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)

It has been clearly established that ischemic heart disease, hypertension and ageing affect diastolic function before any change is observed in contractile function. Though an increasingly recognised clinical entity, cardiac failure with normal systolic function still does not have any specific treatment. Phosphodiesterase inhibitors which increase AMPc, in addition to their inotropic and vasodilator effects, accelerate relaxation. Major and isolated abnormalities of relaxation have been demonstrated in vitro in non necrosed tissues of both the dilated and hypertrophic forms of advanced cardiomyopathy. The myocardium seems unable to restore rapidly the low cytosolic calcium concentrations required for the deactivation of the contractile proteins. The underlying mechanisms are probably very complex but a deficit in AMPc production has been demonstrated in very advanced stages of cardiomyopathy. In ischemia, however, the abnormalities of relaxation seem to be directly related to a defect in free energy production inhibiting the sarcoplasmic reticulum calcium pump. If abnormalities of relaxation due to ischemia and those due essentially to a passive mechanism are excluded, phosphodiesterase inhibitors would seem to have pharmacological effects likely to improve diastolic function. Clinical studies confirm the beneficial effects of Milrinone and Enoximone on relaxation and the rapid phase of diastolic filling, both in acute and chronic studies. However, it has not yet been clearly established whether improved diastolic function is due to a direct action on the myocardium or an indirect action due to improved conditions of load. In order to determine the specific effects of phosphodiesterase inhibitors on diastolic function, further research is required.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

Several large, carefully randomized studies of pharmaceutical agents in the treatment of patients with congestive heart failure (CHF) and left ventricular dysfunction have demonstrated conclusively that angiotensin-converting enzyme (ACE) inhibitors reduce mortality among patients with CHF, as well as the number of hospitalizations for heart failure, myocardial infarction (MI), and angina. ACE inhibitors also have been shown to prevent the development of heart failure in patients with asymptomatic left ventricular dysfunction. Phosphodiesterase inhibitors and the beta agonists have been shown to increase mortality with no beneficial effect on morbidity. The role of digitalis remains controversial. On the one hand, the limited data available suggest that digoxin prevents clinical deterioration in patients with heart failure, even in the presence of sinus rhythm. On the other hand, when administered after MI, digoxin has been associated with increased mortality. Such conclusions are unreliable, however, since it is impossible to adjust statistically for the fact that digoxin is used in sicker patients. This question will be addressed in a large randomized study currently being conducted by the Digitalis Investigation Group. Pharmacologic approaches to the reduction of sudden death currently being explored include amiodarone, oral magnesium supplements, and beta blockers. According to the Cardiac Arrhythmia Suppression Trial and other studies, the class I antiarrhythmic agents appear unpromising or even harmful. The calcium channel blockers also appear to be contraindicated as routine therapy for CHF.
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PMID:Clinical experience in protecting the failing heart. 850 87

Low heart stroke volume syndrome is clinically manifested with hypoperfusion of all body systems. Inotropic or mechanical support is applied. Acute heart failure is one of the most important complications after open heart surgery. Catecholamines have been up to non considered as a therapy of choice for the acute heart failure. Effectiveness of catecholamines could be limited with some side effects. Phosphodiesterase inhibitors promise a new therapeutic approach. PDE III primary act through phosphodiesterase inhibition which leads to a rise of aAPM levels. Thus they show positive inotropic and lusitropic effects, which could be monitored by occlusive pulmonary capillary pressure values. Amrinone is obviously superior to inotropic catecholamines.
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PMID:[Hemodynamic effects of amrinone, dobutamine and dopamine in the cardiac low output syndrome following open-heart surgery]. 864 47

Considerable progress has been made in the medical treatment of chronic heart failure. A large number of patients with NYHA class II and III heart disease can be improved to class I and II. Treatment is maintained on an outpatient basis in order to prevent episodes of acute failure, while avoiding the adverse effects of drugs at high doses or in combination. Diuretics are still the drug class most frequently prescribed, especially loop diuretics (furosemide) which have the advantage of being able to be used in patients with renal failure. Aldosterone antagonists have the pathophysiological value of reducing the development of myocardial fibrosis. Digitalis alkaloids have a positive inotropic effect, which is even observed in the presence of sinus rhythm and which is associated with slowing of the heart rate in tachyarrhythmias. Angiotensin converting enzyme inhibitors are among the most recently used drugs. They decrease the left ventricular post-load and prevent activation of the renin-angiotensin-aldosterone system. Phosphodiesterase inhibitors cannot be administered orally in the long-term and are therefore not suitable for outpatient treatment. However, they are very effective by intravenous injection during the acute phase of heart failure and cardiogenic shock in hospital.
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PMID:[Ambulatory treatment of chronic cardiac insufficiency]. 866

Phosphodiesterase inhibitor (PDEI) has been accepted as an inodilator with positive inotoropic and vasodilating actions. Recently many new PDEIS have been available for the treatment of heart failure. We investigated the effect of a new PDEI-III agent, olprinone, on IL-6 and IL-10 production during and after coronary bypass graft surgery (CABG). Twelve patients scheduled for CABG were assigned to 2 groups. In 6 patients (Group-O), olprinone was administered continuously for 30 minutes at a rate of 0.3 micrograms.kg-1.min-1 (gamma) after the anesthesia induction. Then, the infusion rate of olprinone was decreased to 0.2 gamma and it was kept until the 3rd post-operative day. In another 6 patients (Group-C), phentolamine was used for vasodilator instead of olprinone. The plasma levels of IL-6 in Group-O did not show any significant change during perioperative period, whereas those in Group-C reached the peak at the end of extracorporeal circulation and did not recover to control level until the 3rd post-operative day. The plasma levels of IL-10 in Group-O increased to the maximum level at the end of extra-corporeal circulation and were significantly higher than those in Group-C. It is suggested that olprinone has not only inodilating action but also anti-inflammatory action at therapeutic concentrations used for heart failure.
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PMID:[Effects of olprinone on IL-6 and IL-10 production during and after cardiac surgery]. 945 80

