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: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current heart failure therapy has included both stimulation and inhibition of beta-adrenergic receptors. Full beta-agonists have not been clinically effective because of side effects or loss of efficacy over the long term. Full beta-antagonists are effective in selected patients but are not tolerated in others because of cardiac depression. Partial beta-antagonists (beta-blockers with weak intrinsic sympathomimetic activity) do not possess sufficient agonist activity to counteract their own cardiac depressant action. Partial beta-agonists produce mild beta-antagonism, but not enough to offset their overall cardiac stimulating property. The partial beta-agonists have been clinically effective in some patients with heart failure and appear to be a potentially useful and unique class of agents because of their ability to modulate cardiac beta-receptors in such a way as to avoid an excessive response to endogenous or exogenous stimuli.
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PMID:Beta-receptor-active agents: role of partial agonists in patients with heart failure. 247 9

Recent advances in our knowledge of heart failure have shown that both a central and a peripheral factor are involved in this syndrome. Therefore, the ideal drug should combine the properties of a positive inotropic agent with those of a peripheral vasodilator; many drugs recently introduced into clinical practice have been shown to present both of these features, and the term "inodilators" has been used to characterize them. Inodilators can be further classified on the basis of their mechanism of action, i.e., phosphodiesterase inhibitors, and sympathomimetic and dopaminergic drugs. Phosphodiesterase inhibitors include bipyridine, imidazolone, and benzimidazole derivatives, which present potent inotropic and vasodilatatory actions. Despite their favorable acute effects, long-term studies have often yielded controversial, and sometimes disappointing, results as their chronic administration seems often to be associated with untoward effects and, above all, a poor prognosis. Sympathomimetic agonists act by stimulation of beta-receptors, with a consequent increase of myocardial contractility and peripheral vasodilation. Differently from the parenteral drugs (e.g., dobutamine), the oral agents present many important shortcomings including central nervous system effects, increased myocardial oxygen consumption, tachyarrhythmias, and, above all, development of tolerance during chronic administration. Dopaminergic drugs possess a unique pharmacologic profile since they add to the adrenergic stimulation their selective action on dopaminergic receptors. Dopamine is still one of the most useful drugs for the treatment of acute heart failure; the two oral drugs that more closely resemble its actions are levodopa and ibopamine. The administration of levodopa to patients with heart failure can induce a significant hemodynamic improvement that is maintained during chronic therapy. Ibopamine has been widely shown to cause a significant hemodynamic improvement in patients with heart failure. Its effects can be ascribed to a moderate increase of myocardial contractility accompanied by peripheral and renal vasodilatatory actions. This drug can also counteract some of the neurohumoral mechanisms (e.g., sympathetic stimulation and aldosterone secretion) that are activated in heart failure. These features can explain the favorable results that have also been recently obtained after the chronic administration of ibopamine.
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PMID:Clinical pharmacology of inodilators. 248 42

From September 1985 to August 1988, 32 patients were referred from various intensive care units throughout Paris for urgent cardiac transplantation or for a mechanical bridge to transplantation. At time of admission, under maximal sympathomimetic therapy, the cardiac index (CI) was 1.81 +/- 0.26 l/min per m2, the pulmonary capillary wedge pressure (PCWP 31 +/- 7 mmHg), systemic vascular resistances (SVR) 2053 +/- 469 dynes s cm-5. In 25, diuresis was less than 25 ml/h. Five were anuric. Prior to any final decision, a new inotropic agent, enoximone, was infused in addition to previous treatment as a 10 min bolus iv 1.5-2 mg/kg every 8 h. In 3, the situation further deteriorated, leading to a Jarvik 7-70 implantation within 12 h. In 29 however, within 3 h, the Cl increased to 2.69 +/- 0.56 as SVR dropped to 1410 +/- 453 and PCWP to 18 +/- 7. Diuresis increased to more than 100 ml/h in all. This permitted an indepth evaluation of the transplant candidates leading to contraindications to transplantation in 16. Nine patients could be weaned off iv enoximone. Four of these are still living (NYHA class III) with a follow up of 6-17 months. In 11, transplantation was performed within 2 days. Four died within a month, 2 with multiple organ failure. One patient died after 5 months. Six are back to normal life, NYHA class I (follow up 10 months-2.5 years). This protocol suggests that in patients with extreme heart failure, immediate survival may be increased by iv enoximone therapy, permitting a better selection of the recipients, more efficient pre-transplantation intensive care and consequently a decrease in the indications for a temporary mechanical bridge to a staged transplantation.
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PMID:Pharmacological bridge to cardiac transplantation. 253 76

