Rationale and design of the enoximone clinical trials program

BACKGROUND: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.     

Effects of low dose enoximone for chronic congestive heart failure

To examine the short-term hemodynamic and long-term clinical effects of oral enoximone at low doses, 12 patients with severe, chronic congestive heart failure (CHF) were given 1 mg/kg oral enoximone and followed with serial hemodynamic measurements for 24 hours. Control cardiac index was 1.9 +/- 0.5 liters/min/m2 and it increased significantly by 1 hour, with a peak effect at 2 hours to 2.4 +/- 0.4 liters/min/m2 (p less than 0.05). Similarly, wedge pressure, 22 +/- 8 mm Hg at control, decreased to 16 +/- 10 by 1 hour (p less than 0.05). Six of the 12 patients received 1 mg/kg of enoximone on day 1 and 2 mg/kg on day 2. The higher dose of enoximone caused no further improvement in cardiac performance but prolonged the salutary hemodynamic effect. Subsequently, 79 patients (18 in New York Heart Association class III and 61 in class IV) with CHF (ejection fraction 17 +/- 8%) were followed over a 3 year period; the average enoximone dose was 1.7 +/- 0.7 mg/kg 3 times daily. Improvement of at least 1 functional class occurred in 55 patients (70%) at 1 month, 27 patients (34%) at 6 months and 19 (24%) maintained their improvement for over 1 year. Enoximone was discontinued in 20 patients (25%); in 5 (6%) for adverse effects and in 13 patients because of no clinical benefit. Adverse effects occurred in 14 patients (18%); 6% of all patients required discontinuation of drug. Six month survival was 50%, 42% at 1 year and 30% at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group

OBJECTIVES: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity. BACKGROUND: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated. METHODS: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring. RESULTS: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups. CONCLUSIONS: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.     

Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.     

Bicyclo-prostaglandin E2 metabolite in congestive heart failure and relation to vasoconstrictor neurohumoral principles

Vasodilator prostaglandins may play a role in maintaining circulatory homeostasis in patients with congestive heart failure (CHF). Plasma levels of bicyclo-prostaglandin E2 metabolite (PGEm), a chemically stabilized degradation product of the vasodilator prostaglandin E2, were determined in 45 patients with chronic CHF (New York Heart Association class II, III or IV). Mean circulating levels of bicyclo-PGEm were significantly elevated in patients with functional class III (72 +/- 8 pg/ml) or IV CHF (77 +/- 10 pg/ml) compared with control subjects (49 +/- 3 pg/ml) and patients with functional class II CHF (49 +/- 4 pg/ml). Bicyclo-PGEm concentrations correlated with plasma renin activity (r = 0.68, p less than 0.001) and plasma angiotensin II (r = 0.56, p less than 0.001) and plasma noradrenalin levels (r = 0.34, p less than 0.05). An inverse correlation was found between serum sodium concentrations and levels of bicyclo-PGEm (r = 0.46, p less than 0.01) as well as plasma renin activity (r = 0.66, p less than 0.001). Thus, prostaglandin E2 levels in plasma are increased in patients with severe CHF.     

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)     

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.     

Circulating forms of human atrial natriuretic peptide in patients with congestive heart failure

To elucidate the circulating forms of human atrial natriuretic peptide (hANP) in patients with congestive heart failure (CHF), plasma samples obtained from 36 patients with CHF were analyzed and compared with those from normal subjects. Plasma concentrations of hANP-like immunoreactivity (LI) from normal subjects and patients with mild CHF (class I), as classified by the New York Heart Association (NYHA) functional criteria, did not differ (15 +/- 1 vs. 16 +/- 1 pmol/L, mean +/- SE), whereas plasma levels of hANP-LI in patients with moderate and severe CHF significantly (P less than 0.01) increased in relation to the severity of CHF (class II, 44 +/- 4 pmol/L; class III, 116 +/- 24 pmol/L; class IV, 141 +/- 21 pmol/L). Reverse-phase HPLC and gel permeation chromatography coupled with RIA for hANP revealed that the circulating forms of hANP-LI consisted of alpha-hANP, beta-hANP, and gamma-hANP in CHF, whereas alpha-hANP predominated in normal plasma. The percentage of beta-hANP in total hANP-LI as calculated from the chromatograms by gel filtration was greater in severe CHF (NYHA class III and IV) than those in mild CHF (NYHA class I and II), and apparently exceeded those of other forms. Successful medical treatment for CHF resulted in a marked reduction of total plasma hANP-LI levels with a concomitant disappearance or reduction of beta-hANP in 14 patients examined. These data suggest that beta-hANP and gamma-hANP are secreted from the failing human heart, possibly resulting from the augmented synthesis and/or the altered processing of hANP precursor in cardiocytes, and that circulating beta-hANP may serve as a potential marker for the severity of CHF in man.     