Increased neurohormone and cytokine concentrations are associated with adverse outcome in patients with congestive heart failure, so minimizing these increases may improve outcome, even in the acute phase of decompensated heart failure. The present study was designed to test the hypothesis that phosphodiesterase inhibitors, but not catecholamines, could favorably affect neurohormone and cytokine profiles in patients with acutely decompensated heart failure. Twenty-nine patients underwent monitoring using a Swan-Ganz catheter and were randomly allocated to receive phosphodiesterase inhibitors (PDEI group, n=19) or catecholamines (CA group, n=10). Pulmonary capillary wedge pressure decreased significantly in both groups and cardiac output showed a slight, but not statistically significant increase, in both groups. There was a significant decrease in plasma brain natriuretic peptide concentration in the PDEI group, but not in the CA group, whereas plasma interleukin-6 concentration increased in the CA group, but not in the PDEI group. Phosphodiesterase inhibitors favorably affect neurohormone and cytokine concentrations in patients with acutely decompensated heart failure.
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PMID:Randomized trial of phosphodiesterase inhibitors versus catecholamines in patients with acutely decompensated heart failure. 1166 88

High-risk patients, during anesthesia and after surgery present changes in pharmacokinetics (biotransformation reactions, renal clearance, drug interactions, etc.) modifying the usefulness of most drugs, cardiac inotropics included. This group of substances is formed by adrenergic agents, phospodiesterase inhibitors and digitalis compounds. Adrenergic agents are the catecholamines, adrenaline (A), noradrenaline (NA) and dopamine (D), plus dopaminergic agonists as dobutamine and pirbuterol. Phosphodiesterase inhibitors, as amrinone and milrinone, produce their inotropic action by preserving cyclic adenosine monophosphate (AMPc) from its intracellular catabolism. Recent studies on the utility of digitalis compounds demonstrated the valuable applicability of digoxin in chronic and acute heart failure. Another group of substances whose mechanism of action differs from that of the inotropics, offers future utility in high risk patients, they include: inhibitors of nitric oxide sintases, natriuretic atrial peptide inhibitors, Q-10 coenzyme, endothelin antagonists, and anti-tumoral necrosis factor.
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PMID:[Pharmacology of inotropic agents]. 1200 37

To evaluate the influence of T-1032 (methyl2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate), a potent and relatively selective phosphodiesterase 5 inhibitor, on chronic heart failure, we examined the acute hemodynamic profile of T-1032 and its chronic effect on the survival of Bio 14.6 cardiomyopathic hamsters. In the acute study, T-1032 (1, 10, 100 microg/kg) was administered intravenously by means of a dose-escalating procedure in 55-week-old hamsters. T-1032 significantly reduced both the right and left ventricular end-diastolic pressure in a dose-dependent manner. T-1032 modestly reduced the systemic arterial pressure at the highest dose (100 microg/kg i.v.). T-1032 did not change the heart rate or left ventricular dp/dt(max). In the survival study, chronic administration of T-1032 (50 and 500 ppm in a diet) increased survival, and the survival rate was 24.2%, 45.4% and 48.5% in the control, 50 and 500 ppm-treated groups, respectively. The median survival was 55, 58 and 58 weeks in control, 50 and 500 ppm-treated groups, respectively. Analysis of the survival curves revealed that T-1032 (500 ppm) significantly increased the survival of these hamsters (P<0.05 vs. control). It was concluded that T-1032 had beneficial hemodynamic effects on heart failure in Bio 14.6 cardiomyopathic hamsters, and the favorable hemodynamic changes induced by T-1032 were partly related to the increase in the survival of these hamsters. Phosphodiesterase type 5 inhibitors may have therapeutic potential for the treatment of chronic heart failure.
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PMID:T-1032, a novel phosphodiesterase type 5 inhibitor, increases the survival of cardiomyopathic hamsters. 1204 7

Phosphodiesterase inhibitors such as milrinone can relieve symptoms and improve hemodynamics in patients with advanced congestive heart failure. We retrospectively evaluated the hemodynamic and clinical outcomes of long-term combination therapy with intravenous milrinone and oral beta-blockers in 65 patients with severe congestive heart failure (New York Heart Association class IV function and ejection fraction <25%) refractory to oral medical therapy. Fifty-one patients successfully began beta-blocker therapy while on intravenous milrinone. Oral medical therapy was maximized when possible. The mean duration of milrinone treatment in this combination-treatment group was 269 days (range, 14-1,026 days). Functional class improved from IV to II-III with milrinone therapy. Twenty-four such patients tolerated beta-blocker up-titration and were successfully weaned from milrinone. Sixteen patients (31%) died while receiving combination therapy; one died of sudden cardiac death (on treatment day 116); the other 15 died of progressive heart failure or other complications. Hospital admissions during the previous 6 months and admissions within 6 months after milrinone initiation stayed the same. Meanwhile, the total number of hospital days decreased from 450 to 380 (a 15.6% reduction), and the mean length of stay decreased by 1.4 days (a 14.7% reduction). We conclude that 1) milrinone plus beta-blocker combination therapy is an effective treatment for heart failure even with beta-blocker up-titration, 2) weaning from milrinone may be possible once medications are maximized, 3) patients' functional status improves on the combination regimen, and 4) treatment-related sudden death is relatively infrequent during the combination regimen.
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PMID:Intravenous milrinone in treatment of advanced congestive heart failure. 1280 51

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.
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PMID:Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. 1295 49


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