Beta-adrenergic sympathomimetic agents such as dobutamine and dopamine, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoxamone, exert a direct positive inotropic effect upon the myocardium by causing an increase in cyclic AMP levels. The phosphodiesterase inhibitors also exert a substantial direct vasodilator effect. Both the sympathomimetic agents and the phosphodiesterase inhibitors can be of value in the acute, short-term management of myocardial failure. At present, the use of these agents for long-term therapy of congestive heart failure is unproven, and remains investigational.
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PMID:Positive inotropic/vasodilator agents. 256 61

1. A bicycle exercise test was used to investigate functional capability and haemodynamics in 30 patients with heart failure (13 NYHA Class II, 17 Class III), before and after i.v. xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) 0.2 mg kg-1. 2. Resting heart rate fell from 78 to 74 beats min-1 (P less than 0.05) and cardiac index rose from 2.5 to 2.8 l min-1 m-2 (P less than 0.001) after xamoterol. Blood pressure fell slightly, and systemic vascular resistance was reduced. Stroke work index improved and double product decreased. There were no changes in pulmonary artery wedge pressure ejection fraction or plasma noradrenaline concentrations. 3. On exercise, xamoterol produced a considerable reduction in heart rate increase, improved stroke volume and left ventricular stroke index and lowered double product. Exercise duration increased by 10%, but this did not quite achieve statistical significance. 4. These results are consistent with the concept that a beta 1-partial adrenoceptor agonist with the level of intrinsic sympathomimetic activity (43%) of xamoterol provides moderate inotropic support at rest, and protects the heart against overstimulation on exercise, when sympathetic drive is high. 5. Reduction of double product on exercise implies a lowered oxygen demand, which could be of considerable importance in patients with ischaemic heart disease.
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PMID:Effects of xamoterol on resting and exercise haemodynamics in patients with chronic heart failure. 257 50

Impaired left ventricular diastolic dysfunction is common in patients with ischaemic heart failure. The beta 1-adrenoceptor partial agonist xamoterol was compared with pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity, in a haemodynamic study in 17 patients with ischaemic heart disease. Pindolol caused left ventricular end-diastolic pressure, wall stress and T1 to rise, whereas xamoterol produced improvements in all three parameters. These results suggest that xamoterol may be of greater benefit to patients in heart failure.
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PMID:Contrasting effects of single doses of pindolol and xamoterol on left ventricular diastolic function. 257 64

The left ventricular sensitivity to sympathomimetic amines was assessed in 47 patients with ischemic heart disease and varying degrees of left ventricular dysfunction. Patients were divided into 3 subgroups according to their basal ejection fraction (less than or equal to 35%, between 36 and 54%, and greater than or equal to 55%). After injection of a bolus of isoproterenol (2 micrograms), the isovolumic indexes of inotropic state increased significantly less in patients with an ejection fraction less than or equal to 35% than in other patients, but the heart rate changes and the acceleration in the rate of isovolumic pressure fall were comparable in all subgroups. The dose-response curves to cumulative doses of xamoterol, a beta 1-adrenoceptor partial agonist, confirmed that the magnitude of the inotropic response was reduced during beta 1-stimulation in patients with an ejection fraction less than or equal to 35% when compared with patients with a greater ejection fraction. However, the dose of xamoterol necessary to produce 50% of the maximal inotropic response was not increased in patients with an ejection fraction less than or equal to 35% (range, 1.5-5.2 micrograms/kg; median 2.5 vs. median values of 2.3 and 3.3 micrograms/kg in the other subgroups; NS), and there was no shift to the right of the dose-response curve. It is concluded that in moderate ischemic heart failure, the magnitude of the inotropic response to isoproterenol or xamoterol is reduced. The absence of shift to the right of the dose-response curve to a beta 1-partial agonist suggests that this alteration in myocardial performance is not primarily caused by a decrease in beta-adrenoceptor responsiveness.
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PMID:Left ventricular sensitivity to beta-adrenoceptor-stimulating drugs in patients with ischemic heart disease and varying degrees of ventricular dysfunction. 282 Jun 12

