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)

Flosequinan (manoplax) is a new vasodilating agent for the treatment of congestive heart failure. Although it may have several mechanisms of action, whether it has effects on left ventricular inotropic or luisotropic events in hemodynamically relevant low doses when added to standard therapy for congestive heart failure is unknown. Ten patients with dilated congestive cardiomyopathy who were receiving standard therapy for heart failure were studied. A bipolar right atrial pacing catheter was used to maintain a constant heart rate. A 7F thermodilution catheter was used to measure right heart pressures and obtain cardiac outputs. An 8F micromanometer catheter was used to measure left ventricular and ascending aortic pressures. Gated equilibrium radionuclide angiography was performed both before and during a steady-state infusion of flosequinan. The average flosequinan infusion rate was 2.03 +/- 0.85 mg/min, and the total administered dose averaged 84 +/- 35 mg. The hemodynamic data documented substantial systemic vasodilation manifest by a reduction in right atrial pressure (p = 0.01), mean pulmonary artery pressure (p < 0.0001), pulmonary capillary wedge pressure (p < 0.0001), and left ventricular end-diastolic pressure (p < 0.0001). These hemodynamic changes were associated with increases in cardiac index (p = 0.01) and left ventricular ejection fraction (p = 0.02) and reductions in mean aortic pressure (p = 0.02), systemic vascular resistance (p = 0.01), and left ventricular volumes (p < 0.05). There was, however, no significant effect on left ventricular contractile function measured by end-systolic pressure-volume relationship (Emax), Emax corrected for the change in left ventricular volume, or preload recruitable stroke work (Msw). In contrast, there was an improvement in isovolumic relaxation manifest by an increase in maximum rate of fall of left ventricular pressure standardized for left ventricular end-systolic pressure [(-)dP/dtmin/Pes]; p = 0.02), an acceleration in the rate of isovolumic relaxation (p = 0.01), and an improvement in left ventricular chamber stiffness (p = 0.02). These data indicate that when flosequinan, a new therapeutic agent for the treatment of congestive heart failure, is administered in hemodynamically relevant low doses to patients with dilated congestive cardiomyopathy who were receiving standard therapy for heart failure, left ventricular pump function and diastolic function is further improved. There was, however, no significant effect on left ventricular contractility. This study emphasizes that new therapeutic agents like flosequinan, when administered in lower doses to avoid the potential deleterious effects of enhanced inotropy, may be useful additions to standard therapy in patients with congestive heart failure.
 ...
PMID:Effects of low-dose flosequinan on left ventricular systolic and diastolic chamber performance. 801 65

The efficacy of flosequinan 100 mg once daily was evaluated in 15 patients with severe congestive heart failure (New York Heart Association [NYHA] class II-IV) who had not responded adequately to digoxin and diuretics. Efficacy assessments using non-invasive techniques included exercise capacity, haemodynamics and left ventricular function. Determinations were made after 3 and 21 days' treatment, and compared with baseline. Flosequinan significantly increased exercise capacity by 27% after 3 days (+79 seconds, p = 0.015) and by 43% after 21 days (+123 seconds, p = 0.0007) and was accompanied by an increase in heart rate (+7.2 beats/min, p = 0.03; +9.1 beats/min, p = 0.03, respectively). Cardiac index and cardiac output were also significantly increased but only after 21 days' treatment (+0.3 l/min/m2, +16% and +0.5 l/min, +14%, respectively; both p = 0.008). Flosequinan was well tolerated, with headache being the most frequently reported adverse event and only 1 patient being withdrawn. One patient died but this was not unexpected in a group of patients with severe heart failure. Using non-invasive techniques this study demonstrated that in patients with severe chronic congestive heart failure, flosequinan increased exercise capacity and cardiac output, the latter being achieved mainly by an increase in heart rate.
 ...
PMID:A non-invasive evaluation of flosequinan on haemodynamics and exercise capacity in chronic congestive heart failure. 822 97

