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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)

Animals↗
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.

Aged↗
PubMed1987

A double-blind dose response comparison of oral enoximone and placebo for congestive heart failure.

Enoximone (MDL 17,043), a newly synthesized imidazole derivate, has been shown to possess both positive inotropic and vasodilating properties. Sixteen patients with congestive heart failure were allocated to receive either enoximone, 50, 100 or 150 mg, or placebo, each given 3 times daily for 4 weeks, to investigate the dose-related efficacy and tolerability of oral enoximone. Symptom-limited exercise capacity improved in 5 of 10 patients in the enoximone group. The ejection fraction increased from 28% to 36% after 4 weeks, to 36% after 8 weeks and to 35% after 12 weeks in the enoximone group. Exercise duration and ejection fraction did not change in the patients in the placebo group. With enoximone, heart rate, blood pressure, Holter monitoring and laboratory tests showed no significant drug-related changes. The addition of oral enoximone to existing therapy with digitalis and diuretics may improve the clinical condition and left ventricular function in patients with congestive heart failure. Enoximone shows clinical efficacy at dosages of 50 mg and 100 mg 3 times daily. With the higher dosage, unwanted side effects increased but efficacy did not. Enoximone did not increase ventricular ectopy in the doses given.

Administration, Oral↗
PubMed1993

Interaction between inhalational anaesthetics and enoximone on isolated heart muscle.

1. The present study describes the effects of halothane or isoflurane on enoximone activity in the isolated left atria of the rat. 2. Concentration-response curves were obtained for the positive inotropic effects of enoximone on electrically stimulated left atria. 3. Enoximone significantly (P < 0.01) increased the contractile force (56% maximum) with all the concentrations tested (10(-9) -10(-3) M). 4. When halothane (1.5% v/v) was present in the organ bath, the maximum effect obtained with enoximone (9%) was significantly lower than that obtained with enoximone alone. 5. Similar results were obtained with enoximone in the presence of halothane plus diltiazem. Isoflurane (1.5% v/v) did not significantly modify the maximum effect obtained with enoximone alone. 6. The administration of diltiazem antagonized the positive inotropic effects of enoximone in the presence of isoflurane or halothane. 7. These results shows that halothane, but not isoflurane, decreased the potency of enoximone on the isolated left atria and suggests that this effect may be mediated by the blocking of the influx of extracellular calcium through voltage-dependent calcium channels inhibited by diltiazem.

Anesthetics↗
PubMed1992

The role of enoximone in cardiac surgery.

After cardiopulmonary bypass (CPB), some patients may require circulatory support. This study examined the role of the phosphodiesterase-III inhibitor, enoximone, in cardiac surgery. Eighty patients selected by chance were allocated randomly to two groups: 40 patients received enoximone 1.0 mg kg-1 approximately 10 min before weaning from CPB and 40 served as a control group. Additional pharmacological therapy (adrenaline, noradrenaline, nitroglycerin) was given, when necessary, by anaesthetists who were not involved in the study. In addition to standard monitoring, skin capillary blood flow was assessed using a laser Doppler technique before, during and after CPB until 2 h after the end of the operation. In the period after bypass, cardiac index was always significantly greater in the enoximone than in the control group. Systemic and pulmonary vascular resistance were less in the enoximone-treated patients, indicating a reduction in right and left ventricular wall stress. Oxygen consumption in the enoximone patients was significantly greater after CPB, whereas intrapulmonary shunting was comparable in the two groups. In comparison with baseline values, skin capillary blood flow in the enoximone patients was always greater than that in the control group. In comparison with the control patients, significantly fewer enoximone patients needed adrenaline, and in a smaller dose, even 2 h after operation, whereas more enoximone patients required noradrenaline therapy for a short period. We conclude that the use of enoximone before weaning from CPB improved overall cardiac function, reduced the need of catecholaminergic inotropic support, and provided increased organ perfusion up to 2 h after operation.

Adult↗
PubMed1994

Enoximone in chronic stable angina: a double-blind placebo-controlled cross-over trial.

Enoximone, a phosphodiesterase inhibitor (PDEI), has both positive inotropic and vasodilatory properties. We examined the effect of a single oral dose of enoximone as compared with placebo on myocardial ischaemia and global left ventricular (LV) function using both exercise ECG and Doppler measurements of aortic blood flow, respectively. Twenty patients (16 men, 4 women) with a mean age of 59 years and stable angina were studied. Total exercise duration was significantly longer after enoximone as compared with placebo treatment, with a mean difference of 22.8 s (p = 0.003). Times (mean +/- SD) to onset of angina and development of significant ST-segment decrease were similar after placebo (454 +/- 101 and 352 +/- 155 s, respectively) or enoximone (500 +/- 155 and 413 +/- 192 s, respectively), although both showed trends in favour of enoximone. As compared with placebo, significantly higher heart rate (HR) was measured for enoximone both at rest (75 +/- 18 vs. 90 +/- 22 beats/min, p < 0.01) and on recovery from exercise (81 +/- 18 vs. 89 +/- 19 beats/min, p < 0.05). Enoximone had no significant effect on systolic or diastolic blood pressure (SBP, DBP) or rate-pressure product (RPP) generated at rest or during exercise. Changes in both acceleration and velocity of aortic blood flow during exercise were similar after administration of enoximone or placebo. We showed that a single oral dose of enoximone is well tolerated in patients with ischaemic heart disease, improving both exercise capacity and favourably influencing ST-segment changes with no increase in adverse events or significant haemodynamic disturbances.

