamic improvement (> 30% increase in cardiac index and PCWP corrected to < 18 mmHg) within 3 h after the start of levosimendan infusion. Specifically, cardiac index and stroke volume were significantly increased, while mean arterial pressure, indexed systemic vascular resistance, mean pulmonary pressure, right arterial pressure, and pulmonary capillary wedge pressure were all significantly lowered. Taken together, such changes showed enhanced cardiac output along with significantly decreased preload and afterload--conditions associated with recovery of cardiac function. Levosimendan is thus highly favorable for short-term treatment of patients with low cardiac output following cardiac surgery.

Aged↗
PubMed1999

Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.

The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. Left ventricular developed pressure (LVDP) was used as an index of mechanical function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence of ischemia/reperfusion arrhythmias was also investigated. Control hearts (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of control hearts, 25% developed reperfusion ventricular tachycardia but not ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts.

Adenosine Triphosphate↗
PubMedDate not supplied

[The characteristics of the inotropic effects of Levosimendan on the isolated myocardium of patients with ischemic heart disease].

Effect of the new cardiotonic agent levosimendan on the inotropic response parameters of the isolated myocardium of patients suffering from ischemic heart disease (IHD) was studied in the 0.01-1.00 mumole/liter concentration range. The inotropic response was measured in an isometric mode (electric stimulation frequency, 0.5 Hz; temperature, 37 degrees C; perfusion rate, 10 ml/min). In the range of 0.01-0.1 mumole/liter, levosimendan preferentially increases the rate of stress growth (+dP/dt) and the relaxation time. At concentrations above 0.1 mumole/liter, levosimendan produces a pronounced increase (56%) in the amplitude of single contraction. The mechanogram exhibits the signs of Ca-overload, including the post-contraction wave. It is concluded that the inotropic action of levosimendan on the isolated myocardium of IHD patients is related predominantly to increasing calcium uptake from outside. This circumstance is apparently caused by the initially high calcium content in sarcoplasmic reticulum, which is an important feature of the entire intracellular homeostasis in cardiomyocytes during IHD.

Adult↗
PubMed2001

New pharmacological strategies for the treatment of heart failure.

Heart failure still carries a high morbidity and mortality, necessitating new approaches for its management. Greater understanding of the pathophysiology of heart failure has opened the way for novel therapeutic approaches, including analogs of natriuretic peptides and drugs that modulate endothelin, cytokine release and endothelial vasoconstriction. Other drugs are undergoing laboratory and clinical trials that will eventually supersede or complement less optimal heart failure treatments. Clinical trials will ascertain if these new strategies in the treatment of heart failure will ultimately be successful in the management of these patients.

Adrenergic beta-Antagonists↗
PubMed2001

New therapeutic choices in the management of acute congestive heart failure.

Patients with acute congestive heart failure generally present with profound fluid retention states and dyspnea due to pulmonary edema. If the condition is not aggressively and appropriately treated, irreversible cardiac decompensation may ensue, leading to cardiogenic shock, multiorgan failure, and death. Intravenous inotropic, vasopressor, and vasodilator therapies have proved effective in initial stabilization of acute heart failure decompensation, but these agents, particularly the traditionally used ones, are generally limited by side effects that can be egregious and include substantive ventricular arrhythmias. Dobutamine has largely replaced agents with rather profound toxicity, such as isoproterenol and epinephrine. The phosphodiesterase-inhibiting agent milrinone, having both vasodilator and inotropic properties, can produce tachycardia and significant ventricular arrhythmias, but has proven quite useful for seriously ill patients. Clinical trials of levosimendan have found a positive inotropic response when the drug is given parenterally; vasodilating properties are also evident. Clinical trials are under way to evaluate the potential benefits of endothelin receptor antagonists when given intravenously. Intravenous administration of nesiritide, a recombinant human B-type natriuretic peptide, has been shown to produce favorable hemodynamic effects, including balanced vasodilation associated with a rapid improvement in clinical symptoms.

Acute Disease↗
PubMed2002

Comparison of enoximone, amrinone, or levosimendan enriched St. Thomas' hospital cardioplegic solutions used for myocardial preservation in isolated guinea pig hearts.

