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PubMed1990

Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group.

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1991

Oral enoximone therapy in chronic heart failure: a placebo-controlled randomized trial. The Western Enoximone Study Group.

In a parallel study design, 164 patients with New York Heart Association Functional class II or III heart failure were randomized to receive either enoximone given as 50 mg three times a day, or 100 mg three times a day, or a matching placebo. All patients were receiving digitalis and/or diuretics and had left ventricular ejection fractions less than or equal to 45. Exercise tests were performed after 1, 4, 8, and 12 weeks of treatment. Enoximone produced significantly greater increases in exercise time than placebo treatment at weeks 4 and 8 (p = 0.012, p = 0.029, respectively) but not after 12 weeks. Left ventricular ejection fraction increased significantly after the first dose of enoximone but not after 12 weeks of long-term therapy. Heart failure symptoms and the physicians' evaluations of cardiac status were significantly improved in both enoximone therapy groups during the first 4 weeks of evaluation when compared with evaluations of cardiac status in the placebo group. Diuretic doses were increased more frequently for patients who were receiving a placebo. Adverse events were reported with similar frequency in the placebo and 50 mg enoximone treatment groups; 100 mg enoximone resulted in a significantly greater incidence of adverse events. Mean heart rate and ventricular ectopic activity were not significantly different among the three treatment limbs. Enoximone appears to improve exercise tolerance, ventricular function, and symptoms of heart failure for 4 to 8 weeks. Heart rate, ventricular ectopic activity, and mortality rate were not increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Enoximone Investigators.

OBJECTIVES: To determine the effects of enoximone on mortality and quality of life in patients with severe end stage heart failure. DESIGN: A randomised, double blind, placebo controlled trial of the addition of enoximone to conventional treatment. Planned minimum follow up of one year. SETTING: District general hospitals and cardiological referral centres in the United Kingdom. PATIENTS: Planned 200 patients with severe, symptomatic heart failure despite treatment with diuretics and where appropriate and tolerated angiotensin converting enzyme inhibitors and digoxin. RESULTS: The study was ended early by the ethics committee after 151 patients had been recruited because of an excess mortality in the enoximone group: 27 deaths compared with 18 in the placebo group (P < 0.05). Quality of life measured with a disease specific questionnaire showed a clinically significant improvement at week 2 with a mean increase score of 0.48 in the enoximone treated patients compared with 0.14 in those receiving placebo (P = 0.0086). With the Nottingham health profile questionnaire the physical mobility score was improved after three months in the enoximone group, median 21.3 compared with 41.8 in the placebo group (P = 0.008). CONCLUSIONS: In patients with severe heart failure who remain incapacitated despite conventional treatment enoximone reduced survival but had a beneficial effect on the quality of life. Drugs that improve symptoms in severe end stage heart failure should not be discarded lightly.

Aged↗

PubMed1993

Effect of enoximone alone and in combination with metoprolol on myocardial function and energetics in severe congestive heart failure: improvement in hemodynamic and metabolic profile.

The hemodynamic and myocardial metabolic effects of enoximone (phosphodiesterase III inhibitor), alone or in combination with metoprolol (beta-adrenergic blocker), were studied in patients with congestive heart failure. Ten patients (New York Heart Association Class III-IV) underwent right heart and coronary sinus catheterization, and parameters were assessed at basal condition, at peak enoximone response (mean intravenous loading dose = 2.2 mg/kg), and after the combination with metoprolol (mean intravenous dose = 8.5 mg). Heart rate tended to increase during enoximone administration (from 102 +/- 16 to 107 +/- 16 min-1, ns) and was reduced during enoximone plus metoprolol (to 88 +/- 15 min-1, p < 0.05 vs. basal). Cardiac index was increased during enoximone (from 2.2 +/- 0.2 to 3.8 +/- 0.5 1/min/m2, p < 0.05) and decreased during enoximone plus metoprolol (to 2.8 +/- 0.5 1/min/m2, p < 0.05 vs. enoximone). Mean pulmonary wedge pressure fell during enoximone and remained reduced during enoximone plus metoprolol (from 27 +/- 9 to 9 +/- 3 and to 13 +/- 4 mmHg, respectively, both p < 0.05). Myocardial oxygen consumption did not change during enoximone (from 27 +/- 8 to 25 +/- 13 ml/min, ns) and was reduced during enoximone plus metoprolol (to 19 +/- 8 ml/min, p < 0.05 vs. basal). Myocardial lactate extraction tended to be lower during enoximone and during enoximone plus metoprolol conditions (from 38 +/- 17% to 26 +/- 20% and to 29 +/- 24%, respectively), but no statistical significance was found. Myocardial efficiency was increased during enoximone and during enoximone plus metoprolol (from 9 +/- 3% to 15 +/- 6% and to 14 +/- 6%, respectively, both p < 0.05). Thus in patients with congestive heart failure enoximone improves hemodynamics and, in most cases, it does not influence energetics. The addition of metoprolol to enoximone reduces heart rate, cardiac index, and myocardial oxygen consumption without any other major changes, producing a more physiologic hemodynamic and metabolic profile.

