flosequinan and Heart-Failure

Large drug trials have become very important to determine which drugs should be used in the treatment of patients with chronic heart failure (CHF). When these trials showed "positive" results, publication of the data soon followed, leading to a substantial impact on prescription patterns. In the case of "negative" results, many times they were not published, or were reported as an abstract or as short paper disclosing only the main findings. In this article we will discuss some of these trials that were conducted in the last 10 years, since we believe they may provide insight into the pathophysiology and treatment options in CHF.

Topics: Bosentan; Cardiovascular Agents; Deoxyepinephrine; Heart Failure; Humans; Imidazoles; Mibefradil; Pyrazines; Quinolines; Sulfonamides; Xamoterol

Topics: Animals; Calcium Channel Agonists; Cardiac Glycosides; Cardiovascular Agents; Catecholamines; Cyclic AMP; Heart Diseases; Heart Failure; Hemodynamics; Humans; Phosphodiesterase Inhibitors; Quinolines; Sodium Channels; Vasodilator Agents

Topics: Heart Failure; Humans; Quinolines; Vasodilator Agents

Topics: Chronic Disease; Heart Failure; Humans; Quinolines; Randomized Controlled Trials as Topic; Vasodilator Agents

The crucial issues in the management of congestive heart failure (CHF) are improvement of depressed myocardial contractility and reduction of excessive load. For this purpose, positive inotropic agents and vasodilators have been developed as new oral drugs. The former include Denopamine which possesses beta 1 stimulating effect, Xamoterol which is a unique agent acting as a beta 1-partial agonist, and Ibopamine, Docarpamine and Phosphodiesterase Inhibitors which possess both inotropic and vasodilating effects and are called "Inodilators". The latter include Angiotensin Converting Enzyme Inhibitors. In addition, new vasodilators, such as, Vasopressin Antagonist have also been developed. However, careful long-term clinical trials are required with regard to the efficacy and adverse effects before these agents are widely used with safety in the management of CHF.

Topics: Administration, Oral; Cardiotonic Agents; Deoxyepinephrine; Ethanolamines; Heart Failure; Humans; Phosphodiesterase Inhibitors; Piperidines; Propanolamines; Pyrazines; Quinolines; Quinolones; Vasodilator Agents; Xamoterol

The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure.. Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use.. Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction ≤35% to receive long-term treatment with placebo or flosequinan (75 or 100 mg/day) in addition to their usual therapy. The primary outcome was all-cause mortality.. The trial was terminated after a recommendation of the Data and Safety Monitoring Board, because during an average of 10 months of follow-up, 192 patients died in the placebo group and 255 patients died in the flosequinan group (hazard ratio: 1.39, 95% confidence interval: 1.15 to 1.67; p = 0.0006). Flosequinan also increased the risk of disease progression, which was paralleled by drug-related increases in heart rate and neurohormonal activation. However, during the first month, patients in the flosequinan group were more likely to report an improvement in well-being and less likely to experience worsening heart failure. Similarly, during the month following drug withdrawal at the end of the trial, patients withdrawn from flosequinan were more likely than those withdrawn from placebo to report symptoms of or to require treatment for worsening heart failure.. Although flosequinan produced meaningful symptomatic benefits during short- and long-term treatment, the drug increased the risk of death in patients with severe chronic heart failure.

Topics: Aged; Cause of Death; Chronic Disease; Disease Progression; Double-Blind Method; Early Termination of Clinical Trials; Female; Heart Failure; Heart Rate; Humans; Kaplan-Meier Estimate; Long-Term Care; Male; Neurotransmitter Agents; Prospective Studies; Quinolines; Risk Factors; Vasodilator Agents

The purpose of this study was to assess whether adrenolutin, the inert product of the highly reactive molecules aminochromes, is increased in severe chronic heart failure and whether it is associated with a poor prognosis.. Experimental evidence suggests that oxidative products of catecholamines, aminochromes, are more cardiotoxic than unoxidized catecholamines and may be increased in heart failure.. Adrenolutin was measured at baseline and at 1 and 3 months in 263 patients with chronic New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 22% +/- 7%. Adrenolutin levels were compared with normal levels, and their relation to prognosis was evaluated.. Baseline adrenolutin was increased (55 +/- 90 pg/mL vs 8.4 +/- 9.1 pg/mL for control, P <.02) and remained increased at 1 month (49 +/- 65 pg/mL). During a mean follow-up of 309 +/- 148 days (22-609 days), 57 patients died. Baseline adrenolutin levels correlated with mortality rates by univariate and multivariate analyses (relative risk 1.06, 95% CI 1.01-1.10 for each 17.9-pg/mL rise, P =.032). Left ventricular ejection fraction (P =.013) and New York Heart Association class (P =.009) were the only other variables associated with survival. Age, sex, plasma creatinine, plasma N-terminal atrial natriuretic peptide, and plasma norepinephrine levels were not retained in our model. Adrenolutin levels 1 month after random assignment were not significantly correlated with total mortality rate (P =.061) but were correlated with mortality rate from low output (relative risk 1.14, 95% CI 1.06-1.22, P =.002).. Plasma adrenolutin is increased in patients with heart failure and correlates with a poor prognosis independent of other important predictors of survival. This finding has potentially important pathophysiologic, prognostic, and therapeutic implications.

Topics: Aged; Analysis of Variance; Biomarkers; Canada; Catecholamines; Chronic Disease; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Prognosis; Quinolines; Reference Values; Stroke Volume; Vasodilator Agents

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Myosin Light Chains; North America; Predictive Value of Tests; Prospective Studies; Quinolines; Scandinavian and Nordic Countries; Severity of Illness Index; Stroke Volume; Survival Analysis; Treatment Outcome; Vasodilator Agents

Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure.. At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin II, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo).. Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at baseline to 1625 pmol/L at 1 month [P =. 0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P =. 2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P =.002]). These changes were not observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms.. Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level predicts death. Flosequinan increases plasma norepinephrine level and heart rate in these patients through mechanisms that override its beneficial hemodynamic effects. Our study reinforces the concept that the direct actions of a pharmacologic agent may have a more profound impact on the prognosis of these patients than the hemodynamic effects.

Topics: Aged; Angiotensin II; Atrial Natriuretic Factor; Cause of Death; Cohort Studies; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Prognosis; Protein Precursors; Quinolines; Survival Rate; Vasodilator Agents

In a double-blind, placebo-controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute administration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (-36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and reninangiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.

Topics: Adult; Blood Pressure; Double-Blind Method; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Quinolines; Renin; Vascular Resistance; Vasodilator Agents

Measures of heart rate variability in the frequency domain quantify autonomic activity. However, the relation of these measures to the severity of ventricular dysfunction in patients with congestive heart failure remains uncertain. We applied spectral analysis of heart rate variability to 24-hour Holter monitor recordings obtained from 20 patients with congestive heart failure who were not treated with angiotensin-converting enzyme inhibitors to determine whether significant changes in parameters of heart rate variability reflect the progression of symptoms in patients with ventricular failure. Both total and low-frequency heart rate spectral power were seen to decrease with worsening New Heart Associate (NYHA) functional class. A significant (p = 0.04) higher total power was noted in NYHA class II than in class III patients (3.0 x 10(-3) +/- 3.6 10(-4) and 2.5 x 10(-3) +/- 5.9 x 19(-4) [beats/min]2, respectively). Similarly, low-frequency heart rate spectral power was significantly (p = 0.008) higher in class II than in class III patients (1.7 x 10(-3) +/- 4.6 x 10(-4) and 1.1 x 10(-3) +/- 3.5 x 10(-4) [beats/min]2, respectively). Only the low-frequency component of the spectrum was directly correlated with left ventricular ejection fraction (LVEF) (r = 0.40) with a trend toward statistical significance (p = 0.07). Measures of heart rate variability and the changes in autonomic tone that they reflect may therefore serve as markers of the extent of disease progression in patients with congestive heart failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System; Chronic Disease; Disease Progression; Double-Blind Method; Electrocardiography, Ambulatory; Heart Failure; Heart Rate; Humans; Middle Aged; Placebos; Quinolines; Signal Processing, Computer-Assisted; Stroke Volume; Vasodilator Agents; Ventricular Dysfunction; Ventricular Function, Left

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.

