Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parenterally administered positive inotropic agents remain an important component of the therapeutics of cardiac dysfunction and failure. Dobutamine, a catechol, remains the prototype of this drug group, but recently has been joined by the phosphodiesterase III inhibitor, milrinone. Compared with dobutamine, milrinone has greater vasodilating-unloading properties. The catecholamine, dopamine, is often used as a parenteral positive inotrope; but at moderate to high dose, it evokes considerable systemic vasoconstriction. At lower doses, dopamine appears to augment renal function. Levosimendan and toborinone, new compounds with several mechanisms of action, are under active clinical investigation and review for approval. Parenteral positive inotropic therapy is indicated for short-term (hours to days) treatment of cardiovascular decompensation secondary to ventricular systolic dysfunction, low-output heart failure. More prolonged or continuous infusion of one of these agents may be necessary as a "pharmacologic bridge" to cardiac transplantation, another definitive intervention, or more advanced, intense medical therapy. An occasional patient will require a continuous infusion via indwelling venous catheter and portable pump, simply to be able to be discharged from the hospital setting and function in the home environment. Intermittent parenteral inotropic therapy for chronic heart failure has provoked considerable controversy and passion among cardiologists and heart failure specialists; an attempt is made to present this topic in an objective manner.
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PMID:Parenteral inotropic support for advanced congestive heart failure. 987 7

To evaluate the potency of levosimendan, a newly developed cardiotonic agent, as a phosphodiesterase-3 inhibitor, we examined its effects on the L-type Ca(2+) current (I(Ca,L)) in single human atrial cells using the whole-cell voltage-clamp method. Levosimendan significantly increased I(Ca,L) in a concentration-dependent manner (E(max), 139.0 +/- 1.8%; EC(50), 54 +/- 3.6 nM). The increase in I(Ca,L) induced by 1 microM levosimendan was significantly greater in human atrial cells (136.7 +/- 11.0%, n=8) than in rabbit atrial cells (23.5 +/- 3.5%, n=6) (depolarization to +10 mV in each case). In rat atrial and ventricular cells, I(Ca,L) was unaffected by 1-10 microM levosimendan. These results indicate that the selective phosphodiesterase-3 inhibitor levosimendan increases cardiac-cell I(Ca,L) significantly more strongly in human than in rabbit and rat. It seems likely that the positive inotropic effect of levosimendan on the human myocardium depends on an increase in I(Ca,L) that is modulated by adenosine 3'5'-cyclic monophosphate (cAMP)-dependent phosphorylation.
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PMID:Levosimendan increases L-type Ca(2+) current via phosphodiesterase-3 inhibition in human cardiac myocytes. 1179 Mar 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

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

The concentration dependences of the Ca(2+)-sensitizing and the phosphodiesterase-inhibitory effects of levosimendan (the (-) enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile) and its active metabolite, OR-1896 (the (-) enantiomer of N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl] acetamide), were compared with their positive inotropic effects to reveal their mechanisms of action in guinea pig hearts. In Langendorff-perfused hearts, left ventricular +dP/dt(max) increased by 26+/-4% and 25+/-3% (mean+/-S.E.M.), with EC(50) values of 15+/-2 and 25+/-1 nM for levosimendan and OR-1896, respectively. In permeabilized myocyte-sized preparations, levosimendan and OR-1896 both increased isometric force production via Ca(2+) sensitization (at pCa 6.2), by 51+/-7% and 52+/-6%, with EC(50) values of 8+/-1 and 36+/-7 nM (P<0.05), respectively. Thus, the two molecules could be defined as Ca(2+) sensitizers and positive inotropes with very similar concentration dependences. However, major differences appeared when the phosphodiesterase-inhibitory effects of levosimendan and OR-1896 were probed on the two phosphodiesterase isoforms (phosphodiesterases III and IV) dominant in the left ventricular cardiac tissue. Levosimendan was a 40-fold more potent and a 3-fold more selective phosphodiesterase III inhibitor (IC(50) for phosphodiesterase III=2.5 nM, and IC(50) for phosphodiesterase IV=25 microM, selectivity factor approximately 10000) than OR-1896 (IC(50) for phosphodiesterase III=94 nM, and IC(50) for phosphodiesterase IV=286 microM, selectivity factor approximately 3000). Hence, our data support the hypothesis that levosimendan and OR-1896 both exert positive inotropy via a Ca(2+)-sensitizing mechanism and not via simultaneous inhibition of the phosphodiesterases III and IV isozymes in the myocardium at their maximal free plasma concentrations.
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PMID:The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. 1475 10