Adult↗

PubMed1991

Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors.

During a 3-year period we administered enoximone, a phosphodiesterase inhibitor with positive inotropic and vasodilator properties, to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects, all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone, whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-, 3-, and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%, 82.5%, and 82.5% compared with 92.1%, 83.8%, and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone, ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists, total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists, but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally, patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher, p less than 0.01) or with (65% higher, p less than 0.01) intravenous beta-adrenergic agonists. Finally, isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists, suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.

Adult↗

PubMed1991

Disposition kinetics of orally administered enoximone in patients with moderate to severe heart failure.

Enoximone is a phosphodiesterase inhibitor, which has been studied extensively for use in the management of patients with moderate-to-severe heart failure. The authors have studied the absorption and disposition kinetics of enoximone and its primary metabolite, enoximone sulfoxide, after both single oral doses of enoximone and at steady-state after short-term chronic oral therapy. A total of ten patients (two female, eight male) with moderate-to-severe heart failure (NYHA class II-IV) were enrolled into the study after giving written informed consent. The plasma levels of enoximone sulfoxide were greater than those of enoximone at all sampling times. The peak enoximone sulfoxide plasma concentrations ranged from 3.5 to 17.3 times the peak enoximone plasma levels for individual patients. The average steady-state plasma concentrations for enoximone were 115 +/- 40 ng/mL and 190 +/- 78 ng/mL for 50 mg every 8 hours and 100 mg every 8 hours dosage regimens, respectively. The absorption and disposition kinetics of enoximone were found to be significantly variable between patients. The authors also evaluated the relationship between dose administered and steady-state plasma levels as well as the relationship between the observed and predicted steady-state plasma levels. The authors found a linear relationship between the dose that was administered and the accrued plasma levels, as well as a good correlation between the predicted and observed steady-state levels. Although these data confirm previous reports that the sulfide metabolite of enoximone accumulates extensively in the plasma during oral therapy, reaching levels much higher than those of enoximone, these data do not support previous suggestions that the disposition of enoximone is nonlinear.

Administration, Oral↗

PubMed1991

[Pharmacology and pharmacokinetics of enoximone].

Enoximone belongs to the imidazole class of compounds, that possess positive inotropic and vasodilatory activities. These pharmacologic effects are caused by selective inhibition of a cAMP-specific phosphodiesterase in the heart and in the smooth muscle of blood vessels. Results obtained in intact animals showed a dose-dependent increase in cardiac contractile force and a reduction in peripheral arterial resistance with only a slight increase in heart rate. Following acute administration of enoximone to patients suffering from cardiac failure an almost linear increase of cardiac index with increasing doses was found. Enoximone is eliminated from the body by biotransformation. Sulfoxide formation is the main metabolic step in man. This metabolite is excreted in the urine. Enoximone sulfoxide also possesses some cardiotonic activity. Reconversion of enoximone sulfoxide to enoximone was shown to occur in the liver and, to some extent, also in the kidney. Bioavailability of enoximone after a single oral dose of 3 mg/kg is about 55%, but may be higher following chronic therapy. This is probably due to saturation of the first-pass metabolism. A mean clearance of about 10 ml/min/kg and a mean half-life of 6 h were determined in patients with cardiac failure. These values are different from those measured in normal volunteers, indicating a reduced clearance of enoximone in these patients. In patients with renal failure enoximone sulfoxide accumulates in plasma. The elimination of enoximone is also reduced which might be caused by reconversion of enoximone sulfoxide to enoximone in this pathophysiologic condition. Thus, the dose of enoximone should be reduced in patients with severe impairment of renal function. Clinically significant drug interactions have not been reported so far.

Administration, Oral↗

PubMed1990

[Enoximone, vasodilator and/or inotropic agent in congestive cardiac insufficiency? Hemodynamic and ventriculographic study of 20 cases].