Topics: Atrial Fibrillation; Atrioventricular Node; Cardiotonic Agents; Dose-Response Relationship, Drug; Electrocardiography, Ambulatory; Exercise Tolerance; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Physical Exertion; Placebos; Posture; Quinolines; Supine Position; Vasodilator Agents; Ventricular Function

Diuretics, angiotensin converting enzyme inhibitors and digoxin have become "standard" triple therapy for many patients with chronic cardiac failure. Flosequinan increases exercise duration and improves symptoms when added to standard triple therapy. Despite intensive study, the clinical pharmacology of flosequinan remains uncertain.. The University Hospital of Wales, a Regional Cardiac Centre.. Twenty four patients with chronic heart failure who remained symptomatic despite standard therapy including ACE inhibitors.. A double-blind placebo-controlled parallel group study of 100 mg daily of flosequinan. We measured changes in exercise duration using cardiorespiratory exercise testing and changes in large artery distensibility using Doppler ultrasound.. Exercise duration after 8 weeks flosequinan treatment was significantly greater than following placebo treatment. The flosequinan-related increase in exercise duration (+14%) was associated with a significant reduction in VE/VCO2 slope (-16%). Brachial-radial pulse wave velocities were unaltered by flosequinan treatment.. Our results confirm that flosequinan improves exercise duration in patients with chronic heart failure. They suggest that this observed beneficial effect is independent of any change in large artery distensibility and that in the presence of ACE inhibitors, this improvement may be independent of any vasodilating action of flosequinan. Although this study confirms the beneficial symptomatic effects of flosequinan in chronic cardiac failure, clinical trials have subsequently demonstrated an overall increase in mortality in patients treated with 100 mg flosequinan daily. This has resulted in the withdrawal of flosequinan from routine clinical use.

Topics: Adult; Aged; Blood Circulation; Blood Pressure; Chronic Disease; Double-Blind Method; Exercise Tolerance; Heart Failure; Heart Rate; Hemodynamics; Humans; Middle Aged; Physical Endurance; Quinolines; Vasodilator Agents

Patients with congestive heart failure (CHF) are characterized by an imbalance of the autonomic nervous system, which may contribute to the progression of circulatory failure and influence survival. However, it is still unclear whether CHF is characterized by a suppression of the diurnal variation in autonomic tone that is observed in normal subjects. To characterize the circadian variation in autonomic tone in patients with ventricular failure, ambulatory 24-hour Holter monitor recordings were obtained in 20 patients with CHF; 4-minute epochs of data from every hour of each 24-hour recording were selected. For each epoch we calculated the mean heart rate (HR) and, by applying spectral analysis of heart rate variability (HRV), we quantified the magnitude of the total (0.02 to 0.9 Hz), sympathetically governed low frequency variability (0.02 to 0.1 Hz), and parasympathetically mediated high-frequency variability (0.1 to 0.9 Hz). These areas were also expressed as a ratio to total variability and a ratio of high to low variability. A highly significant change in the mean HR over 24 hours was observed (p = 0.0001); no changes in the measures of HRV were obtained (p < 0.3). No significant correlation was found between mean HR and any frequency domain measures. We conclude that the sustained imbalance of autonomic tone over a 24-hour period, as shown by the spectral analysis of HRV, may promote the progression of circulatory failure and predispose patients with CHF to malignant ventricular arrhythmias and sudden cardiac death.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Autonomic Nervous System; Circadian Rhythm; Double-Blind Method; Electrocardiography, Ambulatory; Female; Heart; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Quinolines; Signal Processing, Computer-Assisted; Vasodilator Agents

Topics: Adult; Aged; Aging; Biotransformation; Heart Failure; Humans; Kidney Diseases; Liver Diseases; Longevity; Male; Prospective Studies; Quinolines; Vasodilator Agents

Two hundred and nine patients with moderate to severe chronic heart failure, all of whom remained symptomatic despite at least 80 mg of frusemide daily, were randomized to 12 months treatment with flosequinan or captopril. The patients were stratified into two groups, a treadmill group and a corridor walk test group, depending upon their exercise capability. Sixty-five out of 102 patients randomized to flosequinan and 43 out of 107 randomized to captopril (p < 0.001) did not complete the study. There was no difference between the groups in mortality: 19 patients died while taking flosequinan and 15 while taking captopril. Both drugs had similar effects on treadmill exercise tolerance; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds (p = 0.57) for the captopril group. For those patients stratified to the corridor walk test only, there was also very little difference in the improvement at 52 weeks; the mean increase for patients randomized to flosequinan was 61 meters and captopril was 75 meters (p = 0.65). However, when the walk tests from all patients are examined, captopril produced a significant improvement compared with flosequinan at week 52 (p = 0.015). Flosequinan has similar long-term efficacy to captopril but is associated with a higher incidence of adverse events.

Topics: Blood Pressure; Captopril; Chronic Disease; Diuretics; Double-Blind Method; Exercise Test; Female; Heart Failure; Heart Rate; Humans; Long-Term Care; Male; Middle Aged; Quinolines; Time Factors; Treatment Outcome; Vasodilator Agents

The vasodilator flosequinan has been shown to be effective in the management of symptoms of congestive heart failure but has been found to influence survival adversely when administered in selected doses. A moderate positive chronotropic response accompanies long-term administration of this agent, which may be associated with an activation of the neurohormonal axis that itself may contribute to the reported increase in mortality. This investigation used the technique of spectral analysis of heart rate variability to examine the autonomic response to long-term flosequinan administration in 39 patients enrolled in a double-blind placebo-controlled trial of this vasodilator to determine whether autonomic mechanisms account for the observed changes in heart rate. Although heart rate significantly increased in the flosequinan-treated patients, parasympathetic tone increased and sympathetic drive decreased compared with placebo, as reflected by high- and low-frequency heart rate variabilities, respectively. It is concluded that (1) autonomic inputs to the myocardium that would be expected to produce increases in heart rate do not result from long-term flosequinan administration; (2) accordingly, a direct positive chronotropic effect must account for the heart rate changes observed with this vasodilator; and (3) the increased mortality associated with the administration of this agent in the doses examined does not appear to result from reflex changes in autonomic tone and must result from other properties of this vasodilator.

