Administration Of Enoximone Research Articles

Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC)

BackgroundPerioperative administration of Enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study was to evaluate the effects of Enoximone after on-pump cardiac surgery. MethodsA protocol for a multicenter observational study was reviewed and approved by local ethic committee. This preliminary report involves the first 29 patients enrolled, in whom Enoximone was perioperatively administered in the context of on-pump cardiac surgery. All patients enrolled were propensity-matched 1:1 with controls not receiving Enoximone, renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. ResultsAfter propensity matching, the two cohorts of patients receiving Enoximone or not did not show any significant differences among baseline characteristics. Patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively. Consistently, maximum difference versus baseline was +12.6 mL/min/1.73 m2 (or +19.3%) among Enoximone patients vs +3.3 mL/min/1.73 m2 (or +4.4%) among controls (p = 0.02). Multivariable regression analysis (R2-adjusted 0.47) showed only age (β −0.53; p = 0.01), preoperative eGFR (β −0.39; p = 0.02), diabetes (β 2.1; p = 0.01), cardio-pulmonary bypass duration (β 0.08; p = 0.05), and Enoximone administration (β −0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30. ConclusionThese preliminary results show that perioperative Enoximone administration improved renal function in patients undergoing on-pump cardiac surgery. Further studies are needed to confirm these findings.

Right Ventricular Pressure Overload and Pathophysiology of Growing Porcine Biomodel.

The primary objective was to create a clinically relevant model of right ventricular hypertension and to study right ventricular myocardial pathophysiology in growing organism. The secondary objective was to analyse the effect of oral enoximone (phosphodiesterase inhibitor) therapy on right ventricular haemodynamic parameters and myocardial changes in biomodel of right ventricular hypertension. The study included a total of 12 piglets of 42days of age. Under general anaesthesia, pulmonary artery banding (PAB) was performed surgically to constrict the main pulmonary artery to about 70-80% of its original dimension. The study presented two groups of animals labelled C (control animals with PAB; n=8) and E (animals with PAB and oral administration of enoximone; n=4). Direct pressure and echocardiographic measurements were taken during operation (time-1), and again at 40days after surgery (time-2). The animals were killed, and tissue samples from the heart chambers were collected for quantitative morphological assessment. Statistical analysis was performed on all acquired data. At time-2, the median weight of animals doubled and the median systolic pressure gradient across the PAB increased (46.59±15.87mmHg vs. 20.29±5.76mmHg; p<0.001). Changes in haemodynamic parameters were compatible with right ventricular diastolic dysfunction in all the animals. Apoptosis, tissue proliferation and fibrosis were identified in all the myocardial tissue samples. Right ventricular pressure overload leads to increased apoptosis of cardiac myocytes, proliferation and myocardial fibrosis. Our study did not show evidence of haemodynamic benefit or myocardial protective effect of oral enoximone treatment.

Emergency treatment of status asthmaticus with enoximone

This report describes the treatment of eight patients with status asthmaticus, six of whom were already maximally treated. They were consequently treated with enoximone, a selective phosphodiesterase III inhibitor, in their refractory phase. Bronchodilatation in these patients was immediate. No side-effects were observed. Enoximone appears to be a valuable addition to the treatment of status asthmaticus. I.V. administration bypasses inhalation incapability in severe asthma. It is likely to reduce or altogether prevent the need for resorting to secondary or tertiary high-tech therapy such as mechanical ventilation or anaesthetics, thus avoiding complications, as well as for transfers to specialized intensive care units. Not only do these aspects enable substantial cost savings, but they also may spare the patient a lot of anguish and a prolonged recovery.