Congestive heart failure (CHF) causes disabling symptoms and increases the likelihood of decreased survival. Diuretics, direct vasodilators, and angiotensin-converting enzyme (ACE) inhibitors can be used to reduce symptoms, prolong life, or both, in these individuals. Diuretics induce sodium and water excretion, leading to decreased cardiac preload and wall tension, and an effective decrease of symptomatic pulmonary and systemic congestion. They have not yet been shown to prolong life in patients with CHF, however. Direct vasodilators, which induce venodilation, arterial dilation, or both (balanced vasodilators), may improve symptoms, and some but not all prolong life. Venodilators, such as nitrates, exert a venous pooling effect, decreasing cardiac preload and symptoms of congestion. Arterial dilators, such as hydralazine, decrease afterload and improve cardiac output. The combination of hydralazine and isosorbide dinitrate provides balanced vasodilation. It also improves survival, but is associated with a relatively high frequency of side effects necessitating discontinuation of one or both agents. The drugs are not approved by the Food and Drug Administration for the treatment of heart failure. Flosequinan, a new orally administered, long-acting, balanced arteriovenous dilator, improves exercise tolerance and symptoms. However, preliminary analysis of data from a large, multicenter trial revealed increased mortality and hospitalization for worsening CHF. The drug has recently been withdrawn from the market. The ACE inhibitors can cause hemodynamic and neurohormonal changes that lead to a reduction of preload and afterload, decreasing symptoms of heart failure. They significantly decrease CHF mortality, and might also deter the development of overt heart failure in some asymptomatic patients with left ventricular dysfunction.
 ...
PMID:Assessing the treatment of congestive heart failure: diuretics, vasodilators, and angiotensin-converting enzyme inhibitors. 823 97

The acute and long-term effects of the orally active vasodilator flosequinan were assessed in 10 patients with New York Heart Association class II to IV cardiac failure. Baseline hemodynamics, exercise capacity, left and right ventricular ejection fraction, and pulmonary transit time were measured by right cardiac catheterization, bicycle ergometer stress testing, and nuclear angiocardiography during a run-in period on placebo. Acute hemodynamic effects of flosequinan were monitored for 48 hours; the drug was then given as a single 100 mg daily dose for 6 weeks. Exercise capacity was reevaluated every 2 weeks, and right cardiac catheterization and nuclear angiocardiography were repeated at the end of the 6-week period. Placebo did not exert any effect. Flosequinan reduced right atrial, pulmonary artery, and pulmonary artery wedge pressures from 60 minutes to 48 hours after dosing. Heart rate was minimally increased. Cardiac index, mean systemic arterial pressure, and systemic and pulmonary vascular resistance were substantially unaffected. These effects were maintained after 6 weeks. Exercise capacity was enhanced after 2, 4, and 6 weeks. Left ventricular ejection fraction was unchanged, whereas right ventricular ejection fraction and pulmonary transit time were improved. In conclusion, flosequinan exerted a potent, long-lasting, venodilating effect that was maintained long-term, without evidence of tolerance.
 ...
PMID:Acute and long-term effects of flosequinan in patients with chronic cardiac failure. 832 57

The acute haemodynamic and neurohumoral effects of flosequinan, a new direct-acting vasodilator, were studied in 12 patients with severe (eight in New York Heart Association grade 3, four in grade 4) cardiac failure. Flosequinan was administered in a single oral dose of 100 mg, with haemodynamic monitoring over a 22 h period. The effects were compared with those observed during high dose intravenous nitroglycerin therapy (276 +/- 100 micrograms.min-1), given to the same patients for an identical period on the previous day. Both flosequinan and nitroglycerin produced significant haemodynamic improvement during the 22 h monitoring period. Cardiac and stroke indices increased with both drugs. However, while systemic and pulmonary vascular resistance were reduced similarly by both drugs, the decrease in right atrial and pulmonary capillary wedge pressures was greater with nitroglycerin and less with flosequinan, indicating a greater venodilator effect for nitroglycerin and a more balanced arterial and venodilator effect for flosequinan. Systemic arterial pressure and heart rate tended to increase with flosequinan and to decrease with nitroglycerin. In contrast to nitroglycerin, flosequinan did not increase plasma renin activity and serum aldosterone levels. Atrial natriuretic peptide decreased appropriately after both drugs, in keeping with the decreases in left and right heart filling pressures. The favourable haemodynamic and neurohumoral profiles of flosequinan suggest that it may be a useful vasodilating drug in the management of patients with severe heart failure.
 ...
PMID:Haemodynamic and neurohumoral effects of flosequinan in severe heart failure: similarities and differences compared with intravenous nitroglycerin therapy. 832 14