The aim of this study was to document the effects of enoximone in congestive cardiac failure. The haemodynamic data (aortic pressure, pulmonary pressures, left ventricular pressure, cardiac output, isovolumic contractility index: Vmax) and left ventricular kinetics of 20 patients with dilated cardiomyopathy (11 ischemic and 9 idiopathic in Stages III or IV of the NYHA Classification before recompensation) were recorded under basal conditions, after 30 minutes infusion of dobutamine (10 micrograms/kg/mn) and after 3 hours infusion of enoximone (total dose: 3.6 mg/kg). The two drugs had an equivalent inotropic effect: ejection fraction + 4 +/- 22% with dobutamine and + 16 +/- 39% with enoximone; Vmax increased from 1.53 +/- 0.5 c/sec to 2.49 +/- 0.8 c/sec with dobutamine and to 1.82 +/- 0.5 c/sec with enoximone. Enoximone induced a greater degree of vasodilation (systemic resistances - 14 +/- 21% with dobutamine and - 21 +/- 27% with enoximone) and a more pronounced fall in ventricular filling pressures (- 35 +/- 42% with dobutamine and - 58 +/- 24% with enoximone). Enoximone was less effective than dobutamine in increasing cardiac output (+ 46 +/- 42% with dobutamine and 16 +/- 33% with enoximone) and stroke volume (+ 23 +/- 47% with dobutamine and + 2 +/- 41% with enoximone). This difference in efficacy may be explained by the major reduction in ventricular preload which enoximone induced after that observed with dobutamine. "Responders" (12 patients) had basal cardiac outputs of less than 2.3 l/mn/m2; the peripheral vasodilatation caused by enoximone was greater. Finally, the reduction in left ventricular end diastolic pressure and the increase in Vmax were significantly less in the 11 patients with ischemic cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Oral enoximone pharmacokinetics in patients with congestive heart failure.

The pharmacokinetics of enoximone and its sulfoxide metabolite were determined following administration of a single oral dose of 1 or 2 mg/kg in seven patients with congestive heart failure, and in two normal volunteers following a single 75-mg capsule, and were compared to those published previously. Plasma concentrations of the metabolite were higher than enoximone, and their terminal slopes were parallel. Enoximone and enoximone sulfoxide plasma concentration-time data were fitted to a simple model that included a lag time. Absorption half-lives in patinets and normal volunteers averaged 17 minutes; the elimination half-life of enoximone in patients averaged 2.9 hours, and was slightly prolonged as compared with normal volunteers. The elimination half-life of enoximone sulfoxide averaged 17 minutes in patients and normal volunteers, and was considerably shorter than that reported in other studies. The oral clearance of enoximone in patients averaged 99 L/hr, and was lower than that observed in normal volunteers. The ratio of the area under the plasma concentration time curve of enoximone sulfoxide to enoximone averaged 4.7 in patients, and was similar to that observed in normal subjects. Enoximone oral clearance and the ratio of metabolite to parent were related to liver blood flow (determined by indocyanine green). Enoximone is 65% bound to albumin, which accounts for most of the drug bound to human plasma protein.

Administration, Oral↗

PubMed1989

The electrophysiologic effects of enoximone in patients with preexisting ventricular tachyarrhythmias.

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart failure (coronary artery disease in 10 and idiopathic dilated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias; eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 +/- 0.89 to 2.96 +/- 0.78), and the pulmonary capillary wedge pressure decreased (22.4 +/- 13.2 to 10.0 +/- 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while receiving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficient to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart failure and preexisting ventricular tachyarrhythmias.

Administration, Oral↗

PubMed1990

Pharmacodynamics of enoximone during intravenous infusion.

Twenty-one patients with heart failure (NYHA class II-IV) received a 24-hour infusion of enoximone, followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I-III received a 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0 or 10.0 micrograms/kg/minute. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/minute without the bolus. Serial assessments of haemodynamics, plasma levels of enoximone and enoximone sulphoxide, and ventricular ectopy were performed. Enoximone produced a significant increase in cardiac index (28.1-46.7%) and a decrease in mean pulmonary artery wedge pressure (6.4-35.7%) and systemic vascular resistance (34.7-78.9%). Enoximone had minimal effect on heart rate and blood pressure. In patients who did not receive an initial bolus of 0.5 mg/kg, haemodynamic changes were delayed by approximately 1 hour. Significant haemodynamic improvement was noted at even the lowest infusion rate and did not increase in linear fashion at higher infusion rates. During infusion of enoximone at 10.0 micrograms/kg/minute, both enoximone and its sulphoxide accumulated non-linearly and did not achieve a steady state. No significant adverse effects were noted in these patients. Enoximone infusion at rates greater than 5.0 micrograms/kg/minute may confer minimal additional haemodynamic benefit, while resulting in significant accumulation of enoximone and enoximone sulphoxide. Ventricular ectopy did not increase significantly in most patients.