Impact of Enoximone on Ischemia Reperfusion Injury-Induced Myocardial Mitochondria Damage

Purpose Enoximone mitigates ischemia reperfusion injury (IR)-induced myocardial dysfunction. However, knowledge about the impact of enoximone on myocardial mitochondria remains limited. Methods and Materials Rats, (6 groups, n=7), served as donors. Hearts were perfused (IR0/30) in a Langendorff apparatus or received 15 min of ischemia at 37°C before reperfusion (IR15/30). Groups were repeated using enoximone application (0,167 μg/min) during reperfusion (Perf-IR0/30; Perf-IR15/30). Another 2 groups underwent 40 min of ischemia at 37°C followed by 30 min of reperfusion with or without enoximone administration (IR40/30; Perf-IR40/30). Cardiac function was determined (LVP,LVP dp/dt). Enzymatic parameters were determined from perfusate and tissue (HFAB,CK/MB, TropT). Myocardial mitochondrial fractions (IFM, SSM) were isolated and analyzed regarding respiratory chain function, mitochondrial swelling and Ca2+-uptake. Results LVP and LVP dp/dt max was impaired in IR15/30 but cardiac function recovered in Perf-IR15/30 (P>0.05). Tissue HFAB content decreased remarkably in Perf-IR15/30. CK/MB and TropT were elevated after ischemia without being affected by enoximone. SSM demonstrated a trend towards impaired respiratory chain function in presence of enoximone at all complexes with significant results at II-V and III-V (P .05). In presence of enoximone mitochondrial Ca2+-uptake velocity was significantly increased (one phase exponential association, K-values P Conclusions Enoximone mitigates IR-induced myocardial insufficiency. However, presented data indicate increased mitochondrial damage in case of enoximone treatment. Accelerated mitochondrial decay may result from impact on mitochondrial Ca2+-uptake.

OP-145 THE INFLUENCE OF PERSONAL ANXIETY ON 16-YEARS INCIDENCE OF MYOCARDIAL INFARCTION MEDIATED BY SOCIAL STATUS IN FEMALE POPULATION IN RUSSIA

Introduction: Surgical revascularization in patients with (CAD) and advanced left ventricular dysfunction has historically carried a high perioperative mortality and morbidity; however, with advances in surgical techniques and myocardial protection methods the safety of CABG surgery in those patients with poor ventricular function has been demonstrated. Those high risk patients are particularly in danger of inability to be weaned from the cardiopulmonary bypass after cardiac surgery; in those patients inotropic agents are used first, followed by the intra aortic balloon pump, if required. Objectives: The aim of the study is to assess the impact of Enoximone administration to poor cardiac function IHD patients undergoing CABG, on short term clinical outcomes. Methods: Between June 2006 and June 2011, 215 patients with ischemic heart disease with poor function i.e. ejection fraction below 30% undergoing coronary artery bypass surgery; operated upon them in Ain Shams University hospitals in Egypt. The study population was divided into two groups: • Group A consisted of 104 patients who received Enoximone (phosphodiesterase inhibitor type 3) immediately after crossclamp removal and continue till the end of the ITU stay. • Group B consisted of 111 patients who did not receive Enoximone. Exclusion criteria were hemodynamic instability, associated surgically significant valvular lesions and severe co-morbidities (renal and hepatic failure, cancer, autoimmune disease).

Perioperative administration of enoximone and renal function after cardiac surgery: A propensity-matched analysis

BackgroundPerioperative administration of enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study is to evaluate the impact of enoximone on postoperative renal function after on-pump cardiac surgery. MethodsA total of 3727 patients undergoing cardiac surgery at one Institution between May 2004 and November 2010 were reviewed. A propensity score was built and a 1:1 perfect matching was performed, providing two fairly comparable cohorts of 712 patients each, receiving or not enoximone after surgery. Renal function was evaluated by lower glomerular filtration rate (GFR) value reached postoperatively. ResultsOverall 30-day mortality rate was 4.3% (62/1424). Cumulative incidence of postoperative renal failure (RF) was 157/1424(11%), of which 99/1424(7%) needed renal replacement therapy. Mean lower postoperative GFR in patients who received or not enoximone was 63±30.1 and 53.5±26.1ml/min/1.73m2 (p<0.0001), respectively. At multivariable analysis age (OR2.75, p=0.0004), diabetes (OR1.82, p=0.006), preoperative GFR (OR3.81, p<0.0001), preoperative cardiogenic shock (OR1.65, p=0.004), previous cardiac surgery (OR2.12, p=0.0002), type of intervention (OR1.96, p=0.005), and enoximone (OR0.38, p=0.001) were found to be independently associated with postoperative RF. Logistic regression analysis showed that the administration of enoximone (OR0.41, p=0.0001), and of no inotropes (OR0.27, p<0.0001) were protective vs. the occurrence of postoperative RF. ConclusionPatients perioperatively receiving enoximone showed a statistically significant better renal function after cardiac surgery.

