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)

In congestive heart failure (CHF), even today, pharmacotherapy renders primarily only symptomatic improvement. The success of the treatment is basically dependent on the degree of functional myocardial impairment, that is, the condition of the inadequately treatable underlying disease. Treatment should be differentially oriented to the nature of the LV dysfunction as systolic or diastolic whereby the latter may account for 20 to 40% of those with CHF. In the case of diastolic LV dysfunction, because of the impaired compliance, vasodilators are not beneficial since small changes in volume may cause marked changes in filling pressures and vice versa. Additionally, inotropic substances are unfavorable since they further increase filling pressure and impedance, that is, diastolic LV function may become more compromised. For systolic LV dysfunction both vasodilators and positive inotropic substances can be employed. Some unsettled issues remaining include the appropriate time to begin treatment, the most suitable form of combined treatment and the best dosing regimens. Digitalis, as dobutamine, increases measured contractility; those seen to profit from digitalis include symptomatic patients with LV dilatation and impaired pump function as well as patients with supraventricular tachyarrhythmias. Prior to use of positive inotropic drugs in CHF, consideration should be given to whether favorable acute effects can be maintained during longterm treatment, adverse reactions such as arrhythmogenicity are acceptable, and the actions on myocardial oxygen balance. New nonglycoside positive inotropic agents which can also be administered orally, acutely improve hemodynamics; these include catecholamine derivatives, phosphodiesterase inhibitors (PDH). Both substance groups increase contractility but arrhythmogenicity as well, in general via increased concentrations of intracellular cyclic AMP. Reservations regarding the use of positive inotropic drugs for CHF have been supported by the results of studies showing that beta 1 agonists such as prenalterol and beta 2 agonists such as salbutamol or pirbuterol, due to down-regulation of beta-receptor density, are not capable of maintaining improved contractility during chronic treatment; intermittent dobutamine treatment resulted in higher mortality; beta-blockers without intrinsic sympathomimetic activity reduced mortality in patients with CHF after myocardial infarction while on use of beta-receptor blockers with intrinsic sympathomimetic activity, this favorable effect was not observed; during chronic PDH treatment, there was an unfavorable one-year mortality rate (50 to 100%); a controlled study with amrinone did not show a higher mortality than placebo. For most PDH, it is not known with certainty at which therapeutically effective dose the positive inotropic effect can best be realized and whether the acute hemodynamic effects are not predominantly attributable to the vasodilatory properties.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Chronic heart failure: effect and evaluation of therapy with positive inotropic substances]. 219 20

The aim of inotropic therapy is to increase the force of myocardial fibre shortening by improving the availability of calcium to the contractile proteins. Digitalis remains the most widely used drug, but its positive inotropic effects are weak and the therapeutic index is low. Dobutamine is the most useful catecholamine because the most cardioselective and it induces the least increase in myocardial oxygen consumption. There are three groups of new inotropic agents: sympathomimetics: pirbuterol and prenalterol are effective in the short term but tolerance is usually observed within a few weeks. Salbutamol and terbutaline have only been assessed in acute studies, phosphodiesterase inhibitors (MDL 17043, MDL 19025) are powerful inotropic agents in the short and medium term. ARL 115 has mainly been studied by parenteral administration, Amrinone has a largely unknown mode of action, but is a very effective positive inotropic drug; its side-effects limit it as age. However, its derivative, milrinone, seems to be more inotropic and less toxic. The new inotropic drugs currently under assessment are active in the short term but their long-term efficacy and side-effects are still little known. The ideal inotropic agent remains to be discovered.
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PMID:[Positive inotropic agents. Generalities and classification]. 286 22

Advances in our understanding of the pathophysiology of cardiac-ventricular failure and the pharmacophysiology of adrenergic receptors have greatly improved the short-term therapy of the low-output, hypotensive-hypoperfused, cardiac failure states. Agents are now specifically selected for these conditions on the basis of their predominant effects on the heart (positive inotropy) and the peripheral vasculature (vasodilatation or vasoconstriction). With the addition of dobutamine therapy, the pharmacophysiologic spectrum now includes norepinephrine (predominant vasopressor), dopamine (combined vasopressor-positive inotrope), dobutamine (predominant positive inotrope), and isoproterenol (combined positive inotrope-vasodilator). Digitalis was introduced to the medical profession 200 years ago. In terms of chronically administered positive inotropic therapy, to date, this "old-timer" has not been replaced. The yet experimental phosphodiesterase inhibitors, enoximone and milrinone, appear promising as long-term nonparenteral inotropes; however, the precise role, clinical effectiveness, and safety profile of these agents remain to be determined.
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PMID:General overview and update of positive inotropic therapy. 294 23