Cardiotonic Agents↗

PubMed1993

[Pharmacodynamic effects of the phosphodiesterase inhibitor enoximone during exposure to the volatile anesthetics halothane and isoflurane in coronary surgery patients].

AIM OF THE STUDY: We investigated the pharmacodynamic effects of the phosphodiesterae inhibitor enoximone in the presence of halothane and isoflurane in 20 patients, ASA class III, aged 45-75 years, undergoing coronary artery bypass grafting. The study was approved by the local Medical Ethics Committee and patients' informed written consent was obtained. METHODS: After induction of anaesthesia (midazolam, fentanyl, etomidate and pancuronium) all patients received either halothane 1 MAC (group I, n = 10) or isoflurane 1 MAC (group II, n = 10), followed 20 min later by enoximone 0.5 mg/kg. Haemodynamic variables were measured and blood samples (arterial, mixed venous) were obtained before the administration of the volatile anaesthetics (control, t0), immediately (t1) and 5 (t2) min after steady state conditions with halothane or isoflurane, as verified by the end-expiratory concentration and 5 (t3) and 10 (t4) min after the injection of enoximone. Heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure, pulmonary capillary wedge pressure and right atrial pressure were recorded. Cardiac (CI) and stroke volume indices, systemic (SVR) and pulmonary vascular resistance, oxygen availability (AO2) oxygen consumption and oxygen extraction rate were calculated using standard formulae. RESULTS: In both groups HR remained essentially unchanged throughout the investigation period. MAP decreased significantly in both groups under steady state conditions with the volatile anaesthetics (group I: 19%; group II: 30%) but remained unchanged after subsequent injection of enoximone. After administration of halothane SVR remained essentially unchanged, whereas isoflurane decreased SVR significantly by 20%. After enoximone, there was a significant decrease in SVR in both groups (group I: 26%; group II: 25% compared with the values obtained after halothane and isoflurane respectively). Halothane and isoflurane decreased CI significantly and to a similar degree (group I: 17%; group II: 17%). After the injection of enoximone CI increased significantly and reached control values in both groups. AO2 decreased significantly after administration of the volatile anaesthetics (group I: 19%; group II: 21%) and increased significantly after administration of enoximone, returning to control values. Halothane (7%) and isoflurane (13%) produced a significant increase in oxygen extraction. After bolus injection of enoximone oxygen extraction decreased significantly and returned to control value in group II. In group I enoximone decreased oxygen extraction significantly compared with control. CONCLUSION: Our results suggest that in the presence of halothane or isoflurane the phosphodiesterase inhibitor enoximone produces a comparable increase in cardiac output and decrease in systemic vascular resistance in patients with coronary artery disease.

Aged↗

PubMed1989

Effects of the phosphodiesterase inhibitor enoximone on the autonomic innervation of the isolated heart.

Enoximone is a selective inhibitor of a low Km, cyclic AMP-specific type of phosphodiesterase (PDE III). In guinea pig and chicken atria, enoximone (0.1-100 mumol/L) caused a weak increase in the force of contraction. The heart rate was slightly enhanced or was unchanged (chicken). Enoximone (30 mumol/L) also failed to shift the concentration-response curves for the positive inotropic and chronotropic effects of norepinephrine in guinea pig atria. Under almost the same conditions, enoximone and the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) markedly potentiated the forskolin-induced mobilization of choline from phospholipids. The concentrations of IBMX (100 mumol/L) and of enoximone (50 mumol/L) used were equieffective and did not enhance choline mobilization by themselves. Cardioinhibition caused by acetylcholine was unaffected by enoximone. In perfused guinea pig hearts, the release of [3H]norepinephrine evoked by field stimulation (5 Hz) was increased by 50 mumol/L enoximone both in the absence and presence of cocaine plus corticosterone. In contrast, enoximone failed to alter the release of acetylcholine in chicken hearts at rest and during field stimulation (5 Hz), which directly depolarizes the intrinsic post-ganglionic nerves. Similar results were obtained in guinea pig hearts using [3H]acetylcholine. In contrast, when the release of labeled or unlabeled acetylcholine was evoked by (preganglionic) vagal stimulation, enoximone (30 and 50 mumol/L) and IBMX (50 mumol/L) reduced the release in both species. Taken together, enoximone and IBMX apparently reduced ganglionic transmission. The results further indicate functional compartmentalization of PDE III in guinea pig myocardial cells. PDE III appears to be involved in the regulation of myocardial choline-phospholipid hydrolysis and of norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1994

[Early echocardiographic identification of viable myocardium after acute myocardial infarct using inotropic agents: comparison of dobutamine and enoximone].