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)     

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)     

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.     

Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double-blind, placebo-controlled study

Twelve patients with congestive heart failure underwent a double-blind, placebo-controlled study for the purpose of examining the central and regional hemodynamic effects of first-dose (1 and 2 mg/kg) oral enoximone, a new phosphodiesterase III inhibitor. Enoximone augmented cardiac output, generally through a positive chronotropic response. Indices of left ventricular contractility, specifically stroke volume, delta P/delta t, fractional shortening rate, and the duration of the preejection period, were only modestly enhanced by enoximone. At 2 mg/kg, systemic vascular resistance fell below baseline values without affecting systemic blood pressure; these parameters were not altered by the 1 mg/kg dose. Both pulmonary artery pressure and pulmonary vascular resistance dropped below baseline and below placebo control for the 2 mg/kg dose. Enoximone at 2 mg/kg lowered right and left heart filling pressures below baseline. Examination of regional hemodynamic responses to both doses demonstrated a reduction in limb vascular resistance and an increase in limb blood flow proportional to the concomitant increase in cardiac output. Renal and hepatic-splanchnic blood flow and vascular resistances were not altered by enoximone. First-dose oral enoximone (1 and 2 mg/kg) alters hemodynamics in heart failure by predominant vasodilatation, particularly of limb-musculoskeletal and pulmonary vascular beds, some positive chronotropism, and modest positive inotropism.     

Comparative hemodynamic and hormonal response of enoximone and dobutamine in severe congestive heart failure

The peak hemodynamic effect and hormonal response of the phosphodiesterase inhibitor enoximone (MDL 17,043) were compared with those of dobutamine in 10 patients with severe congestive heart failure. Both agents significantly (p less than 0.05) increased cardiac index, stroke volume index and heart rate. Enoximone tended to decrease mean systemic arterial and pulmonary artery wedge pressures (0.05 less than p less than 0.1), whereas dobutamine did not. Both agents decreased systemic vascular resistance (p less than 0.05). The increase in heart rate was greater with dobutamine than with enoximone (p less than 0.05). Plasma renin activity increased significantly with dobutamine (from 11.3 +/- 13.5 to 17.8 +/- 15.0 ng/ml/hour, p less than 0.01) and with enoximone (from 13.6 +/- 18.3 to 16.6 +/- 18.8 ng/ml/hour, 0.05 less than p less than 0.1). Dobutamine suppressed plasma norepinephrine level (p less than 0.05) and enoximone did not. Neither agent affected the plasma vasopressin level. These data demonstrate a similar acute hemodynamic and hormonal profile for both enoximone and dobutamine. Further, dobutamine, like other beta agonists, provokes renin secretion and may do so to a greater extent than enoximone.     

Platelet alpha 2 adrenoreceptors in chronic congestive heart failure

Patients with chronic congestive heart failure (CHF) are known to have elevated plasma concentrations of norepinephrine. Although this elevation of catecholamines in plasma may facilitate myocardial contractility, it may also be toxic to the myocardium in the long term. The alpha 2 adrenoreceptor located on noradrenergic nerve terminals regulates neuronal norepinephrine release by feedback inhibition. This receptor is also located on human blood platelets. This study determines the status of platelet alpha 2 adrenoreceptors in 16 patients with CHF (class I and II in 7 and class III and IV in 9) and in 26 normal volunteers. Specific high-affinity binding of the alpha 2 agonist 3H-clonidine and the alpha 2 antagonist 3H-yohimbine was used to determine the number (Bmax) of alpha 2 receptors and the dissociation constant (KD) for the 2 ligands. In the control population, the Bmax (in fmol/mg protein) for 3H-clonidine was 33 +/- 2 and for 3H-yohimbine was 165 +/- 12. There was a 25% difference in the maximum number of specific binding sites for 3H-clonidine in the class III/IV group (Bmax 24 +/- 2, p less than 0.05) and a 43% difference in the maximum number of specific binding sites for 3H-yohimbine (Bmax 94 +/- 9; p less than 0.005). There was a smaller but nonsignificant difference in the number of receptors on platelets from patients in the class I and II group. The KD's were similar in all 3 groups. These differences correlated well with the increases in plasma norepinephrine levels between the normal group (273.8 +/- 44.1 pg/ml) and the class III/IV group (1333.5 +/- 244.9, p less than 0.0005). This study supports the hypothesis that increased levels of circulating norepinephrine in CHF lead to a decrease in platelet alpha 2 adrenoreceptors. Further studies should be performed to determine whether pharmacologic stimulation of these receptors might lead to a decrease in the neuronal release of that norepinephrine which might be toxic to the myocardium. Monitoring of platelet alpha 2 adrenoreceptor number may provide a guide to therapy of CHF.     