Topics: Adult; Aged; Autonomic Nervous System; Blood Pressure; Double-Blind Method; Female; Heart; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Quinolines; Stimulation, Chemical; Survival Rate; Vasodilator Agents

Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients.. In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy.. These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Digoxin; Diuretics; Drug Therapy, Combination; Electrocardiography, Ambulatory; Exercise Test; Female; Heart Failure; Humans; Male; Middle Aged; Quality of Life; Quinolines; Vasodilator Agents

We evaluated the short- and long-term effects of flosequinan in 47 patients with severe heart failure despite ongoing captopril treatment.. There have been no previous evaluations of the long-term hemodynamic effects of any direct-acting vasodilator in patients with heart failure receiving an angiotensin-converting enzyme inhibitor. Flosequinan is an arterial and venous vasodilator with actions similar to those of the hydralazine-isosorbide dinitrate combination.. After baseline hemodynamic measurements using balloon-tipped pulmonary artery and radial arterial catheters, patients were randomized to receive 50, 100 or 150 mg of flosequinan daily. Hemodynamic variables were measured immediately before and after short-term flosequinan administration and after 8 weeks of therapy.. With short-term flosequinan administration, mean arterial, right atrial and left ventricular filling pressures decreased by 6.4 +/- 1.1, 3.8 +/- 0.5 and 7.3 +/- 0.7 mm Hg, respectively (all p < 0.001). Cardiac index increased by 0.5 +/- 0.1 liters/min per m2, systemic vascular resistance decreased by 616 +/- 105 dynes.s.cm-5 and heart rate increased by 4 +/- 1 beats/min (all p < 0.001). After 8 weeks of long-term flosequinan administration, the vasodilator effect of a dose of flosequinan persisted. Compared with pretreatment baseline values, mean arterial, right atrial and left ventricular filling pressures at the peak effect of flosequinan were decreased by 3.5 +/- 1.3, 2.8 +/- 0.7 and 5.1 +/- 1.3 mm Hg, respectively (all p < 0.01). Systemic vascular resistance had decreased by 585 +/- 95 dynes.s.cm-5, cardiac index had increased by 0.5 +/- 0.1 liters/min per m2 and heart rate had increased by 10 +/- 2 beats/min (all p < 0.001).. The arterial and venous vasodilator flosequinan exerts both short- and long-term sustained hemodynamic effects in patients with heart failure receiving angiotensin-converting enzyme inhibitors.

Topics: Adult; Aged; Captopril; Catheterization, Swan-Ganz; Digitalis Glycosides; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Physiologic; Quinolines; Severity of Illness Index; Thermodilution; Time Factors; Vasodilator Agents; Ventricular Function, Left

The aim of this study was to assess the efficacy of flosequinan in chronic heart failure.. Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported.. One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction < 40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant.. After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per min in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treated with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died.. These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined.

Topics: Chronic Disease; Double-Blind Method; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Quinolines; Treatment Outcome; Vasodilator Agents

Angiotensin converting enzyme inhibitors have greatly improved the treatment of patients with chronic heart failure but they are not effective in all patients, and their use may be limited by side effects. There is, therefore, a need to investigate new drugs and to compare their efficacy with angiotensin converting enzyme inhibitors. Flosequinan is a new direct-acting vasodilator that has been shown to be effective in placebo-controlled studies. Patients with chronic heart failure in NYHA classes II or III who remained symptomatic despite at least 80 mg of frusemide daily were recruited from two centers. Following a single-blind placebo run-in period, the patients were randomized double blind to either the addition of captopril or flosequinan for 6 weeks. Following a further 2-week placebo washout period, they were then given the alternative treatment. Symptom-limited treadmill exercise times, scores of perceived exertion, and corridor walk tests were measured at two weekly intervals during the study. Twenty-five patients entered the study, 16 of whom completed without a change in diuretic dose. Five patients were withdrawn while taking captopril and two while taking flosequinan; two were withdrawn during the placebo washout period. For those patients who completed the study, flosequinan increased treadmill exercise tolerance from a mean (SEM) placebo time of 11.5 (1.0) minutes by 2.4 (0.6) (p = 0.0002) and captopril from 12.0 (0.8) minutes by 1.2 (0.6) minutes (p = 0.08). Comparison of the other measures of efficacy revealed no difference between the groups. In this short-term study flosequinan appeared to be equal in efficacy to captopril.

Topics: Aged; Captopril; Exercise Test; Heart Failure; Humans; Middle Aged; Quinolines; Vasodilator Agents

The aim of this study was to evaluate the immediate and long-term systemic and coronary hemodynamic, metabolic and neurohormonal effects of flosequinan in patients with congestive heart failure.. Preliminary studies have shown that this new long-acting oral systemic vasodilator may have beneficial effects in patients with heart failure.. Thirteen patients with congestive heart failure were studied. Systemic and coronary hemodynamic, metabolic and neurohormonal effects of flosequinan were assessed acutely with repeat systemic hemodynamic studies after 6 weeks of treatment.. The administration of flosequinan acutely and after long-term treatment, resulted in a significant increase in cardiac index, stroke work index and stroke volume index with a reduction in systemic and pulmonary vascular resistances. The improvement in ventricular function was associated with an improvement in left ventricular efficiency without a change in myocardial oxygen consumption or coronary sinus blood flow. Myocardial oxygen extraction and net myocardial lactate extraction also did not change significantly with flosequinan therapy. Systemic catecholamine levels and myocardial catecholamine balance did not change. Plasma arterial and coronary sinus atrial natriuretic factor concentrations were elevated at baseline; the latter concentrations at the level of the great cardiac vein were significantly higher than those of arterial concentrations, indicating increased left ventricular release of atrial natriuretic factor in congestive heart failure. Both arterial and coronary sinus atrial natriuretic factor levels were significantly reduced with the administration of flosequinan at peak effect in association with an improvement in systemic hemodynamics.. Flosequinan therapy in patients with congestive heart failure results in a sustained beneficial hemodynamic action and improved cardiac performance without an increase in metabolic demand or activation of the sympathetic nervous system.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output; Catecholamines; Catheterization, Swan-Ganz; Female; Heart Failure; Hemodynamics; Humans; Lactates; Male; Middle Aged; Neurosecretory Systems; Oxygen Consumption; Pulmonary Circulation; Pulmonary Wedge Pressure; Quinolines; Stroke Volume; Vascular Resistance; Vasodilator Agents

Although beneficial effects of a new vasodilating agent, flosequinan, have been demonstrated in patients with severe heart failure, its efficacy has not been studied in patients with a less severe form of chronic heart failure. In this study, the effects of 4 weeks' administration of flosequinan, 50 mg daily, and placebo on exercise capacity, cardiac function, and symptoms of heart failure were investigated in 24 patients with chronic mild heart failure (New York Heart Association functional class, mainly class II) in a double-blind clinical trial. When the parameter changes during the treatment period of the flosequinan and placebo groups were compared, no significant difference was found in any of the measurements except for left ventricular fractional shortening determined from M-mode echocardiograms; it was increased by 2.9 +/- 1.3% in the flosequinan group whereas it was decreased by 1.3 +/- 0.9% in the placebo group (P less than 0.05 vs flosequinan treatment). However, when compared to baseline values, flosequinan significantly increased exercise time in the symptom-limited maximal exercise test (704 +/- 103 to 763 +/- 107 s, P less than 0.05) and the oxygen uptake at the anaerobic threshold (13.8 +/- 1.3 to 16.7 +/- 1.4 ml/min kg, P less than 0.05), and improved symptoms assessed with a new heart failure severity classification (a median value of 2.0-1.5, P less than 0.05). These improvements were not observed in the placebo group. Serious adverse effects were not observed in either group. These results suggest that flosequinan is useful for the treatment of chronic mild heart failure as well as severe heart failure.