BACKGROUND: The reversibility of regional dysfunction early after acute myocardial infarction may be obtained with inotropic adrenergic stimulation, in particular during low dose dobutamine infusion, suggesting the presence of viable myocardium. The aim of this study was to determine whether viable myocardium can be identified by two-dimensional echocardiography after an i.v. bolus of enoximone-positive inotropic non-adrenergic drug, phosphodiesterase III inhibitor as well as during dobutamine infusion, in patients with acute myocardial infarction. METHODS: Twelve male patients, aged 57 +/- 10 years and treated with rtPA (100 mg i.v. in 180 minutes) within the first 6 hours of a first anterior myocardial infarction were studied. All patients underwent a dobutamine infusion (5 and 10 mcg/kg/min, 5 minutes per dose) 4 +/- 1 days after entrance, followed by an enoximone bolus (1 mg/kg over 5 minutes) 1 hour later. Echocardiography was performed before dobutamine and enoximone, during dobutamine, 10 minutes after enoximone and at 6 +/- 2 months follow-up. A Wall Motion Score Index (WMSI) was calculated as recommended by the American Society of Echocardiography. All patients underwent coronarography on days 9-11 post-infarction. RESULTS: Improvement in regional function of basally asynergic segments occurred in 8 patients during dobutamine infusion, as well as after enoximone i.v. bolus, and in 1 patient only during dobutamine infusion. Both dobutamine and enoximone tests were found to be negative in the other 3 patients. A decrease of WMSI was observed with both dobutamine and enoximone tests (from 1.84 +/- 0.32 to 1.73 +/- 0.31; p = .002 with dobutamine; from 1.84 +/- 0.32 to 1.70 +/- 0.27; p = .0132 with enoximone) with concordant wall motion changes between two tests in 73/84 (87%; K = 0.61) basally asynergic segments. There were no complications occurred during the study. Of 8 patients with positive response for viable myocardium to both tests, 6 had a patent and 2 an occluded infarct-related artery. However, in the latter a collateral circulation toward necrotic area was present. At follow-up improvement in regional function of basally asynergic segments, with a decrease of WMSI (from 1.74 +/- 0.23 to 1.59 +/- 0.24; p < .05), was observed in 4 of 8 patients with viable myocardium detected by either dobutamine or enoximone. CONCLUSIONS: 1) Viable asynergic myocardium may be identified early after acute myocardial infarction by enoximone bolus, as carefully and safely as by dobutamine infusion; 2) transient recovery of post-ischemic myocardial dysfunction may be obtained independently of beta-receptor stimulation.

Aged↗

PubMed1994

[Neurohumoral and hemodynamic effects in combination therapy of enoximone and dopamine].