This study evaluated the effects of flosequinan on ventricular rate in patients with congestive heart failure and atrial fibrillation to determine whether this agent has a facilitatory effect on atrioventricular conduction and whether such an effect may be deleterious. Flosequinan is known to have a dose-dependent positive chronotropic effect on the sinus node, but its effect on atrioventricular conduction has not been evaluated. An excessive increase in ventricular rate during the treatment of heart failure could raise a safety concern and counterbalance beneficial responses. Data were analyzed from 338 patients participating in three similarly designed placebo-controlled exercise trials with flosequinan who also underwent ambulatory electrocardiographic monitoring. The effects of two doses of flosequinan on supine, standing, ambulatory, and exercise heart rates and on exercise capacity in patients in sinus rhythm and atrial fibrillation were compared. Flosequinan increased heart rate in a dose-dependent manner, in patients both with sinus rhythm and atrial fibrillation. A 100 mg once daily dose produced significant increases, in both rhythms, ranging from 6 to 11 beats/min, in supine and standing heart rate, ambulatory heart rate, and exercise heart rate. With a dose of 75 mg twice daily, heart rates under these conditions increased by >20 beats/min in flosequinan-treated patients in atrial fibrillation, a change significantly greater than that observed with placebo or flosequinan, 100 mg once daily and also more than in patients in sinus rhythm treated with the same dose. These results indicate that flosequinan facilitates atrioventricular nodal conduction, increasing the ventricular response in atrial fibrillation, especially at higher dosages. This finding could result from a direct drug action, such as phosphodiesterese inhibition, or reflex sympathetic activation. This response is of sufficient magnitude potentially to impair left ventricular function and interfere with clinical benefit. The effect of heart-failure drugs on ventricular responses in atrial fibrillation should be examined to provide insight into potential mechanisms of both action and safety in this common patient group.
 ...
PMID:Importance of assessing changes in ventricular response to atrial fibrillation during evaluation of new heart failure therapies: experience from trials of flosequinan. 870 55

Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohormonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 +/- 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 +/- 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of flosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenuated during long-term treatment, flosequinan induces sustained arterial dilatation and improves cardiac pump function without activation of circulating neurohormones.
 ...
PMID:Long-term vasodilator treatment with flosequinan does not lead to hemodynamic tolerance or neurohormonal activation in severe heart failure. 942 Jun 41

An arteriovenous vasodilator, flosequinan, has been shown to be effective for the treatment of acute heart failure. However, little is known as to its effect on aortic impedance, which is known to be a proper and precise expression of left ventricular (LV) afterload. To evaluate the acute cardiovascular effect of flosequinan in failing heart, we administered flosequinan intravenously to seven dogs with cardiac failure produced by an infusion of carbon powder (20-50 microm in diameter) into left main trunks of coronary artery. The LV-pump function was severely impaired after intracoronary injection of carbon powder, as evidenced by the findings that cardiac output, circumferential shortening velocity (mean Vcf), and peak +dP/dt of LV pressure were all decreased, associated with a significant increase in LV end-diastolic pressure. Flosequinan (0.9 mg/kg, i.v.) increased cardiac output by 28%, mean Vcf by 44%, and peak +dP/dt by 24%, whereas it decreased total systemic resistance by 32%, time constant of LV pressure decay by 22%, and LV end-diastolic pressure by 18%. Moreover, flosequinan substantially decreased the pulsatile components of LV afterload (i.e., characteristic impedance by 11% and arterial wave reflection coefficient by 45%). Thus flosequinan exerted not only positive inotropic but also positive lusitropic effects, in association with a significant reduction of both pulsatile and steady components of LV afterload, contributing to an improvement of LV-pump function in acute cardiac failure.
 ...
PMID:Effects of balanced vasodilator, flosequinan, on aortic impedance in failing heart. 973 61

The myocardial contractile protein myosin light chain 1 isoform (MLC-1) is released into the circulation during myocyte necrosis and could thus be a marker of low-grade myocardial damage and of poor prognosis in patients with heart failure. Two hundred eighteen patients with stable heart failure (ejection fraction [EF] <35%) and in New York Heart Association (NYHA) class III to IV had MLC-1 measured at baseline and 1 month after being randomized to the direct vasodilator flosequinan or placebo. Patients were followed a mean of 302 +/- 142 days. The prognostic value of an increase in MLC-1 above the 98th percentile of normal controls was compared with that of conventional prognostic variables in heart failure. MLC-1 was increased in over half of patients at baseline and 1 month, and this was associated with increased age, NYHA class IV, and renal insufficiency. By Kaplan-Meier survival analysis, patients with a baseline increase in MLC-1 had a greater mortality (26%) than those without an increase (15%) (p = 0.043). A significant interaction among MLC-1, survival, and treatment was found (p = 0.043). In the placebo group, MLC-1 was associated with increased mortality (29% vs 12%, p = 0.025), whereas there was no significant difference among patients receiving flosequinan. In a multivariate logistic regression model including age, treatment, and left ventricular (LV) ejection fraction, the MLC-1 chain was most predictive of mortality (p = 0.049). Thus, circulating MLC-1 is elevated in over half of patients with stable severe heart failure, and this increase is associated with a poor prognosis. Flosequinan treatment eliminates this association, highlighting the complexity of the relation between cardiac myocyte damage, drug treatment, and mortality.
 ...
PMID:Relation of circulating cardiac myosin light chain 1 isoform in stable severe congestive heart failure to survival and treatment with flosequinan. 1239 64


<< Previous 1 2 3