Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with acute congestive heart failure generally present with profound fluid retention states and dyspnea due to pulmonary edema. If the condition is not aggressively and appropriately treated, irreversible cardiac decompensation may ensue, leading to cardiogenic shock, multiorgan failure, and death. Intravenous inotropic, vasopressor, and vasodilator therapies have proved effective in initial stabilization of acute heart failure decompensation, but these agents, particularly the traditionally used ones, are generally limited by side effects that can be egregious and include substantive ventricular arrhythmias. Dobutamine has largely replaced agents with rather profound toxicity, such as isoproterenol and epinephrine. The phosphodiesterase-inhibiting agent milrinone, having both vasodilator and inotropic properties, can produce tachycardia and significant ventricular arrhythmias, but has proven quite useful for seriously ill patients. Clinical trials of levosimendan have found a positive inotropic response when the drug is given parenterally; vasodilating properties are also evident. Clinical trials are under way to evaluate the potential benefits of endothelin receptor antagonists when given intravenously. Intravenous administration of nesiritide, a recombinant human B-type natriuretic peptide, has been shown to produce favorable hemodynamic effects, including balanced vasodilation associated with a rapid improvement in clinical symptoms.
 ...
PMID:New therapeutic choices in the management of acute congestive heart failure. 1243 58

Heart failure is characterized by sodium and fluid retention, sympathetic overactivity, parasympathetic withdrawal, vasoconstrictor activation and cytokine elevation. New therapies for heart failure attempt to control neurohormonal activation and limit progressive left ventricular dysfunction. Nesiritide (human B-type natriuretic peptide) is a recently approved new vasodilator that has been given to almost 1,000 patients in numerous clinical investigations; it belongs to a new class of heart failure drugs known as natriuretic peptides. Nesiritide decreases pulmonary capillary wedge pressure, systemic vascular resistance, mean right atrial pressure and pulmonary artery pressure, while improving cardiac index, stroke volume and heart failure symptoms. Many endothelin receptor antagonists are in various stages of development. Early clinical studies have demonstrated beneficial cardiovascular hemodynamic effects. Other new drugs for heart failure also include calcium sensitizers, neutral endopeptidase and vasopeptidase inhibitors, aldosterone receptor antagonists, vasopressin antagonists and cytokine inhibitors. All are being actively investigated and many show significant promise as beneficial therapies in the treatment of heart failure.
 ...
PMID:New therapies for the treatment of congestive heart failure. 1253 83

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.
 ...
PMID:[New expansion of endothelin research: perspectives for clinical application of endothelin-receptor antagonists]. 1261 54

Pharmacologic clinical trials in heart failure (HF) have provided substantial advances in effective treatment of this condition, moving us from our focus on short-term symptom relief to an expectation of substantial improvement in long-term clinical outcomes for our patients. Based on an appreciation of the importance of neurohormonal activation in the pathophysiology of HF, clinical trials have demonstrated the value of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers in impeding the progression of HF and in reducing morbidity and mortality for patients with this condition. Clinical trials have further demonstrated the benefits of digoxin in improving symptoms and reducing hospitalization frequency, as well as in aldosterone blockade, at least in patients with severe symptoms. Given the ethical imperative to treat with ACE inhibitors, the angiotensin receptor antagonists have been difficult to study; nevertheless, their value is becoming increasingly clear, particularly for patients intolerant of ACE inhibitors. Trials with several classes of newer agents-cytokine antagonists, endothelin receptor blockers, and vasopeptidase inhibitors-have recently yielded disappointing results. Early results with vasopressin receptor antagonists provide some promise of long-term benefit. Clinical trials have provided significant treatment advances; ongoing and future trials will demonstrate the degree to which we can improve on what we have achieved to date with pharmacologic treatments.
 ...
PMID:Improving clinical outcomes with drug treatment in heart failure: what have trials taught? 1267 Jun 37

In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical.
 ...
PMID:New developments in the pharmacological treatment of chronic heart failure. 1272 Apr 87

Tezosentan is an endothelin receptor antagonist in development by Actelion Ltd and Genentech Inc for the potential treatment of cardiovascular disorders, including acute heart failure (AHF) and congestive heart failure. Actelion has conducted a phase III study of tezosentan in AHF patients, however, following disappointing trial results a new phase III study in AHF was planned using lower doses of the compound. By January 2003, Actelion anticipated that the first results of a two-year phase III study evaluating mortality/morbidity would be available by early 2005.
 ...
PMID:Tezosentan. Actelion/Genentech. 1273 33

