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)

In severe chronic heart failure, myocardial beta-adrenoceptors are downregulated and G-proteins inhibiting adenylate cyclase activity are augmented. Because of these biochemical changes, all positive inotropic drugs that need cAMP for their contractile effects lose their efficacy. Among the positive inotropic drugs used today for treatment of heart failure, only cardiac glycosides remain effective without development of tolerance as long as enough contractile myocardium is left. Controlled studies with phosphodiesterase III inhibitors (milrinone and enoximone) have revealed an unfavorable prognosis in these patients in comparison to placebo. Thus, these drugs are not indicated in chronic heart failure. In higher classes of chronic heart failure, therapy should always be a combination of diuretics, digitalis, and ACE-inhibitors.
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PMID:[Positive inotropic substances--therapeutic perspectives]. 179 36

Enoximone is a phosphodiesterase inhibitor, which has been studied extensively for use in the management of patients with moderate-to-severe heart failure. The authors have studied the absorption and disposition kinetics of enoximone and its primary metabolite, enoximone sulfoxide, after both single oral doses of enoximone and at steady-state after short-term chronic oral therapy. A total of ten patients (two female, eight male) with moderate-to-severe heart failure (NYHA class II-IV) were enrolled into the study after giving written informed consent. The plasma levels of enoximone sulfoxide were greater than those of enoximone at all sampling times. The peak enoximone sulfoxide plasma concentrations ranged from 3.5 to 17.3 times the peak enoximone plasma levels for individual patients. The average steady-state plasma concentrations for enoximone were 115 +/- 40 ng/mL and 190 +/- 78 ng/mL for 50 mg every 8 hours and 100 mg every 8 hours dosage regimens, respectively. The absorption and disposition kinetics of enoximone were found to be significantly variable between patients. The authors also evaluated the relationship between dose administered and steady-state plasma levels as well as the relationship between the observed and predicted steady-state plasma levels. The authors found a linear relationship between the dose that was administered and the accrued plasma levels, as well as a good correlation between the predicted and observed steady-state levels. Although these data confirm previous reports that the sulfide metabolite of enoximone accumulates extensively in the plasma during oral therapy, reaching levels much higher than those of enoximone, these data do not support previous suggestions that the disposition of enoximone is nonlinear.
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PMID:Disposition kinetics of orally administered enoximone in patients with moderate to severe heart failure. 183 16

In heart failure, many alterations occur in the ventricle as a whole, as well as in the myocardial cell. In the first part of this review we report on the macroscopic structure of the left ventricle by analysing the relation between left ventricular dilatation and left ventricular hypertrophy in terms of ventricular wall stress. Peak systolic stress in dilated ventricles of patients with compensated heart failure does not differ from values obtained in normal ventricles, whereas the systolic stress-time integral is increased by more than 40%. The stress-time integral is a major determinant of myocardial oxygen consumption, and its reduction by peripheral vasodilation leads to a proportional decrease in left ventricular oxygen consumption. In contrast, the phosphodiesterase inhibitor, enoximone, decreases the stress-time integral without a proportional decrease in myocardial oxygen consumption, due to the competition between positive inotropic effect with increased oxygen consumption and a vasodilating effect with decreased oxygen consumption. Beta-1 adrenoceptor agonists increase myocardial oxygen consumption. In the second part of this review we report on the functional alterations of the following subcellular and molecular structures in the failing myocardium: (1) adrenoceptors and G-proteins; (2) sarcoplasmic reticulum with an altered force-frequency relationship; (3) the acto-myosin system with decreased velocity of shortening and increased economy of force generation. On the basis of these alterations, a disadvantageous chain of events develops in the failing myocardial cell.
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PMID:The heart in heart failure. Ventricular and myocardial alterations. 183 95

The efficacy of enoximone (EN), a new phosphodiesterase inhibitor, was studied in 24 patients (pts.) with end-stage cardiac disease due to dilative cardiomyopathy (21 pts.) or coronary heart disease (3 pts.). All pts. admitted for urgent transplantation or mechanical circulatory support demonstrated advanced cardiac failure unresponsive to conventional pharmacotherapy. Despite maximal catecholamine and vasodilator therapy the cardiac index averaged 2.08 l/min per m2, the pulmonary capillary wedge pressure (PCWP) 24 mmHg, and the systemic vascular resistance (SVR) 1450 dyn* s* cm-5. In addition to the previous sympathomimetic medication EN was administered as a bolus injection of 1 mg/kg followed by a continuous infusion of 4 to 10 micrograms/kg/min. In all but 4 non-responding pts., who eventually died, clinical and hemodynamic conditions improved significantly within 4 h: CI increased from 2.08 to 3.1 l/min/m2, PCWP dropped from 24 to 17 mmHg, and SVR decreased from 1450 to 950 dyn* s* cm-5 (all p less than 0.05). After initial improvement, 9 pts. experienced acute hemodynamic and clinical deterioration leading to implantation of a biventricular-assist device (Berlin Heart) in 6 pts., while 3 pts. died of irreversible cardiogenic shock. However, of the remaining 15 pts., who demonstrated sustained hemodynamic improvement, 11 could be weaned off their adrenergic medication and remained on oral EN (1.0 to 1.5 mg/kg TID). Three pts. received heart transplants within 8 to 12 weeks; 7 pts. were still on the waiting list at the end of the study, and 1 pt. died after withdrawal of oral EN.2
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PMID:[Enoximone as pharmacologic "bridging" to heart transplantation]. 183 94