Myocardial contractile function after cardioplegic arrest is often depressed and an ideal cardioplegic solution has not been developed yet. The aim of this study was to assess the efficacy of phosphodiesterase III inhibitors, amrinone and enoximone, and levosimendan, a novel Ca2+ sensitizing agent, on recovery of hearts after normothermic cardioplegic arrest when added to the St. Thomas' hospital cardioplegic solution. In the control group, isolated guinea pig hearts were perfused in Langendorff apparatus and arrested with standard St. Thomas' solution. In other groups, amrinone (10(-5) mol.L-1), levosimendan (10(-5) mol.L-1), or enoximone (10(-4) mol.L-1) were added to the cardioplegic solution. In all hearts, intraventricular pressure, +dp/dtmax, -dp/dtmax, area under pressure-time curve, heart rate, coronary flow, lactate dehydrogenase and creatine kinase enzyme leakage, and oxygen consumption were measured. In the enoximone group, contractility force and +dp/dtmax, were found to be significantly high in the reperfusion and inotropic periods in comparison with other groups (p < 0.05). -dp/dtmax and area under contractility-time curve values were significantly high in inotropic period in enoximone group (p < 0.05). No statistically significant difference was noted in other groups. Cardioplegic solution enrichment with enoximone augmented mechanic functions in reperfusion period. No positive effect of amrinone or levosimendan was observed in this study.

Amrinone↗
PubMed2003

[The best of clinical pharmacology in 2002].

The results of several large therapeutic cardiovascular trials were reported in 2002. The LIFE study concluded that losartan is superior compared to atenolol in terms of prevention of cardiovascular morbidity and mortality, the benefit being for CVA without changing the incidence of myocardial infarction. The OPTIMAAL study stated the disappointing results of post-infarct losartan. The IONA study represents a first demonstration with nicorandil of benefit not only in angina crises but equally on cardiac morbidity and mortality. The HPS study confirms the benefit of a statin in secondary prevention but for the first time, no matter what the initial level of LDL-cholesterol. Finally in the LIPS study, it is reported that statins reduce major cardiovascular events after coronary angioplasty. The year 2002 was marked elsewhere by imagination after the publication of the RAVEL study on coated stents delivering anti-proliferative drugs in order to avoid coronary restenosis. Three drugs were the subject of work confirming their potential significance in cardiovascular pathology: a) ezetimibe, representing a new class of cholesterol lowering drugs with which the association with statins seems especially synergic, b) nesiritide recombinant type B natriuretic peptide, whose significance was confirmed in acute cardiac insufficiency. c) levosimendan (calcium sensitisor) which moreover can be a significant treatment in cardiac decompensation as suggested by the LIDO study with a follow up of 180 days. By contrast, omapatrilate did not confirm its potential superiority over ACE inhibitors in the treatment of cardiac insufficiency. Some encouraging data were reported in 2002 in the field of therapeutic angiogenesis as much at the myocardial level as in lower limb arteritis. Finally, 2002 was marked by the publication of the WHI study which intensified suspicions regarding hormonal substitution treatment, confirming the advantage of not only secondary but perhaps primary cardiovascular prevention.

Anticholesteremic Agents↗
PubMed2002

The development of new medical treatments for acute decompensated heart failure.

There were almost 1 million hospitalizations for heart failure in 1999, representing a 155% increase over the last 20 years, and the treatment of these patients is an important and growing problem. However, currently available therapies, which are based on three basic mechanisms of action (diuresis, exogenous vasodilators, and cyclic adenosine monophosphate-dependent positive inotropes), have significant limitations that have encouraged the development of newer agents. The leading medications for this indication are representatives of three different therapeutic approaches, which include endogenous vasodilatory neurohormones (nesiritide), calcium sensitizers (levosimendan), and neurohormonal antagonists (tezosentan). These three agents represent a new generation of therapeutics for this important medical problem and may provide the means not only to treat symptoms, but also to improve longer-term clinical outcomes.

Acute Disease↗
PubMedDate not supplied

[Levosimendan: a new option in the pharmacologic management of cardiac insufficiency].

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.

Angiotensin Receptor Antagonists↗