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials

AimsUse of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy.Methods and resultsThe Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial.ConclusionAlthough low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Enoximone in cardiac arrest caused by propranolol: two case reports

We report two clinical cases of cardiac arrest, the former due to an adverse effect of intravenous (i.v.) propranolol in a patient with systemic sclerosis, the latter from a propranolol suicidal overdose. In both cases, conventional advanced life support (ALS) was ineffective but both patients eventually responded to the administration of enoximone, a phosphodiesterase III (PDE III) inhibitor. After the arrest, both patients regained consciousness and were discharged home. The chronotropic and inotropic effects of PDE III inhibitors are due to inhibition of intracellular PDEIII and are therefore unaffected by beta-blockers. These cases suggest that PDEIII inhibitors may be useful in restoring spontaneous circulation in cardiac arrest associated with beta-blocker administration when standard ALS is ineffective.

Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: A randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol

ObjectivesWe compared the hemodynamic effects of dobutamine and enoximone administration before and after long-term beta-blocker therapy with metoprolol or carvedilol in patients with chronic heart failure (HF). BackgroundPatients with HF on beta-blocker therapy may need hemodynamic support with inotropic agents, and the hemodynamic response may be influenced by both the inotropic agent and the beta-blocker used. MethodsThe hemodynamic effects of dobutamine (5 to 20 μg/kg/min intravenously) and enoximone (0.5 to 2 mg/kg intravenously) were assessed by pulmonary artery catheterization in 29 patients with chronic HF before and after 9 to 12 months of treatment with metoprolol or carvedilol at standard target maintenance oral doses. Hemodynamic studies were performed after ≥12 h of wash-out from all cardiovascular medications, except the beta-blockers that were administered 3 h before the second study. ResultsCompared with before beta-blocker therapy, metoprolol treatment decreased the magnitude of mean pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP) decline during dobutamine infusion and increased the cardiac index (CI) and stroke volume index (SVI) response to enoximone administration, without any effect on other hemodynamic parameters. Carvedilol treatment abolished the increase in heart rate, SVI, and CI and caused a rise, rather than a decline, in PAP, PWP, systemic vascular resistance, and pulmonary vascular resistance during dobutamine infusion. The hemodynamic response to enoximone, however, was maintained or enhanced in the presence of carvedilol. ConclusionsIn contrast with its effects on enoximone, carvedilol and, to a lesser extent, metoprolol treatment may significantly inhibit the favorable hemodynamic response to dobutamine. No such beta-blocker–related attenuation of hemodynamic effects occurs with enoximone.

Inhaled alternatives to nitric oxide.

should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.

Effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients

Study Objectives: To study the in vitro effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible (MHS) and normal (MHN) patients. Design: Prospective study. Setting: Malignant hyperthermia (MH) laboratory at a university hospital. Patients: 47 patients with clinical suspicion for MH undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility. Interventions: Biopsies of M. quadriceps femoris were performed in adult patients with a 3-in-1 nerve block and in children with trigger-free general anesthesia. Measurements and Main Result: Patients were first classified as MHS or MHN by the IVCT according to the protocol of the European MH Group (EMHG). Patients with equivocal results (MHE) or with neuromuscular diseases were excluded from the study. Enoximone was added to the organ bath to surplus vital muscle specimens in single bolus concentrations of 0.4, 0.6, 0.8, or 1.6 mmol/L. The in vitro effects of enoximone on muscle contractures and twitch were measured. Seventeen patients were classified as MHS and 30 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles in a dose-dependent manner. Contractures of MHS compared to MHN muscle specimens were significantly larger at all concentrations used in this study. No overlap in maximum contractures was seen between MHS and MHN muscles at a bath concentration of 0.6 mmol/L enoximone only. Conclusions: Diagnosis of MH by an IVCT test with a single bolus administration of enoximone seems to be possible using a concentration of 0.6 mmol/L. The findings of this study may indicate an involvement of the phosphodiesterase-III and cAMP system in pathogenesis of MH. Further in vivo investigation should determine the trigger potency of enoximone in MH susceptible individuals.