The comparison of two invasive studies using intravenous application of the phosphodiesterase enoximone demonstrated unchanged cardiac output in patients with dilated cardiomyopathy NYHA II-III, and increased cardiac output (from 3.22 +/- 1.15 to 5.04 +/- 2.05 l/min; p less than 0.01) in acute heart failure. This comparison of hemodynamic parameters in addition to studies on myocardial oxygen consumption support the use of intravenous enoximone in acute heart failure, whereas the long-term application of enoximone in chronic heart failure is judged to be critical.
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PMID:[Vasodilatation and positive inotropic effect of the phosphodiesterase inhibitor enoximone]. 183 95

Enoximone, a new phosphodiesterase-inhibitor with positive inotropic and vasodilating activities is available for intravenous use in patients with severe heart failure. A review of the current knowledge regarding the adverse effects of this substance reveals that they are characterized by cardiovascular, central nervous, and gastrointestinal side effects. Adverse effects occurred in 20% of patients and were mostly due to the pharmacological properties of enoximone. Cardiovascular side effects (10%) were the most frequent; ventricular and supraventricular arrhythmias were most common. Two to three percent of the patients experienced hypotension due to the vasodilator activity of enoximone. Headache, insomnia, and anxiety were the most frequent adverse effects on the central nervous system. Three percent of the patients treated experienced vomiting, nausea, abdominal pain, and diarrhea. An increase of liver enzymes and serum glucose could be observed, mostly in patients with previous liver disease or diabetes. Pharmacokinetic drug interactions are not known; possible pharmacodynamic interactions result from the pharmacological properties of the drugs. Intravenous therapy with enoximone causes a few serious side effects that can only be controlled by careful observation of the patients treated.
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PMID:[Tolerance of enoximone in patients with heart failure]. 183 4

Since the discovery of cyclic nucleotide phosphodiesterase 30 years ago, there have been major advances in our knowledge of this group of isoenzymes. Five families, each composed of several isoforms and having differing tissue distributions, have been described. David Nicholson and colleagues compare the tissue distribution of phosphodiesterase isoenzymes and discuss the differential effects of inhibition of particular isoenzymes, with differing subcellular localization, on tissue function. They also review the potential use of isoenzyme selective phosphodiesterase inhibitors in a range of clinical disorders such as heart failure, asthma, depression and dementia.
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PMID:Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. 184 33

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate--catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.
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PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 185 89

Congestive heart failure is an increasingly common patient problem. It is a multisystem disease that involves not only the heart but also the kidneys and neurohormonal systems. Any treatment for heart failure should address depressed contractility and exercise intolerance, as well as control compensatory mechanisms. There are many different approaches to the treatment of congestive heart failure: among the drugs used are diuretics, digitalis compounds, nitrates, calcium channel blockers, beta-blockers, beta-agonists, vasodilators, angiotensin-converting enzyme (ACE) inhibitors and the new phosphodiesterase inhibitors. The therapy usually involves a multiple drug treatment plan to achieve the maximum effect for the patient with the lowest incidence of side effects. Heart failure involves a large spectrum of patients with left ventricular dysfunction, and success at achieving treatment goals with these patients will vary with the severity of that symptom. A major concern is that increasing contractility may further damage the myocardium and shorten the survival of these patients, although there is as yet no evidence of such shortening. The new phosphodiesterase inhibitor drugs are an exciting development in the treatment of heart failure, because they add a dimension to the treatment for patients who are not sufficiently improved by a regimen of digoxin, diuretics and ACE inhibitors. Any new heart failure medication should be able to improve rest and exercise haemodynamics, maintain its benefits when given orally and result in an improved exercise capacity and quality of life, and prolonged survival.
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PMID:Risks and benefits of the treatment of heart failure. Current status. 188 43

A model of heart failure produced by rapid ventricular pacing in the conscious dog instrumented with a conductance catheter to monitor instantaneous left ventricular volume has been developed. This experimental model is capable of analysis of the left ventricular pressure-volume relationship on a beat-to-beat basis, and has been used to assess ventricular function serially in the progress of heart failure and effects of pharmacological intervention. In seven dogs the magnitude of cardiotonic effects were significantly attenuated after development of heart failure. These findings support the concept that in the failing heart there is subsensitivity to beta-adrenergic stimulation in proportion to the severity. The failing heart was characterized by incomplete left ventricular relaxation. Dobutamine improved left ventricular early relaxation but did not affect chamber distensibility. In contrast new phosphodiesterase inhibitor, E-1020, improved ventricular distensibility with less marked changes in active relaxation; improved left ventricular relaxation appeared to be mediated by increased systolic shortening with enhancement of internal restoring forces, and improved distensibility by accelerated function of sarcoplasmic reticulum through increased intracellular cyclic AMP.
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PMID:Mechanics of contraction and relaxation of the ventricle in experimental heart failure produced by rapid ventricular pacing in the conscious dog. 191 38


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