Topics: Adult; Aged; Double-Blind Method; Echocardiography; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Vasodilator Agents; Ventricular Function, Left

The effects of flosequinan and enalapril on exercise capacity (bicycle exercise duration), quality-of-life symptomatology (visual analogue scales) and New York Heart Association (NYHA) grading, were compared in 61 patients with chronic heart failure (NYHA, grade III). Bicycle exercise duration improved similarly with flosequinan (+27%) and enalapril (+18%); in patients completing the study, flosequinan produced a significantly greater increase in exercise time at week 12, compared with enalapril (P = 0.02). Improvements in visual analogue scores relating to general health, energy and vitality, ability to perform physical activities and breathing performance, were equivalent for both drugs. Changes in NYHA classification showed that 27 (55%) of 49 patients completing the study had improved by at least one NYHA grade (15 (68%) patients on flosequinan; 12 (44%) on enalapril). The overall safety and tolerability of the two treatments was similar; 18 patients reported adverse effects while on flosequinan, compared with 19 patients on enalapril. Neither treatment was associated with any clinically important changes in haematological or biochemical variables, although some treatment-related effects were observed. This study confirms that flosequinan achieved similar efficacy to enalapril in the symptomatic relief of chronic heart failure. The effect of flosequinan on survival in chronic heart failure has not been tested; pending such studies, our data suggest that it may prove a useful alternative therapy in patients where ACE inhibitors are contraindicated or poorly tolerated.

Topics: Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Enalapril; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pain Measurement; Quinolines; Vasodilator Agents

The effects of the new arterial and venous vasodilator flosequinan have been evaluated in a variety of ways in different groups of patients with chronic heart failure. Flosequinan improved the central hemodynamic effects of heart failure in one group, with benefits still apparent up to 24 hours after a single oral dose. In another group it also improved calf blood flow and, therefore, blood flow to skeletal muscle. Also, using a number of different tests, it improved the exercise performance of the patients. In a further group the improvement in exercise tolerance produced was similar to that of captopril. Flosequinan has the necessary properties of a drug that is likely to be of benefit in the treatment of patients with chronic heart failure.

Topics: Aged; Captopril; Drug Evaluation; Exercise; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Vasodilator Agents

The duration and reproducibility of hemodynamic effects of flosequian, a direct-acting, balanced-type vasodilator, were studied in 19 heart failure patients (NYHA class 3.0 +/- 0.7) receiving 100 mg orally (day 1), placebo (day 2), and again 100 mg (day 3). Flosequinan immediately reduced systemic and pulmonary resistance (23% and 35%, respectively, at 60-90 minutes postdrug) and decreased pulmonary wedge, right atrial, mean pulmonary artery, and mean arterial pressure by 38%, 50%, 25%, and 7%, respectively. Concomitantly, cardiac output, and stroke volume and work increased by 26%, 20%, and 22%, respectively. Most hemodynamic effects persisted for 48 hours. In contrast, changes in pulmonary wedge and arterial pressures, stroke volume, and stroke work only lasted for 2-12 hours. Maximum absolute changes on day 3 were generally comparable with first-dose effects with, again, long-lasting effects on systemic resistance and cardiac output. However, changes in pulmonary artery, wedge, and resistance were significantly shorter than after first dose administration. These data indicate sustained and reproducible arterial dilating effects of flosequinan, but less pronounced and shorter lasting pulmonary arterial and venodilator properties.

Topics: Aged; Atrial Function; Blood Pressure; Drug Administration Schedule; Female; Heart; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Wedge Pressure; Quinolines; Reproducibility of Results; Time Factors; Vasodilator Agents

1. Twenty patients with moderate to severe chronic cardiac failure were entered into a double-blind parallel group study comparing flosequinan 100 mg daily with matching placebo. 2. After at least three prior exercise tests, cardiopulmonary parameters were assessed at rest and during submaximal exercise before and after 2 and 8 weeks of active drug or placebo. 3. Resting minute ventilation and respiratory rate were reduced by flosequinan compared with placebo, but oxygen uptake was unchanged. 4. Comparison of minute ventilation, carbon dioxide production and venous lactate levels at the end of the exercise stage approximating to 50% of peak oxygen uptake demonstrated significant reductions in the flosequinan group compared with placebo at week 2 and week 8 (P less than 0.05). 5. Flosequinan increased the oxygen uptake at anaerobic threshold from 13.2 +/- 2.8 ml min-1 kg-1 to 15.9 +/- 3.4 ml min-1 kg-1 at week 2 and 15.8 +/- 3.7 ml min-1 kg-1 at week 8. These increases were significant when compared with placebo (P less than 0.05). 6. We conclude that flosequinan improves submaximal exercise performance in patients with chronic cardiac failure, probably by enhancing skeletal muscle blood flow.

Topics: Adult; Aged; Anaerobiosis; Carbon Dioxide; Chronic Disease; Exercise; Heart Failure; Hemodynamics; Humans; Lactates; Middle Aged; Muscles; Oxygen Consumption; Quinolines; Respiratory Function Tests; Vasodilator Agents

This study was conducted to determine the long-term effect of flosequinan, a new orally administered arterial and venous dilator, on the clinical course of patients with moderate to severe congestive heart failure. Seventeen patients on chronic digitalis and diuretic therapy were randomized to receive either flosequinan (n = 9) or placebo (n = 8) in a double-blind fashion. Changes in symptomatology, exercise performance, and left ventricular function were assessed serially during the two-month treatment period. During the course of therapy, a modest improvement in the symptom scores and functional classification of the flosequinan-treated patients was observed. Flosequinan evoked a significant increase in maximal exercise capacity. While long-term flosequinan administration also effected a progressive increase in resting heart rate, it did not consistently improve indices of left ventricular systolic function. The addition of chronic vasodilator therapy with flosequinan to standard digitalis-diuretic regimens is capable of inducing clinical improvement in patients with moderate to severe chronic heart failure. Trials involving larger patient populations will be necessary to confirm the results of this preliminary study and to determine the extent of clinical improvement, subpopulations benefited, role in heart failure therapeutics, and so forth.

Topics: Adult; Aged; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Randomized Controlled Trials as Topic; Vasodilator Agents

Twenty patients with severe chronic cardiac failure caused by ischaemic heart disease were treated with flosequinan 100 mg daily or placebo in addition to their existing treatment with diuretics and, in some, digoxin in a randomised double blind trial. After eight weeks of treatment, flosequinan significantly improved treadmill exercise time, increased peak achieved oxygen consumption, and improved the New York Heart Association symptom grade when compared with placebo. One patient in the placebo group died and another was withdrawn because heart failure worsened. One patient in the flosequinan group was lost to follow up but there were no other withdrawals. Flosequinan was well tolerated with few adverse effects, and it may prove to be a useful addition to diuretics and digoxin in the treatment of chronic cardiac failure.

Topics: Adult; Aged; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Exercise Test; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Random Allocation; Vasodilator Agents

The central and regional hemodynamic effects of flosequinan, a new orally administered vasodilator, were examined in 10 patients with moderate to severe congestive heart failure. A single-blind design was used to compare a standard dose of flosequinan (100 mg) with placebo. Flosequinan produced a statistically significant increase in cardiac output, primarily through its augmentation of stroke volume. This response was accompanied by significant reductions in systemic vascular resistances and right and left ventricular filling pressures. A reduction in pulmonary artery pressure and total pulmonary vascular resistance also was observed. The vasodilatory actions of flosequinan improved overall left ventricular performance; the inotropic indexes measured were not altered. There were no significant changes in upper limb, renal or hepatic-splanchnic blood flow or in the vascular resistances of these regions after flosequinan administration. The upper limb venous capacitance increased significantly. First-dose flosequinan evokes favorable central hemodynamic changes and improves overall left ventricular performance in patients with congestive heart failure. The acute augmentation in cardiac output, however, is not accompanied by a preferential alteration of flow to any of the major vascular regions studied.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Placebos; Quinolines; Vasodilator Agents