During 10 years of clinical use involving almost 3 million patient-years, acebutolol has become established as a remarkably safe and well-tolerated beta-blocking agent, effective in treating essential hypertension and cardiac arrhythmias. The existence of a long-lived active metabolite (diacetolol) confers a 24-hour duration of action, which permits effective use of a once-daily regimen, particularly for hypertension. Acebutolol has low lipid solubility and low protein binding; the former property reduces the risk of central side effects, and the latter means that displacement interactions with other drugs are unlikely. Because acebutolol and its metabolite normally have both renal and hepatic excretion pathways, an alternative pathway is available should either be compromised through disease. Acebutolol is cardioselective, and clinical use has borne out the low incidence of bronchospasm in patients with impaired lung function. The possession of intrinsic sympathomimetic activity (ISA) leads to only modest reductions in cardiac output, which in turn reduces the chance of excessive bradycardia and the likelihood of precipitating heart failure. A combination of selectivity and ISA may be responsible for the low incidence of tiredness and cold extremities observed with acebutolol compared with other beta blockers. The unique pharmacologic and pharmacokinetic profile of acebutolol confers several therapeutic advantages and may be responsible for the generally low level of side effects experienced in clinical use.
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PMID:Acebutolol: ten years of experience. 285 85

The ideal sympathomimetic derivative should possess the positive inotropic and relaxing effects of catecholamines whilst remaining free of their side-effects. Theoretically, such properties could be present in beta 1-adrenoceptor partial agonists. Xamoterol (ICI 118,587, Corwin; ISA 43 p. 100) seems to be the most promising beta 1 partial agonist. The aim of the study was to determine if the beneficial effects of Xamoterol were maintained during long term administration. Xamoterol (200 mg twice dialy) was administered to 14 patients with anterior myocardial infarction and moderate heart failure (class II-III NYHA). After 3 months' therapy, left ventricular function improved as indicated by reduction in left ventricular (LV) end-diastolic pressure (23 +/- 5 to 16 +/- 5 mm Hg; P less than 0.0005), LV end-diastolic volume (153 to 140 ml/m2; P less than 0.05) and in LV end-systolic volume especially in 11 patients with a control end-systolic volume less than 100 ml/m2 (- 15 p. 100; P less than 0.05). LV inotropic state was also enhanced as indicated by 21 p. 100 increases in EMax, the maximal LV pressure/volume ratio (P less than 0.02) and 20 p. 100 increases in the ratio end-systolic stress/ end-systolic volume (P less than 0.02). Myocardial oxygen consumption was unchanged, global lactate extraction fraction increased from 20 +/- 18 to 33 +/- 14 p. 100 (P less than 0.05) and LV alanine release was reduced (-1.7 to -0.2 muMol/min; P less than 0.05). The rate of LV pressure fall accelerated from 57 to 52 ms (P less than 0.05) and the mean diastolic wall stress was reduced by 35 p. 100 (P less than 0.05), reflecting the improvement in LV relaxation and diastolic function. Thus, the beneficial effects of Xamoterol were maintained after prolonged therapy particularly in patients with class II-III heart failure; patients in class IV benefited less from this therapy. No tachyphylaxis or side-effects were observed.
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PMID:[Role of adrenergic beta receptor partial agonists in left ventricular failure of ischemic origin. Value of xamoterol (ICI 118,587, Corwin)]. 286 23

A new cardioselective beta 1-adrenoceptor partial agonist, xamoterol, has been developed for the treatment of heart failure, especially that associated with ischemic heart disease. To investigate the hemodynamic effect of xamoterol in relation to sympathetic nervous activity, hemodynamic variables and plasma norepinephrine (NE) levels were measured at rest and during three graded bicycle exercise tests before and after a single intravenous dose of 0.15 mg/kg xamoterol in 10 patients with mild-to-moderate left ventricular dysfunction. Plasma NE increased with increasing grade of exercise and a linear correlation between plasma NE and heart rate was observed at four time points (at rest and three exercise levels) before and after xamoterol. After administration of xamoterol, the slope of the regression line of plasma NE-heart rate relation was significantly less steep than that before drug. Predose and postdose regression lines crossed at 440 pg/ml of plasma NE. Similar effects were observed on the plasma NE-cardiac index and plasma NE-systolic blood pressure relations (regression lines crossed at 380 and 530 pg/ml of plasma NE, respectively). Thus, xamoterol had a dual agonist-antagonist effect in relation to plasma NE, and the crossover point lay approximately between 400 pg/ml and 500 pg/ml. This level of plasma NE was achieved at a low exercise level and at a heart rate of about 100 beats/min. These results indicate that xamoterol has intrinsic sympathomimetic activity comparable to relatively low sympathetic activity (400 to 500 pg/ml of plasma NE) and therefore acts as a beta 1-agonist when sympathetic nervous activity is below this level and as an antagonist when sympathetic activity is above this level.
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PMID:Hemodynamic effects of the beta 1-adrenoceptor partial agonist xamoterol in relation to plasma norepinephrine levels during exercise in patients with left ventricular dysfunction. 287 42


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