Treatment of heart failure comprises the use of diuretics, vasodilators and inotropic substances. Unloading of the heart and the circulation in hydropic states is classically achieved with diuretics. The retention of salt and water in chronic heart failure requires chronic treatment with diuretics. This mode of treatment is basic to all forms of hydropic heart failure. Inotropic substances such as digitalis glycosides, sympathomimetic amines or phosphodiesterase inhibitors have certain disadvantages: Inotropic stimulation increases energy demand of the working heart muscle. Most of the substances used today increase energy consumption inordinately, thereby decreasing economy of myocardial contraction. This aspect calls for caution in the application of these substances in chronic heart failure, although they seem indispensable (sympathomimetic amines) in acute hypotensive failure and shock. Digitalis glycosides, basically suited for longterm treatment, exert only mild inotropic effects. In addition inotropic stimulation brings with it arrhythmogenic effects. All inotropic substances can induce ventricular arrhythmias already at therapeutic levels. Vasodilating substances have found increasing acceptance as a particularly useful and safe group of drugs for the treatment of heart failure. Nitrates: With the different nitrate compounds and nitrate preparations an effective venodilation with preload reduction can safely be achieved. At higher doses, arteriolar also dilatation can be induced. Although tolerance may be a problem with chronic application, this can be avoided with prudent dosing. The strong venodilating property makes these drugs together with their rapid onset of action ideally suited for the treatment of acute heart failure with pulmonary congestion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Treatment of heart failure: status of therapy with vasodilator agents]. 343 15

The use of positive inotropic agents in the acute and chronic treatment of heart failure is associated with a variety of hemodynamic effects. The beneficial effects of these agents, however, are not without associated adverse effects. An increase in cardiac output is achieved through diverse pharmacologic mechanisms of action depending on the specific inotropic agent. Digitalis glycosides, beta-adrenergic agonists, and phosphodiesterase inhibitors are described.
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PMID:Pharmacologic management of heart failure: positive inotropic agents. 829 49

Congestive heart failure is a lethal condition that affects an increasing number of patients. In recent years a great amount of data have accumulated on the pathophysiology and medical and surgical therapy of this condition. In spite of the advances in its management and the great number of patients affected, common errors are still made by internists and cardiologists in the use of drugs and therapeutic strategies. Digitalis has only recently been shown to affect hemodynamics, exercise capacity, and clinical symptoms, but the effects on survival still have to be demonstrated. Loop diuretics, eventually combined with thiazides and antialdosterone drugs in patients with clinical signs and symptoms of fluid retention, are the mainstays of therapy of congestive heart failure. In order to make diuretic therapy efficacious, moderate salt and water intake restriction is mandatory. Angiotensin-converting enzyme (ACE) inhibitors are now considered unavoidable drugs in the management of heart failure, and an attempt to reach the doses that have been shown to be efficacious for survival in the large trials has to be made in every patient with this condition. Other vasodilators, such as hydralazine and nitrates, which show a less pronounced effect on survival but more effective hemodynamic actions than ACE inhibitors, may be used to control mitral insufficiency or to improve hemodynamics in very sick patients. Hemodynamic instability refractory to increasing doses of vasodilators and diuretics is a severe condition that requires hospital admission to administer drugs parenterally. These patients are usually treated with the combination of catecholamines and phosphodiesterase inhibitors associated with intravenous diuretics until clinical stability is again achieved and oral therapy is resumed and restructured. The use of aggressive pharmacological therapy and phosphodiesterase inhibitors has reduced the need for assisted circulatory support in these patients. Beta-blockers have shown promising results when administered to patients with heart failure, although a definitive demonstration of their effects on survival is still lacking. Other additional measures that need to be considered in patients with end-stage congestive heart failure are the use of antiarrhythmic drugs and anticoagulation.
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PMID:Medical treatment of end-stage heart failure. 911 55

Medical therapy for chronic heart failure has recently been extensively revised on the basis of a reduction of mortality in randomized trials. However, there are almost no available trials in children whose treatment for heart failure is adapted from what is known in adults. Digitalis play a role in heart rate variability but there is no evidence for an effect on mortality. Angiotensin-converting enzyme inhibitors lead to an improvement of left ventricular function and reduces mortality; in addition, they are well tolerated in children. Diuretics are useful in congestive heart failure but chronic administration may have deleterious effects. Beta-blocking agents reduce mortality and improve symptoms and the ejection fraction; however, they must be given cautiously and the up-titration phase must be very progressive. New promising drugs are emerging (calcium sensitizers, phosphodiesterase inhibitors, angiotensin receptor [AT1] blockers) but at the present time their use in chronic heart failure has not proven to be efficient.
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PMID:[Treatment of chronic heart failure in the child]. 1181 Oct 37

Cardiotonic drugs mainly include digitalis, catecholamines, phosphodiesterase inhibitors, and calcium sensitizers, which have been successively discovered and applied in clinical practice. However, there are only a few new drugs available in this field, and the selection is very limited. Digitalis, catecholamines, and phosphodiesterase inhibitors increase myocardial contractility by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca²⁺, and this increase in intracellular calcium ion concentration enhances myocardial oxygen consumption and causes arrhythmia. For these reasons, the research focus on positive inotropic agents has shifted from calcium mobilization to calcium sensitization. Intracellular calcium sensitizers are more effective and safer drugs because they do not increase the intracellular concentration of calcium ions. However, only three calcium sensitizers have been fully developed and used in the past three decades. One of these drugs, levosimendan, has multiple molecular targets and exerts its pharmacological effects by not only increasing myocardial contractility, but also enhancing respiratory muscle function and liver and kidney protection, and it is useful for patients with severe sepsis and septic shock. Recently, more than 60 randomized controlled clinical trials of levosimendan have been reported; however, these clinical trials have occasionally shown different findings. This article reviews the research progress of levosimendan in critical illnesses in recent years.
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PMID:Multiorgan Drug Action of Levosimendan in Critical Illnesses. 3164 70

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