Levosimendan is a novel calcium sensitizer that increases contraction force without change in intracellular calcium ([Ca2+]i); milrinone is a phosphodiesterase inhibitor that exerts a positive inotropic effect by increasing [Ca2+]i. The effects of levosimendan and milrinone on oxygen consumption in the isolated guinea-pig heart were studied. Isolated guinea-pig hearts were paced (280 beats/min) and perfused according to the Langendorff technique. Levosimendan (0.01-1 microM) or milrinone (0.1-10 microM) were added cumulatively and changes from baseline for diastolic and systolic pressure (LVEDP and LVSP), contractility and relaxation (+dP/dt and -dP/dt), and coronary flow and oxygen consumption (CF and VO2) were calculated. Levosimendan was found to be 10 to 30 times more potent than milrinone as an inotropic agent. The effect on VO2 was markedly lower in levosimendan-perfused hearts than in milrinone-perfused hearts (P = 0.031 between the concentration-dependent effects of the two drugs). The maximum increase in VO2 was 10 +/- 4% in the levosimendan group and 38 +/- 15% in the milrinone group. The economy of the contraction was more advantageous in levosimendan-perfused hearts (P </= 0.005 vs. milrinone group on both VO2/+dP/dt and VO2/LVSP). It was concluded that levosimendan exerts a positive inotropic effect without disturbing the energy balance of the heart.
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PMID:Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart. 1508 67

Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calcium-dependent manner, improving inotropy without adversely affecting lusitropy. It does not exhibit clinically relevant phosphodiesterase inhibition at therapeutic concentrations. It also exerts vasodilatory effects, possibly through activation of several potassium channels and other less well characterized mechanisms. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction. In preclinical and clinical studies, levosimendan exerted potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. The most common adverse effects are attributable to the vasodilation. Two large, double-blind, randomized trials demonstrated favorable hemodynamic effects, improved tolerability, and a possible mortality benefit over dobutamine and placebo in patients who had acute symptoms of failure and required inotropic therapy. The long-term effect on patient outcomes is being confirmed in ongoing placebo- and inotrope-controlled trials. Levosimendan appears to be an effective inodilator devoid of the detrimental effects of conventional inotropes. In the future, levosimendan may provide a promising alternative to conventional inotropes for patients with acutely decompensated heart failure.
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PMID:Levosimendan, a new calcium-sensitizing inotrope for heart failure. 1562 34

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.
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PMID:Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure. 1572 64

The clinician's primary objective in treating a patient with decompensated heart failure is rapid and effective stabilization. This goal often is achieved through the use of inotropic support. Classic inotropic agents (beta-adrenergic agonists and phosphodiesterase III inhibitors) can provide short-term hemodynamic benefits, but their long-term use has been correlated with poor survival rates. Calcium sensitizers comprise a new drug class that offers hemodynamic and symptomatic improvements without increasing cAMP and intracellular calcium concentrations. These agents enhance contractility without a concurrent increase in the risk of cardiac events and thus represent a significant improvement over classic positive inotropic agents. Levosimendan is the most potent calcium sensitizer to date, exhibiting a unique dual mechanism of action that combines a positive inotropic action mediated via calcium sensitization and a vasodilator property via ATP-dependent potassium channels. Available clinical data suggest that calcium sensitizer agents represent a promising class of inotropic agents in a field that has seen few advances in recent decades.
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PMID:Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure. 1630 57


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