We studied the hemodynamic effect of a single dose of the new direct-acting vasodilator, flosequinan, in 18 patients with severe heart failure of acute onset complicating acute myocardial infarction, which was resistant to high doses of diuretics, nitrates and dobutamine given intravenously. Flosequinan was added to conventional therapy at 3.5 +/- 0.8 days from the infarction, in the form of a single oral dose of 100 mg. Hemodynamic measurements were performed every hour for 4 hours after the administration, without any other drug being added. The infusion rate of nitrates was kept constant. Flosequinan produced hemodynamic improvement in this group. The effect peaked at 2 hours and remained at this level at 4 hours. Pulmonary capillary wedge pressure decreased from 27.6 +/- 4.3 to 16.8 +/- 2.8 mm Hg and cardiac output increased from 3.5 +/- 0.3 to 4.1 +/- 0.4 l/min (P less than 0.001). Pulmonary arterial and right atrial pressures and systemic and pulmonary vascular resistances were also significantly reduced. Heart rate and mean systemic arterial pressure were not significantly altered. Administration of flosequinan was not associated with symptomatic hypotension, cardiac arrhythmias or other adverse events. We conclude that flosequinan is effective in producing acute hemodynamic improvement in patients with heart failure, complicating acute myocardial infarction, which is resistant to conventional therapy. Flosequinan is safe and well tolerated. Studies for longer time periods are indicated.

Topics: Acute Disease; Adult; Aged; Clinical Trials as Topic; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Quinolines; Vasodilator Agents

The hemodynamic effects of flosequinan, a new balanced vasodilator, were evaluated in 12 patients with chronic congestive heart failure. The drug was added to diuretics and digitalis and given as an oral dose of 100 mg, once daily in the morning, over 3 days, and hemodynamic monitoring was performed before the first dose and for 72 h thereafter. Hemodynamic improvement, peaking between 1 and 2 h after oral administration, was observed on all 3 days. On day 1 pulmonary capillary wedge pressure (PCWP) was reduced from 27.8 +/- 8.6 to 13.0 +/- 3.1 mm Hg and cardiac output (CO) increased from 3.3 +/- 0.6 to 4.5 +/- 0.9 liters/min (p less than 0.05). After 12-16 h the effect was slightly attenuated but remained significant at 24 h. A similar response was observed after the doses given on days 2 and 3. At 72 h PCWP was 15.5 +/- 4.1 mm Hg and CO 3.8 +/- 1.1 liters/min (p less than 0.05 for the difference from baseline). Heart rate was slightly increased only at 2 h after the dose. Pulmonary arterial and right atrial pressure and systemic and pulmonary vascular resistances were significantly reduced (except for systemic resistance at 72 h). In conclusion, flosequinan produces hemodynamic improvement in patients with chronic congestive heart failure. The response to subsequent doses is similar to the response to the first dose.

Topics: Aged; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Physiologic; Quinolines; Time Factors; Vasodilator Agents

There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.

Topics: Aged; Catecholamines; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Random Allocation; Renin; Vasodilator Agents

Topics: Heart Failure; Humans; Quinolines; Vasodilator Agents

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.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Dogs; Electric Impedance; Heart Failure; Myocardial Contraction; Quinolines; Systole; Vasodilator Agents; Ventricular Function, Left

The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure.. After a single dose of 100 mg, Cmax of the parent compound (2.52 mg.l-1) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (Cmax 8.4 vs 3.21 mg.l-1). No adverse effects were observed.. It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity.

Topics: Aged; Aged, 80 and over; Blood Pressure; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Quinolines; Vasodilator Agents

Topics: Ethics, Medical; Heart Failure; Humans; Placebos; Quinolines; Randomized Controlled Trials as Topic; Vasodilator Agents

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.

Topics: Aged; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Neurotransmitter Agents; Quinolines; Quinolones; Vasodilator Agents

We wished to provide comparative information regarding the direct effects of flosequinan, a novel quinolone under development for treating heart failure, on isolated human arterial, venous, and cardiac muscle. A similar assessment was made for four other agents--milrinone, ouabain, captopril and diltiazem--that have been used to treat heart failure patients, as well as for flosequinoxan, which is the primary metabolite of flosequinan. Flosequinan produced a potent and balanced relaxant effect on norepinephrine (NE)-contracted human arterial and venous smooth muscle, with IC25 values of 0.32 and 0.50 microM, respectively. At higher concentrations, flosequinan also produced a positive inotropic effect on human cardiac muscle (EC25 = 32 microM). A similar pattern of responses was observed with flosequinoxan. The pharmacologic profile obtained for the other agents examined differed from that observed with flosequinan and flosequinoxan in the following ways: Milrinone produced both vascular relaxant and positive inotropic effects, but at comparable concentrations; ouabain produced both vasoconstrictor and positive inotropic effects; diltiazem exerted a vascular relaxant effect at low concentrations and a negative inotropic effect at higher concentrations; and captopril had slight arterial relaxant and negative inotropic effects. These results demonstrate that the pharmacologic profile of flosequinan and flosequinoxan is unique as compared with that of other agents that have been used to treat patients with heart failure.

Topics: Captopril; Diltiazem; Heart Failure; Humans; In Vitro Techniques; Milrinone; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Ouabain; Pyridones; Quinolines; Quinolones; Vasodilator Agents

1 The acute and chronic (8 weeks) haemodynamic responses to oral flosequinan have been investigated in 12 male patients of mean age 58.9 years with congestive heart failure of N.Y.H.A. classes II and III. 2 Flosequinan 125 mg orally significantly reduced right atrial pressure, pulmonary artery pressure and pulmonary wedge pressure prior to and following 8 weeks chronic treatment (125 mg daily). A significant decrease in systemic pressure and an increase in heart rate were also observed with acute flosequinan prior to chronic treatment. A reduction in systemic vascular resistance and an increase in cardiac index reached significance in response to flosequinan 125 mg orally following 8 weeks of therapy. 3 In the erect position, flosequinan reduced pulmonary wedge pressure and tended to reduce systemic vascular resistance, without decreasing mean arterial pressure. 4 Following chronic treatment, there was a trend towards a reduction in pulmonary wedge pressure and an increase in cardiac index, otherwise resting and exercise haemodynamics were unchanged. 5 The response to flosequinan was similar at week 1 and after 8 weeks of treatment for all of the haemodynamic parameters. 6 Flosequinan increased bicycle exercise times and attenuated exercise-induced increases in pulmonary arterial and systemic pressures. There was a trend towards an increase in treadmill exercise time. 7 Sublingual glyceryl trinitrate (0.5 mg) and oral flosequinan (125 mg) had similar effects on right atrial pressure, pulmonary arterial and pulmonary wedge pressures at 5 min and 2 h respectively post-dosing. A small additive effect on pulmonary arterial and wedge pressures was observed.

Topics: Adult; Aged; Exercise; Exercise Test; Exercise Tolerance; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Nitroglycerin; Posture; Quinolines; Vasodilator Agents

To examine the concentration of circulating tumour necrosis factor alpha (TNF alpha) in patients with severe congestive heart failure (New York Heart Association class IV) during one year and to correlate changes in this cytokine with changes in plasma noradrenaline, plasma renin activity, and weight.. A prospective study of the role of TNF alpha in severe chronic heart failure. Blood samples were collected at intervals of three months.. Medical research centre of a teaching hospital.. 16 patients with chronic stable severe heart failure.. Vasodilator treatment with captopril or flosequinan.. Changes in TNF alpha and the correlation with changes in plasma noradrenaline, plasma renin activity, and weight during optimal medical treatment for one year.. The mean concentration of TNF alpha was greater than the upper 95% confidence interval for healthy controls throughout the year of the study but there was considerable between and within patient variation. No correlation was seen between TNF alpha and plasma noradrenaline, plasma renin activity, or weight.. The stimulus resulting in enhanced plasma concentrations of TNF alpha in congestive heart failure remains unclear and concentrations at any particular time were not prognostic.