Twelve patients with severe heart failure (NYHA class III-IV) were investigated by intraindividual comparison for the hemodynamic and neurohumoral effects of dopamine (3 and 6 micrograms/kg/min), enoximone (8 micrograms/kg/min), and the combination of both medications (dopamine 3 micrograms/kg/min+enoximone 8 micrograms/kg/min) using right heart catheterization. The duration of active treatment was 8 h for each substance with a subsequent washout time of 16 h. Dopamine led to a dose-dependent increase in cardiac index of 10-13% and 18-37% under 3 and 6 micrograms/kg/min, respectively (p < 0.001). Enoximone monotherapy produced a comparable increase in cardiac index between 27 and 32% (p < 0.001). Enoximone, but not dopamine, resulted in a significant decrease in mean pulmonary artery pressure (21-26%; p < 0.01), pulmonary capillary wedge pressure (24-30%; p < 0.01), and right atrial mean pressure (26-28%; p < 0.001). The systemic vascular resistance was without significant changes at low-dose dopamine therapy, decreased by 10-19% insignificantly at a dose of 6 micrograms/kg/min, and reached the level of significance with enoximone therapy (-20 to -25%; p < 0.001). There was a highly significant decrease by 49-55% in systemic vascular resistance with enoximone (p < 0.001), in contrast to dopamine. Heart rate and blood pressure remained without significant changes at low-dose dopamine, with the heart rate increasing significantly by 25% at a dose of 6 micrograms/kg/min within the first 2 h (p < 0.01). Enoximone produced a heart rate increase by 8-13% (being significant after 2 h; p < 0.05) with no changes in blood pressure. The combination therapy with dopamine and enoximone led to an additive increase in cardiac index by 35-43% (p < 0.001), a decrease in right atrial mean pressure by 28-36% (p < 0.01), a decrease in systemic vascular resistance by 27-30% (p < 0.01) and in pulmonary vascular resistance by 46-51%. An additive effect on heart rate was not observed. The respective monotherapies with low-dose dopamine and enoximone had no remarkable effect on plasma catecholamines, while dopamine at a dose of 6 micrograms/kg/min and combination therapy led to a significant increase in noradrenaline levels. There was a highly significant decrease in the plasma concentration of the atrial natriuretic factor under enoximone and combination therapy (p < 0.001) as well as a significant decrease in aldosterone (0 < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1994

[Clinico-pharmacologic aspects of therapy with enoximone].

Enoximone is an imidazole derivative which proved to be a selective inhibitor of the isoenzymes III/IV of the cAMP-specific phosphodiesterase. It has been shown in various experimental models that the drug exerts both positive inotropic and vasodilating properties which can be attributed to the proposed mode of action. A marked dose-dependent improvement in left ventricular pump performance was observed, with only minor changes in heart rate or systemic blood pressure, if enoximone was administered as i.v. -bolus to patients with moderate to severe congestive heart failure. These effects coincided with vasodilatory effects as determined by decreases in systemic vascular resistance and pulmonary capillary wedge pressure. Enoximone is eliminated by intensive metabolism, predominantly in the liver, with enoximone sulfoxide being the major metabolite in man. Enoximone exhibits a marked firstpass metabolism following oral administration. There is evidence in the literature that the metabolism can be saturated either during long-term administration or by increasing the dose of enoximone. In experimental settings, the metabolite exerts weak positive inotropic effects, too, and reconversion to the parent compound enoximone has been demonstrated in addition. The half-life of elimination of enoximone seems to be about 1 h in healthy volunteers and approximately 3 to 7 h in patients with congestive heart failure, with marked inter-individual differences. In patients with renal failure mainly enoximone sulfoxide accumulates in plasma depending on the degree of renal impairment. The elimination of enoximone seems to be impaired in these patients, too, which might be caused by enhanced reconversion due to the high plasma concentrations of the metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗

PubMed1987

Pharmacology of enoximone.

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1987

Comparative effects on hemodynamics of enoximone (MDL 17,043), dobutamine and nitroprusside in severe congestive heart failure.

To assess their comparative effects on hemodynamics, nitroprusside, dobutamine and enoximone were sequentially administered to 10 patients with severe congestive heart failure. Nitroprusside, dobutamine (at 10 micrograms/kg/min) and enoximone (at 2 mg/kg) increased stroke volume index to a similar extent (31%, 34% and 36%, respectively). Enoximone produced less tachycardia than dobutamine and, consequently, a smaller improvement in cardiac index. Mean arterial pressure was not altered by dobutamine but was reduced 9% by enoximone, 2 mg/kg. This finding accounts for the larger (although not significant) increase in left ventricular stroke work index observed with dobutamine compared with enoximone. Ventricular filling pressures and vascular resistances were significantly decreased by all 3 drugs (p = 0.001). All 3 drugs improved cardiac pump function when assessed by the increase in stroke index to a similar extent; however, enoximone (2 mg/kg) resulted in less hypotension than nitroprusside (mean arterial pressure -9% vs -22%, p = 0.0001) and in less tachycardia than dobutamine 10 micrograms/kg/min. Those differences in mode of action account for the variations observed in the heart rate-blood pressure product (dobutamine 10 micrograms/kg/min, +18%, enoximone 2 mg/kg, -5%, p = 0.003). Enoximone thus appears to be of great value in the management of severe congestive heart failure by its combination of vasodilatory and inotropic properties. Enoximone (2 mg/kg) provides a clinically significant increase in cardiac index, a clear reduction of ventricular filling pressures, a moderate reduction of mean arterial pressure and only minor changes of heart rate and of rate pressure product.

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