Administration, Oral↗
PubMed1990

Pharmacology and pharmacokinetics of enoximone.

Enoximone is an inotropic vasodilating agent. Its principal effects are positive inotropism and vasodilation, which are not accompanied by changes in myocardial oxygen consumption. An inotropic dose of enoximone increases the level of cyclic AMP in the isolated, blood-perfused dog papillary muscle owing to its selective inhibition of the one isoform of cyclic AMP phosphodiesterase from the dog heart that is inhibited by cyclic GMP. Studies on the metabolism and pharmacokinetic profile of enoximone have been carried out in the rat, dog and monkey. Enoximone is metabolized mainly by oxidation to enoximone sulphoxide in all species studied, and this is reversible. In congestive heart failure patients, approximately 74% of a rapidly administered intravenous dose of enoximone is excreted in a 24-hour urine collection as the sulphoxide metabolite; only about 0.49% is recoverable as intact drug. Enoximone sulphoxide has the same inotropic and vasodilator activities as enoximone but is 0.13-0.14 times as potent and has a 13 times longer duration of inotropic action in the dog. It is suggested that the metabolite may contribute to some of the effects that follow enoximone administration.

Animals↗
PubMed1990

Drug interactions: the new phosphodiesterase inhibitor enoximone and the calcium channel blocker nifedipine in coronary surgery patients--influence on hemodynamics and plasma concentrations.

The calcium channel blocker nifedipine and the new phosphodiesterase (PDE) inhibitor enoximone are used in the treatment of cardiovascular diseases. Since both substances are acting on slow calcium channels and because systemic elimination of these two agents is dependent on oxidative drug metabolizing enzyme activity, this study was performed in order to investigate hemodynamic changes and effects on plasma levels when both substances are given simultaneously. Forty-five patients undergoing aortocoronary bypass grafting were randomly subdivided into three groups: (a) group (n = 15) received 0.3 micrograms/kg/min of nifedipine as an infusion (N patients); (b) group (n = 15) received 0.5 mg/kg of enoximone as a bolus (E patients); and (c) group (n = 15) received nifedipine and enoximone in the same dosages (E + N patients). In addition to various hemodynamic variables, plasma levels of nifedipine, enoximone, and enoximone sulfoxide were measured until the end of the operation. Injection of enoximone was followed by an increase in cardiac index and right ventricular ejection fraction, decrease in pulmonary artery pressure, pulmonary capillary pressure, and systemic vascular resistance, whereas heart rate and mean arterial pressure remained almost unchanged. These changes were comparable for E and E + N patients. Plasma concentrations of enoximone and enoximone sulfoxide were not affected by nifedipine infusion and showed a comparable course in E and E + N patients. Nifedipine plasma level dropped to values less than 15 ng/ml at the end of extracorporeal circulation in N and E + N patients. It can be concluded that enoximone improved hemodynamics even in patients pretreated with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Human serum and plasma protein binding of enoximone and its sulfoxide metabolite.

Experimental factors and determinants of the protein binding of enoximone (a new cardiotonic agent) were investigated in human serum from healthy, drug-free subjects using a rapid ultrafiltration method; these factors and determinants included nonspecific binding to the apparatus, ultrafiltrate volume, temperature, serum pH, enoximone serum concentration, and enoximone sulfoxide (metabolite) concentration. It was demonstrated from mass balance experiments that nonspecific binding to the apparatus did not occur. Within the range investigated, ultrafiltrate volume did not affect the binding result. However, serum pH and temperature were critical variables. At pH 7.4 and 37 degrees C, enoximone serum binding occurred to the extent of approximately 70%; over the therapeutic serum concentration range, this binding was concentration independent. Experiments with purified albumin solutions indicated that much of the serum binding could be accounted for by albumin. At concentrations exceeding those observed clinically, enoximone sulfoxide did not affect enoximone serum binding. In another experiment, enoximone binding to serum was compared with that from plasma containing either heparin or disodium EDTA. There were essentially no differences. Enoximone sulfoxide serum protein binding was also investigated in serum from healthy, drug-free human subjects; binding occurred to the extent of approximately 5%.