Topics: Body Weight; Captopril; Epinephrine; Heart Failure; Humans; Middle Aged; Prospective Studies; Quinolines; Renin; Tumor Necrosis Factor-alpha; Vasodilator Agents

Topics: Acute Kidney Injury; Heart Failure; Humans; Male; Middle Aged; Quinolines; Renal Artery Obstruction; Vasodilator Agents

Topics: Heart Failure; Humans; Quinolines; Vasodilator Agents

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.

Topics: Aged; Amiloride; Cardiac Output; Chronic Disease; Echocardiography; Exercise; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Hydrochlorothiazide; Male; Middle Aged; Quinolines; Vasodilator Agents; Ventricular Function, Left

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.

Topics: Aged; Chronic Disease; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Time Factors; Vasodilator Agents

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.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aldosterone; Atrial Natriuretic Factor; Cardiac Output; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitroglycerin; Quinolines; Renin; Vasodilator Agents

Topics: Heart Failure; Humans; Male; Middle Aged; Quinolines; Time Factors; Vasodilator Agents

The lesson learned from recent advances in the understanding of congestive heart failure is that it is too complex a process to be managed in a simple fashion. At present, incremental improvement such as that provided by ACE inhibitors, and now possibly by new agents such as flosequinan, are what we have to offer our patients, short of transplantation, to control symptoms and increase exercise tolerance. No one knows what the future holds for these patients, but one can hope that the current therapy and those drugs being studied in clinical trials will provide agents that will continue to reduce the morbidity and mortality associated with current therapies. However, only so much can be done with drugs in the failing heart, and research must continue in the area of cardiac transplantation as well as in the area of totally implantable ventricular assist devices.

Topics: Angiotensin-Converting Enzyme Inhibitors; Drug Therapy; Heart Failure; Humans; Quinolines; Vasodilator Agents

Topics: Heart Failure; Humans; Quinolines; Vasodilator Agents

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Heart Failure; Humans; Quinolines; Vasodilator Agents

We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks. In the single dose study, the tmax of flosequinan was 2.5 h, Cmax was 1.17 microgram.ml-1 and t1/2 was 5.63 h. The tmax of the metabolite BTS 53554 was 20.3 h, Cmax was 1.44 microgram.ml-1 and t1/2 was 62.0 h. BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate. Adverse reactions were not observed in either the single or repeated dose study. It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg.

Topics: Aged; Aged, 80 and over; Chronic Disease; Creatinine; Drug Administration Schedule; Female; Heart Failure; Humans; Kidney; Male; Quinolines; Vasodilator Agents

Topics: Heart Failure; Humans; Quinolines; Vasodilator Agents

1. In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.

Topics: Animals; Calcium; Colforsin; Dose-Response Relationship, Drug; Ferrets; Heart Failure; Heart Ventricles; Humans; In Vitro Techniques; Male; Milrinone; Myocardial Contraction; Pyridones; Quinolines; Quinolones; Stimulation, Chemical; Vasodilator Agents

This study was designed to assess the direct effects of flosequinan on myocardial function.. Flosequinan has been shown to improve symptoms and exercise tolerance in patients with heart failure. Although previous studies have established that flosequinan is a vasodilator, it is not known to what extent direct actions of the drug on myocardial contractility or diastolic properties contribute to its beneficial hemodynamic effects.. Nitroprusside and intravenous flosequinan were administered sequentially to 18 patients with severe heart failure (New York Heart Association functional class III or IV, left ventricular ejection fraction 0.14 +/- 0.02). Micromanometer left ventricular pressure and radionuclide volume data were combined to construct pressure-volume loops during 1) a baseline period, 2) nitroprusside infusion, 3) a second baseline period, and 4) flosequinan infusion.. The peak rate of left ventricular pressure development increased from 899 +/- 84 to 1,070 +/- 94 mm Hg/s (p less than 0.05) with flosequinan. The baseline left ventricular end-systolic pressure-volume relation was constructed in 15 patients from the two baseline pressure-volume loops and from that obtained during afterload manipulation with nitroprusside. During flosequinan administration, the relation between end-systolic pressure and volume was shifted upward and leftward, indicating enhanced contractility, in 14 of 15 patients (p less than 0.001). The maximal rate of decrease in left ventricular pressure during isovolumetric relaxation increased in magnitude with flosequinan from 882 +/- 63 to 1,026 +/- 68 mm Hg/s (p less than 0.05).. These results indicate that intravenous flosequinan has positive inotropic and lusitropic effects in patients with heart failure. Further studies are needed to assess the direct myocardial effects of oral flosequinan.

Topics: Cardiac Catheterization; Cardiotonic Agents; Female; Gated Blood-Pool Imaging; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Nitroprusside; Quinolines; Vasodilator Agents

The hemodynamic effects of the peripheral vasodilator flosequinan, 100 mg/day, were evaluated in 20 patients with Stage IIA-IIB (the Lang-Strazhesko-Vasilenko classification) heart failure. The doses of digoxin and diuretics were found to be stable. The right cardiac cavities and pulmonary artery were catheterized by Swan-Ganz balloon catheters. The agent was demonstrated to produced profound effects showing decreased pre- and afterload when given both in a single dose or in course therapy.

Topics: Adult; Chronic Disease; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Vasodilator Agents

The acute central haemodynamic and neuroendocrine effects of intravenous flosequinan were studied in a group of 10 patients with severe heart failure. Flosequinan improved cardiac output by a maximum of 1.59 l.min-1, it reduced pulmonary capillary wedge pressure by 11.9 mm Hg and it also caused a reduction in right atrial pressure by a maximum of 7.2 mm Hg. It tended to cause a fall in plasma adrenaline levels but not in plasma noradrenaline. There was little fall in blood pressure in response to flosequinan and no patient developed an adverse event. Intravenous flosequinan may be a useful candidate drug for controlled clinical studies in patients with severe heart failure.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Catecholamines; Chromatography, High Pressure Liquid; Epinephrine; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Norepinephrine; Pulmonary Wedge Pressure; Quinolines; Vascular Resistance; Vasodilator Agents

Flosequinan is an oral arterial and venous vasodilator that is currently under investigation for the treatment of congestive heart failure. The effects of flosequinan on ventricular performance and myocardial contractility were studied in 10 patients with severe congestive heart failure during right and left cardiac catheterization. Sixty minutes after a 100 mg oral dose of flosequinan, the peak rate of rise in left ventricular pressure (dP/dt) increased from 940 +/- 180 to 1050 +/- 240 mm Hg/sec (p less than 0.05), while left ventricular end-diastolic pressure decreased from 32 +/- 5 to 26 +/- 8 mm Hg (p less than 0.05), and cardiac index increased (2.1 +/- 0.4 to 2.3 +/- 0.5 L/min/m2, (p less than 0.05). The mean pulmonary artery pressure and vascular resistance decreased from 40 +/- 8 to 33 +/- 12 mm Hg (p less than 0.05) and from 330 +/- 240 to 290 +/- 170 dyne-sec/cm5 (p less than 0.05), respectively. Heart rate, mean aortic pressure, right atrial pressure, systemic vascular resistance, and serum norepinephrine levels did not change significantly. The increase in left ventricular peak dP/dt that was concomitant with a decrease in left ventricular end-diastolic pressure, and no change in systemic arterial pressure or sympathetic tone, argue for a direct positive inotropic effect of flosequinan.