Overdose of Metoprolol Treated with Enoximone

To the Editor: Severe poisoning with β-adrenergic–receptor blocking agents, which leads to decreased production of cellular cyclic AMP and impaired release of calcium from the sarcoplasmic reticulum, causes bradycardia and hypotension that can be refractory to treatment with catecholamines, calcium, and glucagon.1 We report on a patient with a life-threatening overdose of metoprolol, whose hemodynamic condition improved dramatically with the administration of enoximone, an inhibitor of phosphodiesterase III. The patient was a 55-year-old woman who intentionally ingested metoprolol in a total dose of 10 g. She was found unconscious about one hour later, with a heart rate of 55 beats . . .

Effects of enoximone on right-ventricular function in patients with impaired myocardial performance.

The effects of an enoximone monotherapy on left-ventricular and especially on right-ventricular haemodynamics were investigated in fourteen patients with impaired left-ventricular function secondary to coronary artery disease. Anaesthesia was induced and maintained with fentanyl and flunitrazepam. After reaching steady state, a bolus of 0.5 mg/kg enoximone was administered, followed by an infusion of 0.5 microgram/kg/min. Besides the common haemodynamic parameters particulary the right-ventricular ejection fraction (RVEF) was measured using a special thermodilution technique. The predefined time points were: before administration of enoximone (baseline) and 5 min, 10 min, 15 min, 20 min, and 30 min after bolus injection of enoximone. Compared to the baseline the maximum effects of enoximone were a 28% increase of cardiac index accompanied by a 39% decline of systemic vascular resistance and an unchanged left-ventricular stroke-work index. While central venous pressure and mean pulmonary artery pressure remained unchanged. RVEF (+20%) and right-ventricular stroke-work index (+30%) were significantly augmented, augmented, indicating improved right-ventricular performance. No adverse effects of the enoximone administration were observed perioperatively. We conclude that an enoximone monotherapy is beneficial for patients with impaired myocardial function undergoing cardiac surgery.

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 μM) 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 umol glucose/g/20 min), of epinephrine (from 7. 1 to 38. 7 umol glucose/g/20 min), of norepinephrine (from 9. 8 to 32 μmol/g/20 min) and of phenylephrine (from 25. 5 to 40. 8 umol 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.

Oral enoximone as a substitute for infravenous catecholamine support in end-stage congestive heart failure

We performed a double-blind, placebo-controlled study to determine whether oral enoximone would aid weaning dobutamine-dependent patients. Twenty-four patients 64 +/- 10 years, with an echocardiographic ejection fraction of 0.20 +/- 0.06, and receiving maximal therapy were studied. After failure of dobutamine weaning, a dobutamine infusion was set up at 10 micrograms.kg-1.min-1 for 48 h. Oral enoximone (100 mg t.i.d.) or placebo was added from D0 for the next 28 days, while the dobutamine dosage was progressively decreased after D4 and eventually stopped at D7. The patients were then followed-up for 21 days (i.e. until enoximone administration had continued for 28 days). In the placebo group, two patients suffered a relapse of congestive heart failure (CHF) before D4, six patients withdrew during dobutamine tapering (five with a relapse of CHF and one with septic shock) and two during follow-up (one with a relapse of CHF and one with sustained ventricular tachycardia). In the enoximone group, three patients withdrew during dobutamine tapering (two with a relapse of CHF, one with a cutaneous rash). Four patients on placebo and nine receiving enoximone could be weaned from dobutamine, P < 0.05. Echocardiographic LV ejection fraction significantly increased and Doppler-derived indexes of systolic function tended to increase when enoximone but not placebo was associated with dobutamine. Oral enoximone might be helpful in weaning patients with end-stage congestive heart failure from i.v. dobutamine.