Animals↗
PubMed1990

The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery--pharmacokinetics and influence on parameters of coagulation.

Enoximone is a selective inhibitor of the phosphodiesterase-III enzyme (PDE-III) and possesses positive inotropic and vasodilatory properties. The PDE-inhibitor amrinone has been associated with adverse effects on coagulation by decreasing platelets. To investigate the influence of enoximone on hemostasis, 18 patients undergoing elective aorto-coronary bypass grafting and receiving enoximone were compared to a control group (n = 18). In addition, the plasma levels of enoximone and its major metabolite (enoximone-sulfoxide) were studied following a single injection (0.5 mg/kg) and during a continuous infusion (5 and 10 micrograms/kg.min) before, during and after extracorporeal circulation (ECC). No difference between study and control groups was found for the parameters of coagulation during the investigation period; in particular there were no differences in platelet count and platelet function (thrombelastography). Following the single bolus, peak plasma levels decreased during ECC to ineffective levels. Continuous infusion, however, maintained effective plasma levels of enoximone; sulfoxide levels were twice as high as enoximone concentrations up until the end of the investigation period. It is concluded that enoximone can be judged to be safe in respect to its effects on coagulation even following ECC and at relatively high doses. The use of continuous infusion results in plasma levels which remain at an effective concentration through to the time that the patient is transferred to the intensive care unit.

Aged↗
PubMed1991

Clinical pharmacology of intravenous enoximone: pharmacodynamics and pharmacokinetics in patients with heart failure.

Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to 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 to III received an 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0, or 10.0 micrograms/kg/min. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/min without a loading dose. Serial assessment of hemodynamics, plasma levels of enoximone and enoximone sulfoxide, and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index, and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate, and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate, and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg, the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 micrograms/kg/min), rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in guiding the intravenous administration of enoximone.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Arterial hemodynamics and cardiac effects of enoximone, dobutamine, and their combination in severe heart failure.

The acute systemic and regional hemodynamic effects of dobutamine (5, 10, and 15 micrograms/kg/min intravenously), of enoximone (1, 1.5, and 2 mg/kg intravenously), and of the dobutamine-enoximone combination were compared in eight patients with severe congestive heart failure. Dobutamine and enoximone similarly and dose-dependently increased cardiac index and decreased systemic vascular resistance, right atrial pressure, and mean capillary wedge pressure. Dobutamine, but not enoximone, increased heart rate after 10 and 15 micrograms/kg/min. The combination of the two drugs caused a greater increase in cardiac index and a greater decrease in total peripheral resistance than did each drug alone. In the forearm vascular bed, brachial blood flow and brachial artery diameter were increased by enoximone significantly and dose-dependently and by dobutamine only at 5 micrograms/kg/min. Finally, the combination of the two drugs increased brachial blood flow but not brachial artery diameter to a larger extent than enoximone alone. Hepatosplanchnic and renal blood flows were not altered by any of the treatments. These results indicate that (1) enoximone exerts a significantly greater muscular vasodilator action than dobutamine; (2) the dobutamine-enoximone combination potentiates the systemic and brachial vasodilator effects of each drug; and (3) high doses of dobutamine (10 and 15 micrograms/kg/min) improve hemodynamics through their positive inotropic and chronotropic effects, whereas at low doses (5 micrograms/kg/min) a peripheral vasodilation also contributes.

Adult↗
PubMed1987

A dose-response study of intravenous enoximone in congestive heart failure.

Previous clinical studies with intravenous enoximone have used cumulative dosing to quantify enoximone's hemodynamic effects. The magnitude and duration of the hemodynamic effects of single intravenous doses of enoximone were evaluated in patients with congestive heart failure. Sixty patients, who were in New York Heart Association functional classes III and IV, received single intravenous doses of enoximone, either 0.25 (12 patients), 0.5 (13 patients), 1 (14 patients), 1.5 (10 patients) or 2 mg/kg (11 patients). Cardiac index was increased by 20% with the 0.25 mg/kg dose and by 48% and 42% with the 1.5 and 2 mg/kg doses, respectively. These increases were statistically significant (Student's paired t test with Bonferroni's correction, p less than 0.007) for 1 hour after 0.25 and 0.5 mg/kg, for 2 hours after 1 mg/kg and for 4 hours after 1.5 and 2 mg/kg. Enoximone also reduced pulmonary artery diastolic pressure by 19% with 0.25 mg/kg and by 29% with 2 mg/kg. The duration of effect varied from 1 hour with 0.25 mg/kg to 4 hours with 2 mg/kg. Enoximone produced no consistent or dose-related effects on heart rate or blood pressure. Eighteen adverse reactions were reported by 15 patients, of which 11 were minor and transient (vein pain, flushes, nausea). In 5 patients ventricular or supraventricular arrhythmias were observed, including nonsustained ventricular tachycardia and extrasystoles; 3 of these patients had evidence of arrhythmias before enoximone. Laboratory studies before and after treatment showed no drug-related effects. Dose-related effects on the magnitude and duration of hemodynamic responses to intravenous enoximone were evident within the dose range of 0.25 to 2 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Enhancement of hepatic glucose release and bile flow by the phosphodiesterase-III-inhibitor enoximone in the perfused rat liver.