Topics: Adult; Aged; Cardiac Catheterization; Drug Evaluation; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Quinolines; Stimulation, Chemical; Time Factors; Vasodilator Agents; Ventricular Function, Left

The exercise capability of 12 patients with heart failure was investigated by a variety of different methods before and after treatment with the vasodilator flosequinan. Two treadmill protocols were used, a modified Bruce with incremental workloads and a fixed workload protocol. On placebo, mean exercise time was greater with the Bruce protocol, 526 (64) s, than with the fixed protocol, 359 (59) s, P less than 0.005. Flosequinan increased exercise time more with the fixed protocol, so after 5 weeks' treatment exercise time was the same with both protocols; 680 (64) s with the Bruce and 673 (147) s with the fixed protocol. When the results are expressed as work, the patients achieved less with the Bruce protocol, 7.8 (1.9) kJ, than with the fixed protocol 12.5 (1.5) kJ on placebo, P less than 0.01. After flosequinan, the respective values were 14.5 (2.8) and 25.3 (5.1) kJ. Flosequinan improved corridor walk test times but there was no relationship between this and either treadmill test. Pedometer scores of customary activity were unchanged by flosequinan and were not correlated with any other exercise test. Different methods of assessing exercise capability provide different measures of patients' incapacity.

Topics: Clinical Protocols; Exercise Test; Heart Failure; Humans; Oxygen Consumption; Quinolines; Vasodilator Agents

Flosequinan (BTS 49465) is a putative, selective direct-acting balanced vasodilator currently undergoing evaluation for the treatment of congestive heart failure (CHF) and hypertension. We examined the pharmacologic action of flosequinan and compared it to milrinone and nitroprusside (SNP). In ferret papillary muscle, in vitro, flosequinan (1-100 microM) increased the rate of force development up to 116%. The effect was not blocked by nadolol (10 microM). Flosequinan was less effective than milrinone and SNP as a relaxant of canine renal and coronary arteries, in vitro, since 100 microM of flosequinan produced less than 50% relaxation of the arteries, whereas milrinone or SNP (100 microM) produced between 85 and 125% relaxation of the precontracted arteries. Flosequinan, SNP, and milrinone (100 microM) completely relaxed precontracted canine mesenteric veins. Fifteen minutes after intraduodenal administration (i.d.) of flosequinan (0.3, 1.0, and 3.0 mg/kg) to anesthetized dogs (n = 7), mean left ventricular (LV) dP/dT increased by 11, 27, and 54%, respectively, whereas total peripheral resistance (TPR) decreased by 4, 4, and 13%, and mean arterial pressure (MAP) decreased by 7, 14, and 23%, respectively. flosequinan was 4.6 times more potent as a positive inotrope than as a vasodilator. The hemodynamic profile of milrinone was similar to that of flosequinan, except milrinone produced greater increases in LV dP/dT and decreases in MAP and TPR. In contrast, SNP (1, 3, and 10 micrograms/kg/min i.v.) decreased TPR (7, 18, and 34%, respectively) and MAP (14, 32, and 41%, respectively) without any increase in LV dP/dT. In dogs with propranolol-induced heart failure (PIHF), flosequinan (1.0 and 3.0 mg/kg, i.d.) increased mean myocardial dP/dT by 54 and 84% (n = 5) and MAP, but decreased TPR. The data show that (a) the hemodynamic effects of flosequinan in the normal and PIHF dogs were primarily due to positive inotropy rather than to arterial vasodilation and (b) the positive inotropic effect of flosequinan is independent of catecholamines, since it occurred in dogs with PIHF. The beneficial effect of flosequinan in patients with CHF may not be mediated by balanced vasodilation.

Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Ferrets; Heart Failure; Heart Rate; Hemodynamics; In Vitro Techniques; Muscle, Smooth, Vascular; Myocardial Contraction; Papillary Muscles; Pulmonary Artery; Quinolines; Vascular Resistance; Vasodilator Agents

We evaluated the responses to 90 minutes and 8 days of therapy with a new long-acting vasodilator flosequinan in ten patients with moderate chronic congestive heart failure in an open, uncontrolled study. Acute administration of 100 mg orally resulted in a decrease of preload, with a reduction of left ventricular end-diastolic volume, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and right atrial pressure. Following the acute administration, we found no significant changes of heart rate, cardiac index, stroke volume, peripheral vascular resistance, ejection fraction, and dp/dt. Chronic application for 8 days (100 mg/day) showed persistent effects on preload, with a significant decrease of pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. After 8 days of treatment, cardiac index was significantly increased from 2.2 +/- 0.2 l/min/m2 to 2.8 +/- 0.2 l/min/m2 (p = 0.013) and stroke volume from 57 +/- 10 ml to 74 +/- 9 ml (p = 0.022). Peripheral vascular resistance decreased by ml (p = 0.022). Peripheral vascular resistance decreased by 28%. After 8 days, bicycle exercise capacity increased significantly from 383 +/- 44 sec to 422 +/- 43 sec (p = 0.01) and the patients were able to increase their walking distance over a 6-minute exercise test from 426 +/- 46 m to 477 +/- 33 m (p = 0.007), with a concomitant decrease of dyspnea (p = 0.013). Plasma renin concentration showed only a rise 90 minutes after the acute administration on day 8 of the study, and atrial natriuretic peptide and 6-keto-prostaglandin F1-alpha decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Chronic Disease; Drug Administration Schedule; Exercise Test; Heart Failure; Humans; Neurotransmitter Agents; Quinolines; Vasodilator Agents

Topics: Clinical Trials as Topic; Europe; Heart Failure; Humans; Quinolines; United States; Vasodilator Agents

Flosequinan, a new orally active vasodilator, and its sulfone metabolite were evaluated for inotropic activity in isolated ferret papillary muscles and pentobarbital anesthetized open-chest dogs. In vitro, flosequinan and its sulfone derivative increased tension development in a concentration-dependent manner (1-50 microM) in electrically stimulated papillary muscles pretreated with the beta-adrenergic blocking agent atenolol (2 microM). Peak increases in tension of 75 +/- 17%, and 111 +/- 46% with potencies (EC50) of 15 and 10 microM were observed for flosequinan and its metabolite, respectively. In vivo, flosequinan increased left ventricular dP/dtmax (74 +/- 12%) and right ventricular contractile force (CF) (104 +/- 10%) after administration of 1.875 mg/kg, i.v. Inotropic activity was dose-dependent and remained elevated for at least 60 min postinfusion. Flosequinan also increased heart rate (HR) (14 +/- 2%) and reduced mean arterial pressure (-9 +/- 3%). The i.v. potency of flosequinan (ED50 = 0.45 mg/kg) and its metabolite (ED50 = 0.38 mg/kg) were similar to that of the inotropic vasodilator amrinone (ED50 = 0.38 mg/kg). Inotropic activity was not significantly altered by pretreatment with propranolol (0.5 mg/kg) and atropine (1.0 mg/kg), further supporting the in vitro data indicating that flosequinan can directly stimulate myocardial contractility independent of beta-adrenergic receptor activation. Additional hemodynamic studies were conducted in an acute heart failure model produced by an overdose of propranolol. Flosequinan (2 mg/kg, i.v.) increased cardiac output (CO) (50 +/- 9%) and stroke volume (SV) (29 +/- 8%) while reducing total peripheral vascular resistance (TPR) (-36 +/- 4%), right atrial pressure (-62 +/- 5%), and left ventricular end-diastolic pressure (LVEDP) (-41 +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amrinone; Anesthesia; Animals; Ferrets; Heart Failure; Heart Rate; Hemodynamics; In Vitro Techniques; Infusions, Intravenous; Male; Milrinone; Myocardial Contraction; Papillary Muscles; Pentobarbital; Pyridones; Quinolines; Vasodilator Agents