With recognition of the significant role of the endothelin system in cardiovascular and pulmonary vascular diseases, attention has turned to the therapeutic application of agents that antagonize this system. Three strategies can be employed: dual endothelin receptor (ETA and ETB) antagonism, selective ETA antagonism and inhibition of endothelin-converting enzymes. The first two strategies have been evaluated in late-phase clinical trials, with mixed results. The use of the dual endothelin receptor antagonist bosentan in pulmonary arterial hypertension has been successful. Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure. Both types of receptor antagonists, however, have been evaluated in systemic hypertension and chronic systolic heart failure and are unlikely to be further developed in these areas. For the treatment of hypertension, their (moderate) efficacy and safety/tolerability profiles appear no more favorable than existing antihypertensive agents. In terms of treatment for chronic heart failure, these agents appear to offer no further benefit over standard therapy for the treatment of chronic heart failure, and in fact, may be associated with poorer outcomes. The complexity of the endothelin system and its diverse roles in multiple disease states will ensure its position as a target for drug development.
 ...
PMID:Current status of endothelin blockade for the treatment of cardiovascular and pulmonary vascular disease. 1274 22

Selective endothelin receptor-A antagonists are a promising new treatment in patients with heart failure and/or pulmonary hypertension. Animal studies have suggested that these agents may have additional cardiac electrophysiologic actions, however, no data exist in man. We examined the effects of acute endothelin receptor-A blockade on the sinus node, the atrioventricular node and on the ventricular myocardium, in patients with single-vessel coronary artery disease and preserved left ventricular function. The selective endothelin receptor-A antagonist BQ-123 was administered by the intracoronary route, in order to achieve maximum local cardiac effects. After endothelin receptor-A blockade, QT interval increased from 373 +/- 30 msec (mean +/- SD) to 395 +/- 20 msec (p < 0.01) and QTc interval increased from 394 +/- 36 msec to 421 +/- 28 msec (p < 0.01). QT-dispersion, calculated from 12-lead ECG, decreased from 40 +/- 18 msec to 24 +/- 8 msec (p < 0.01) and QTc-dispersion decreased from 44 +/- 20 msec to 26 +/- 9 msec (p < 0.05). These changes were evident only after infusion in the left, but not in the right coronary artery. No effect was found on the sinus node, the atrioventricular node, or the ventricular effective refractory periods. We conclude that selective endothelin receptor A blockade lengthens ventricular repolarization and decreases its inhomogeneity. Further studies are needed to evaluate possible antiarrhythmic actions of this class of agent.
 ...
PMID:Electrophysiologic effects of endothelin receptor-A blockade in patients with coronary artery disease. 1281 2

Despite major advances in conventional medical therapy, patients with heart failure continue to experience significant morbidity and mortality. Endothelin-1 (ET-1) is a potent vasocontrictor and mitogenic peptide that is activated in heart failure. There is increasing experimental and clinical evidence in support of an important role of ET-1 in the pathophysiology of heart failure. Manipulation of the activity of ET-1, especially using endothelin receptor blockers, has allowed for the further elucidation of the role of this neurohormonal system and development of novel therapeutic strategies in heart failure. Published clinical studies of these agents to date have involved relatively small numbers of patients with severe heart failure, followed for a relatively short period of time, and have mainly examined surrogate endpoints. Large-scale trials that address to hard clinical outcomes are ongoing and their results forthcoming. A key question that remains concerns whether selective ETA or dual ETA-ETB receptor blockade will be more effective.
 ...
PMID:Role of endothelins in congestive heart failure. 1283 70

The effects of endothelin on the transient outward K(+) currents were compared between Kv1.4 and Kv4.3 channels in Xenopus oocytes expression system. Both transient outward K(+) currents were decreased by stimulation of endothelin receptor ET(A) coexpressed with the K(+) channels. Transient outward current of Kv1.4 was decreased by about 85% after 10(-8) M ET-1, while that of Kv4.3 was decreased by about 60%. By mutagenesis experiments we identified two phosphorylation sites of PKC and CaMKII in Kv1.4 responsible for the decrease in I(to) by ET-1. In Kv4.3 a PKC phosphorylation site was identified which is in part responsible for the decrease in I(to). Differences in the suppression of I(to) could be ascribed to the difference in intracellular signaling including the number of phosphorylation sites. These findings might give clues for the understanding of molecular mechanism of ventricular arrhythmias in heart failure, in which endothelin is involved in the pathogenesis.
 ...
PMID:Differential inhibition of transient outward currents of Kv1.4 and Kv4.3 by endothelin. 1452 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>