The use of phosphodiesterase-III-inhibitors (PDI) as inotropic substances in the treatment of cardiac failure can be associated with hyperglycaemia. This phenomenon could be caused by hepatic events induced by PDI. The purpose of our study was to investigate the effects of the PDI enoximone on hepatic carbohydrate metabolism and bile flow. In the rat liver perfusion model, hepatic glucose and lactate production, portal flow and bile flow were determined. Administration of enoximone (1, 10, 100 microM) increased hepatic glucose output and bile acid-independent bile flow in a dose-dependent manner. The PDI enhanced the glycogenolytic effects of glucagon (from 15.7 to 38.6 mumol glucose/g/20 min), of epinephrine (from 7.1 to 38.7 mumol glucose/g/20 min), of norepinephrine (from 9.8 to 32 mumol/g/20 min) and of phenylephrine (from 25.5 to 40.8 mumol glucose/g/20 min). Furthermore, lactate production was significantly reduced by enoximone. The effect of epinephrine and phenylephrine on portal flow was blocked or diminished by enoximone administration. In summary, it was shown that the PDI enoximone is able to enhance hepatic glucose production. Bile acid-independent bile flow was increased by the inhibition of phosphodiesterase-III. The effects of enoximone and glycogenolytic hormones on glucose release were synergistic. The vasoconstrictive action of catecholamines was reduced or completely prevented by enoximone. In conclusion, enoximone has glycogenolytic, vasodilatory and choleretic properties in the liver.

Animals↗
PubMed1990

Placebo-controlled trial of oral enoximone in end-stage congestive heart failure refractory to optimal treatment.

A double-blind, randomized, concurrent trial of enoximone vs placebo was undertaken to assess the efficacy and safety of enoximone, 100 mg t.d.s. added to optimal therapy in 30 patients (mean age, 66.4 +/- 14 years) with severe congestive heart failure. Before inclusion, all patients remained markedly symptomatic despite treatment with diuretics, digitalis, vasodilators and angiotensin converting enzyme inhibitors. Symptoms and quality of life were evaluated at inclusion, and at days 4 and 31; 24-hour electrocardiography and Doppler echocardiography were performed at inclusion and at day 31. Clinical and echocardiographic baseline characteristics were similar in the two groups. During the study, 10 patients dropped out: 3 in the enoximone group (1 death) and 7 in the placebo group (3 deaths). At day 4, symptoms were improved in 13 enoximone-treated patients and in 8 patients on placebo (P less than 0.05). At day 31, symptoms were still improving in 10 of 12 patients on enoximone and in 6 of 8 patients on placebo (NS). No serious clinical side-effects were reported, and no statistically significant difference in the frequency of premature ventricular contractions between the two groups was apparent on Holter monitoring. Peak acceleration of ascending aortic blood flow at entry was 17 +/- 6 m/second2 in the enoximone group and 18 +/- 5 m/second2 in the placebo group (NS). At day 31, the change in peak acceleration was +20% in the enoximone group vs -6% in the placebo group (P less than 0.05). Cardiac index increased by 18% in the enoximone group (from 2.17 +/- 0.7 litres/minute/m2 to 2.4 +/- 1.0 litres/minute/m2 (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Enoximone inhibits hepatic mitochondrial long-chain acyl-CoA synthetase.

The phosphodiesterase inhibitor, enoximone, was previously shown to cause paradoxical effects on cardiac lipid metabolism. The present study was undertaken to elucidate the effects of enoximone on the hepatic mitochondrial pathway of fatty acid oxidation. Results presented here show that in isolated rat liver mitochondria, palmitate oxidation was inhibited progressively by increasing concentrations of enoximone. Maximum inhibition (35%) of mitochondrial oxygen uptake was attained at 250 microM enoximone. At this concentration, enoximone did not affect the oxidation of either palmitoyl-CoA or palmitoyl carnitine. Also, enoximone did not inhibit the oxidation of the short-chain fatty acid, hexanoate, neither did it affect the respiratory chain in the mitochondria. These data suggest that enoximone specifically inhibits long-chain acyl-CoA synthetase activity. This was confirmed experimentally when the activity of this enzyme was determined in the absence and presence of enoximone. Discovering inhibitors of specific steps in lipid metabolism should provide a useful tool to investigate mechanisms regulating this pathway.

Animals↗