We studied the hemodynamic effect of a single dose of the new direct-acting vasodilator, flosequinan, in 25 patients with severe acute-onset heart failure complicating acute myocardial infarction, which was resistant to high doses of diuretics, nitrates and dobutamine given intravenously. Flosequinan was added to conventional therapy within 3.7 +/- 0.8 days of the infarction in the form of a single oral dose of 100 mg. Hemodynamic monitoring was performed every hour for 4 hours after the administration, without any other drug being added. Flosequinan produced hemodynamic improvement in all patients. The effect peaked at 1 to 2 hours and remained at this level at 4 hours. Pulmonary capillary wedge pressure decreased from 28.4 +/- 4.5 to 17.8 +/- 5.7 mmHg and cardiac output increased from 3.5 +/- 0.3 to 4.0 +/- 0.4 L/min (p less than 0.05 for both). Pulmonary arterial and pulmonary vascular resistances were also significantly reduced. Heart rate was not significantly altered. Mean systemic arterial pressure was slightly but not significantly reduced. Administration of flosequinan was not associated with symptomatic hypotension, cardiac arrhythmias or other adverse events and the hemodynamic effect was not related to the pre-treatment serum sodium concentration. We conclude that flosequinan is effective in producing acute hemodynamic improvement in patients with heart failure complicating acute myocardial infarction which is resistant to conventional therapy. Flosequinan is well tolerated in this group of patients and therefore further studies to determine the duration of action of the drug in this condition are appropriate.

Topics: Acute Disease; Aged; Cardiac Output; Drug Evaluation; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Pulmonary Circulation; Pulmonary Wedge Pressure; Quinolines; Vascular Resistance; Vasodilator Agents

We studied the hemodynamic effect of a single dose of the new direct-acting vasodilator, flosequinan, in ten patients with severe acute-onset heart failure complicating acute myocardial infarction (MI) resistant to high iv doses of diuretics, nitrates, and dobutamine. Flosequinan was added to conventional therapy at 3.8 +/- 0.5 days after infarction in the form of a single 100-mg oral dose. Hemodynamic measurements were performed every hour for 4 h after administration, without any other drug being added. The nitrate infusion rate was kept constant. Flosequinan produced hemodynamic improvement in this group. The effect peaked at 1 to 2 h and remained at this level at 4 h. Pulmonary capillary wedge pressure decreased from 27.2 +/- 5.4 to 16.4 +/- 3.0 mm Hg, and cardiac output increased from 3.5 +/- 0.3 to 4.1 +/- 0.4 L/min (p less than .001 for both). Cardiac index, stroke index, and left ventricular stroke work index were significantly increased. Pulmonary arterial and right atrial pressures, and systemic and pulmonary vascular resistances were also significantly reduced. Heart rate was not significantly altered. Mean systemic arterial pressure was slightly reduced. Flosequinan administration was not associated with symptomatic hypotension, cardiac arrhythmias, or other adverse events, and the hemodynamic effect was not related to the pretreatment serum sodium concentration. We conclude that flosequinan is effective in producing acute hemodynamic improvement in patients with heart failure complicating acute MI resistant to conventional therapy.

Topics: Administration, Oral; Aged; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Quinolines; Vasodilator Agents

Pharmacologic tolerance develops rapidly to the hemodynamic effects of many vasodilator drugs used in the treatment of congestive heart failure. We evaluated the responses to 3 days of therapy with a new long-acting vasodilator drug, flosequinan (BTS 49465), in 16 patients with severe chronic heart failure. On each of the 3 days, flosequinan (100 or 150 mg orally) produced marked increases in cardiac index and decreases in left ventricular filling pressure, mean right atrial pressure, and systemic vascular resistance (all p less than 0.01) without significant changes in heart rate. Whereas the effects of flosequinan on right and left ventricular filling pressures on the first and third days were similar, cardiac index was higher and systemic vascular resistance was lower after the third dose than after the first dose of the drug, indicating the occurrence of a cumulative vasodilator effect on arterial resistance vessels. Since all hemodynamic changes persisted for longer than 24 h after each dose of the drug, the daily administration of flosequinan also produced a progressive improvement in the hemodynamic state recorded before each dose of the drug. These data indicate that pharmacologic tolerance does not develop to the effects of flosequinan during short-term therapy with the drug in patients with severe chronic heart failure. Instead, further hemodynamic improvement may occur because of a cumulative vasodilator effect that results from the drug's prolonged duration of action.

Topics: Adult; Aged; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines; Vasodilator Agents

The hemodynamic effects of a single dose of flosequinan, a new balanced vasodilator, were studied in twelve patients with severe acute onset heart failure complicating acute myocardial infarction. Flosequinan was added to conventional therapy within 3.8 +/- 0.5 days of the infarction, in the form of a single oral dose of 100 mg in ten of the patients. In the remaining two, reinfarction developed on the sixth day and they received flosequinan immediately thereafter. Hemodynamic monitoring was performed for four hours after the administration, without any other drug being given. Flosequinan produced hemodynamic improvement in all patients. The effect peaked at one to two hours and remained at this level at four hours. Pulmonary capillary wedge pressure decreased from 27.4 +/- 5.0 to 16.5 +/- 2.9 mm Hg and cardiac output increased from 3.5 +/- 0.3 to 4.1 +/- 0.4 l/min (p less than 0.001 for both). Pulmonary arterial and right atrial pressures and systemic and pulmonary vascular resistances were also significantly reduced. Heart rate was not significantly altered (from 84.0 +/- 4.5 to 87.4 +/- 4.6). Mean systemic arterial pressure was slightly reduced. Administration of flosequinan was not associated with any adverse effects and the hemodynamic effect was not related to the pre-treatment serum sodium concentration. We concluded that flosequinan can produce acute hemodynamic improvement in patients with heart failure, complicating acute myocardial infarction. The drug is well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Quinolines; Vasodilator Agents

The hemodynamic effects of BTS 49465, a new oral, direct-acting systemic vasodilator drug, were investigated in 10 patients with severe chronic congestive heart failure. One to 2 hours after the administration of 1.5 mg/kg orally, BTS 49465 produced significant increases in cardiac index, stroke volume index, and stroke work index (26%, 27%, and 23%, respectively, p less than 0.01 to 0.001) and marked decreases in left ventricular filling pressure (-12.6 mm Hg, 44%), mean pulmonary artery pressure (-13.2 mm Hg, 31%), and mean right atrial pressure (-7.7 mm Hg, 63%), all p less than 0.001, without significant changes in heart rate. These hemodynamic responses were accompanied by notable declines in systemic vascular resistance (-28%, p less than 0.001) and pulmonary arteriolar resistance (-24%, p less than 0.05). These effects persisted throughout the 24-hour period of observation. The decline in left ventricular filling pressure in our patients ranged in magnitude from 8 to 21 mm Hg, and varied linearly and directly with pretreatment values for left ventricular filling pressure (r = 0.69). The decrease in systemic vascular resistance ranged in magnitude from 3% to 40% and varied linearly and directly with pretreatment values for systemic vascular resistance (r = 0.85). These data indicate that BTS 49465, a new oral, direct-acting vasodilator agent, exerts balanced cardiocirculatory effects in patients with severe chronic heart failure, which may be sustained with once-daily oral administration.

Topics: Administration, Oral; Adult; Aged; Drug Evaluation; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Quinolines