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 the treatment of heart failure-also in the aged-digitalis preparations remain indispensable. At the present time, in particular in combination with diuretics and ACE inhibitors, they are experiencing a revival in the treatment of severe stages (NYHA stages III and IV). In addition, a spectrum of newly developed positive inotropic substances of various classes is now available. Among the catecholamines, apart from dopamine, dobutamine and their derivatives, new drugs with a beta-adrenergic agonistic effect are presently undergoing clinical testing. Another heterogeneous group of substances combine positive inotropic with vasodilatory properties. In this connection, mention might be made of the phosphodiesterase inhibitors, the H2 receptor antagonists, and certain catecholamine derivatives. However, digitalis remains the only substance that can be given orally over the long-term without tolerance developing. Particular aspects of the use of digitalis in geriatric patients are discussed.
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PMID:[Positive inotropic substances. Possible use in heart failure in the aged]. 193 36

To assess hemodynamic and energetic effects of different drug interventions on idiopathic dilated cardiomyopathy (IDCM), we determined hemodynamic variables of myocardial oxygen consumption (MVO2) in 37 patients with IDCM. Hemodynamics were measured during routine left and right heart catheterization. MVO2 was analyzed from myocardial blood flow (measured by the argon method) and aortocoronary sinus blood oxygen difference. The hemodynamic variable which correlated best with MVO2 was shown to be the systolic stress time integral (STI). Four different representative compounds were tested with respect to their acute effects on myocardial energetics (MVO2/STI) in patients with IDCM who were in compensated heart failure (NYHA class II-III). The drug interventions were performed at rest. Intravenous injection of the vasodilator nitroprusside yielded a 35% reduction in STI and a 30% reduction in MVO2; in other words, the ratio MVO2/STI was not altered. Injection of the calcium sensitizer and phosphodiesterase inhibitor pimobendan also did not alter this ratio, as both STI (36%) and MVO2 (33%) were lowered. The profound reduction in STI (60%) seen with the phosphodiesterase inhibitor enoximone was accompanied by a much smaller decrease in MVO2 (19%); therefore, the ratio of MVO2/STI increased significantly. An increase of this ratio was also seen with the partial beta-1 receptor agonist xamoterol. However, in this case STI did not change, whereas MVO2 increased by 26%. In summary, vasodilation has energy-saving effects, whereas positive inotropism is an energy-consuming process. We conclude that the overall effect on myocardial energetics of a drug which possesses both positive inotropic and vasodilating properties depends on the balance of the two properties.
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PMID:Myocardial energetics in dilated cardiomyopathy. 197 66

Cardiac muscle cell hypertrophy, hyperplasia of connective tissue, abnormal peripheral circulation and metabolic changes in the cardiac fibre and in the smooth muscle cell as a consequence of mechanic overload are described in variable proportions in heart failure. These changes in turn are essential factors for progression of the disease. Results of early drug intervention in patients with few or no symptoms suggest that decrease of mechanic overload by vasodilator therapy slows down the progression of the disease. In late stages, treatment with diuretics and vasodilators improves the symptoms and the outcome of heart failure. Diuretics alone and inotropic positive substances bring about some improvement of symptoms and maximal oxygen consumption, but they have no favourable effect on the outcome. Positive inotropic substances remain restricted to late forms of heart failure, in which they seem to ameliorate symptoms but have a rather unfavourable effect on the outcome. The role of diuretics, ACE inhibitors and digoxin is well defined. This is not the case for newer calcium-channel blockers from the dihydropyridine group, of beta blockers, of phosphodiesterase inhibitors and of substances with partial beta agonist and partial beta blocking activity. These drugs must still be classified as experimental agents for the treatment of heart failure.
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PMID:[Current problems of pharmacotherapy--heart failure]. 197 5

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs]. 197 43

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute positive inotropic intervention: the phosphodiesterase inhibitors. 203 20

The myocardial effects of milrinone are mediated through inhibition of myocardial phosphodiesterase III. This inhibition results in accumulation of cyclic adenosine monophosphate and consequently increased calcium influx through voltage-dependent channels. The vascular effects also result from increased cyclic adenosine monophosphate. Direct coronary artery infusion of milrinone causes a concentration-related increase in left ventricular +dP/dt and substantial improvement in pump function as indicated by increased stroke work at lower left ventricular end-diastolic pressures. Subsequent intravenous administration of milrinone produces additional hemodynamic improvement, which is associated with a further reduction in systemic vascular resistance and left and right heart filling pressures. There is also a downward displacement of the left ventricular pressure-volume curve and acceleration of isovolumic relaxation, findings which indicate improved diastolic filling and accelerated isovolumic myocardial relaxation, respectively. The former action may reflect unloading of the right ventricle, whereas the latter may be due to improved calcium reuptake in the myocardium. Myocardial oxygen demand is unaltered because peripheral vasodilatation reduces wall stress and counteracts the increased oxygen requirement necessary to support enhanced contractility. This therapeutic profile differs from that of inotropic agents such as dobutamine and vasodilators such as nitroprusside, and contributes significantly to the usefulness of phosphodiesterase III inhibitors such as milrinone in the short-term management of patients with heart failure.
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PMID:Cardiovascular effects of milrinone. 203 24

Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs, we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure, the calcium channel blocker, felodipine, causes a marked reduction in systemic vascular resistance and left ventricular filling pressures, but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril, but venous volume increases by 16%, and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor, it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment, cardiac index, which was measured by thermodilution, increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of venous tone in heart failure. 203 25

The addition of enoximone, a phosphodiesterase inhibitor, to adrenergic agents has been found useful in increasing cardiac output in severe heart failure. In one study of 13 patients in cardiogenic shock already receiving adrenergic support, enoximone was administered as a bolus of 0.5 mg/kg over 20 minutes. Pulmonary artery occlusion pressure decreased significantly from 21.7 +/- 5.8 mm Hg to 19.8 +/- 6.0 mm Hg (P less than 0.01) and cardiac index increased markedly. A second study investigated the effects of the addition of small boluses of enoximone to adrenergic agents in low flow states associated with heart failure (n = 8) or postoperative states after cardiac surgery (n = 10). Each of the 18 patients was treated with dobutamine; 12 patients were also treated with dopamine and 4 with noradrenaline. Enoximone was administered as small but increasing intravenous boluses. No significant change in mean arterial pressure was observed, but on 0.5 mg/kg of enoximone pulmonary artery occlusion pressure decreased significantly from 24.6 +/- 8.7 mm Hg to 19.4 +/- 9.9 mm Hg (heart failure) and from 18.2 +/- 3.3 mm Hg to 15.3 +/- 3.8 mm Hg (cardiac surgery) after the initial dose of 0.125 mg/kg. Cardiac index increased markedly after enoximone, 0.25 mg/kg. These changes were significant after the initial dose of 0.125 mg/kg. Thus, the addition of even small doses of enoximone to adrenergic agents can markedly increase cardiac index without significant effect on arterial pressure in medical or surgical cardiac patients.
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PMID:Addition of phosphodiesterase inhibitors to adrenergic agents in acutely ill patients. 214 39

Cardiac transplantation is theoretically the optimal final treatment of terminal cardiac failure but the indications, especially in the emergency situation, should be carefully considered. Sympathomimetic agents are of limited use in patients with severe cardiac failure partly because of the down regulation of the myocardial beta-receptors. The phosphodiesterase inhibitors, represented by enoximone, are valuable because of their action on the cardiac muscle (inotropic and lusitropic) and their direct systemic vasodilator effect. Enoximone can be administered by intravenous bolus resulting in a rapid onset of action (peak at 30 minutes) with a prolonged effect due to its hepatic metabolites. The authors' experience in this indication dates over 5 years and over 50 patients were included. A preliminary study in 34 patients with cardiac failure resistant to betamimetic drugs, referred to the intensive care unit for urgent cardiac transplantation, or, in the absence of a donor, circulatory assistance is reported. A Swan Ganz catheter and radial artery canula were inserted for haemodynamic monitoring and enoximone was administered in an intravenous bolus over 15 minutes every 8 hours in addition to sympathomimetic agents. A haemodynamic improvement was observed after the 30th minute in 30 patients. The cardiac index increased from 1.82 to 2.67 l/mn/m2 and the pulmonary capillary pressures decreased from 30.8 to 18.9 mmHg. Systemic arterial resistances fell from 2,170 to 1,520 dynes.s.cm-5. No haemodynamic improvement was observed in 4 patients who were treated by mechanical ventricular assistance. After investigations to detect contra-indications to cardiac transplantation, 12 of the 30 patients remained candidates for cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Medical strategy in patients awaiting emergency heart transplantation]. 214 25

Enoximone, a phosphodiesterase inhibitor, is a positive inotropic agent with direct vasodilator properties. Its acute effects after I.V. administration and the possibility of oral relay were studied in 14 patients (13 men and 1 woman), 40 to 78 years of age (mean 61 years) with Stage IV cardiac failure (NYHA Classification). Eleven patients had dilated cardiomyopathy, 2 had ischemic heart disease and 1 a dilated hypertrophic cardiomyopathy. The haemodynamic inclusion criteria were: cardiac index less than or equal to 2.2 l/mn/m2 and pulmonary capillary pressure greater than or equal to 18 mmHg. Patients with cardiogenic shock and severe renal or hepatic failure were excluded. The drug was administered as a bolus of 1 mg/kg followed by a continuous infusion of 5 to 15 g/kg/mn (average 8.9 +/- 2.6 for 7 to 72 hours; average 27 +/- 16 hours). Haemodynamic effects of I.V. administration: no change in heart rate, slight lowering of blood pressure, very significant reduction in right atrial and pulmonary capillary pressures, of pulmonary artery pressures, of arteriolo-capillary and systemic resistances and marked increase in cardiac output. General tolerance was excellent with no clinical secondary effects and no signs of hepatic, renal or haematological (platelets) toxicity. Cardiac tolerance was also excellent, no aggravation of preexisting arrhythmias. There was no immediate mortality. Oral relay was undertaken in 14 patients with a daily dose of 300 mg in 12 cases, 400 mg in 1 case and 500 mg in 1 case. Six patients underwent control haemodynamic evaluation on the 8th day: there were no signs of the haemodynamic improvement obtained by I.V. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Enoximone: hemodynamic effect in patients with cardiac insufficiency]. 214 30


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