Pharmakodynamische Effekte des Phosphodiesterasehemmers Enoximon unter dem Einfluß der volatilen Anästhetika Halothan und Isofluran beim koronarchirurgischen Patienten

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. 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. 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. 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.

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.

HAEMODYNAMIC CHANGES PRODUCED BY INHALATION ANAESTHETICS IN THE PHOSPHODIESTERASE INHIBITION

We have investigated the circulatory effects of halothane and isoflurane in the presence of the phosphodiesterase inhibitor, enoximone, in 20 patients, ASA class III, aged 40-70 yr, undergoing coronary artery bypass grafting. After induction of anaesthesia (midazolam, fentanyl, etomidate and pancuronium) all patients received enoximone 0.5 mg kg-1, followed, 10 min later, by either halothane 1 MAC (group I; n = 10) or isoflurane 1 MAC (group II; n = 10). Haemodynamic variables were measured and blood samples (arterial and mixed venous) were obtained before (control, t0), 5 (t1) and 10 (t2) min after the injection of enoximone and immediately (t3) and 5 (t4) min after steady state conditions with halothane or isoflurane, as verified by the end-expiratory concentration. Heart rate, 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 (QO2), oxygen consumption and oxygen extraction rate were calculated using standard formulae. MAP decreased significantly in both groups after bolus injection of enoximone (group I: 11%; group II: 7%). Under steady state conditions with the volatile anaesthetics, a further significant decrease in MAP was observed (group I: 12%; group II: 12%). Enoximone produced a significant increase in CI (group I: 25%; group II: 27% compared with control). After administration of isoflurane, CI remained essentially unchanged, while halothane decreased CI significantly by 20%. In both groups, SVR decreased significantly after administration of enoximone (group I: 26%; group II: 24%).(ABSTRACT TRUNCATED AT 250 WORDS)

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 μg/kg/min. Group IV patients received a maintenance infusion of 5.0 μg/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 μg/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 gulding the intravenous administration of enoximone. Intravenous doses of enoximone above 5.0 μg/kg/min may not provide very much additional hemodynamic benefit compared with lower doses and yet may result in significant accumulation of enoximone and its metabolites, leading to an increased potential for toxicity. An initial intravenous bolus of enoximone should be administered prior to continous infusion of enoximone in cases where immediate hemodynamic benefit is desirable.

Antiischemic and hemodynamic effects of an oral single dose of 150 mg of the phosphodiesterase inhibitor enoximone in patients with coronary artery disease—relation to plasma concentration

The hemodynamic and antiischemic effects of a 150-mg single oral dose of the PDE inhibitor enoximone were correlated with the plasma levels of enoximone and its sulfoxide metabolite. Twenty-one patients with angiographically documented coronary artery disease were investigated by exercise testing 1 and 2 hours after drug administration. The control group consisted of 15 patients with proven coronary artery disease and stable reproducible angina pectoris on exercise. The enoximone group included 14 responders with therapeutic plasma concentrations 2 hours after drug intake and significantly reduced mean pulmonary artery pressures on exercise (from 42.4 +/- 8.6 to 30.9 +/- 11.2 mmHg, p less than 0.05). Compared to basal exercise values, responders showed a reduced ST-segment depression by 1 hour after drug intake (2.1 +/- 1.2 vs. 1.3 +/- 3 mm, p less than 0.05) and minimal values after 2 hours (0.9 +/- 1.0 mm, p less than 0.01) at comparable workloads. There were no significant changes in heart rate, blood pressure, cardiac output, and systemic vascular resistance. No significant improvement in the hemodynamic parameters and ST-segment depression was found in nonresponders with plasma concentrations below 100 ng/ml and 500 mg/ml for enoximone and its metabolite, respectively. In summary, oral administration of enoximone in patients with coronary artery disease led to favorable acute hemodynamic and antiischemic effects at sufficiently high plasma levels of enoximone and its sulfoxide metabolite.