慢性心衰患者血浆尾加压素Ⅱ与嗜铬粒蛋白A的相关性

目的：探讨血浆尾加压素Ⅱ（urotensinⅡ,UⅡ）和嗜铬粒蛋白A（CgA）浓度在不同心力衰竭分级患者中的变化及其两者之间的相关性。方法：各种病因导致的慢性心力衰竭（CHF）患者41例（心力衰竭组）,按NY-HA心功能分级标准,分为心功能Ⅱ级12例,Ⅲ级14例,IV级15例,并设健康对照组20例。采用放射免疫法测定血浆UⅡ含量,酶联免疫法测定血CgA含量,并对两组指标进行相关分析。结果：①CHF患者血浆UⅡ含量较健康对照组明显降低[心功能Ⅱ级组（2.99±0.16）pg/ml：III级组（2.57±0.12）pg/ml：IV级组（2.13±0.17）pg/ml：健康对照组（5.52±0.10）pg/ml,P〈0.01];②血浆CgA含量较健康对照组明显升高[心功能Ⅱ级组（147.00±1.41）ng/ml：III级组（276.75±2.00）ng/ml：IV级组（521.47±68.21）ng/ml：健康对照组（64.21±2.75）ng/ml,P〈0.01];③Pearson相关性分析显示,血浆UⅡ和CgA存在负相关（r值为-0.809,P〈0.01）。结论：（1）在充血性心衰患者中,随心功能级别的升高,尾加压素II含量降低,嗜铬粒蛋白A含量升高;（2）血浆尾加压素Ⅱ、嗜铬粒蛋白A共同参与了心衰的发生发展,其水平是判断心力衰竭及心室重构的可靠指标。     

Intravenous Iron in Heart Failure: Beyond Targeting Anemia

Iron deficiency is commonly seen in congestive heart failure (CHF) in both anemic and nonanemic patients. In six studies in which these iron-deficient patients with CHF were treated with intravenous (IV) iron, five found an improvement in the hemoglobin. In uncontrolled and controlled studies, the New York Heart Association (NYHA) class, quality of life, and exercise capacity were improved consistently with IV iron. In some studies, cardiac function also was improved. In one large, double-blind, placebo-controlled study of IV iron, the patient global assessment, quality of life, and NYHA class improved rapidly in both those who were anemic or not anemic. In contrast to these studies, another controlled study of anemia in CHF showed no effect of oral iron on hemoglobin or on any cardiac parameters over 1 year. These studies suggest that CHF in both anemic and nonanemic iron-deficient patients may benefit from a course of IV iron, but not oral iron.     

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.     

Enoximone treatment of impaired myocardial function during cardiac surgery: combined effects with epinephrine

Enoximone belongs to a new class of noncatecholamine-positive inotropes, which selectively inhibit phosphodiesterase type III and increase cyclic AMP (cAMP). This study was performed in 30 coronary artery surgery patients with impaired myocardial function (ejection fraction [EF] < 50%). The study's two purposes were to investigate the hemodynamic effects of enoximone, 0.5 mg/kg, administered following induction of anesthesia (phase I), and to assess whether enoximone can potentiate the actions of sympathomimetic agents during weaning from cardiopulmonary bypass (CPB) (phase II). Starting with already reduced hemodynamics, induction of anesthesia led to a further deterioration of blood pressure and cardiac output (CO). Administration of enoximone produced a significant increase in cardiac index (CI) (+47%), whereas pulmonary capillary wedge pressure (PCWP) (−37%), pulmonary artery pressure (PAP) (−17%). and systemic vascular resistance (SVR) (−17%) were significantly reduced. Heart rate (HR) was not increased, and no dysrhythmiss occurred during the investigation. The hemodynamic effects were maintained for 30 minutes until the start of the operation. In phase II, where weaning from CPB was not possible without pharmacological support, either enoximone (0.5 mg/kg) + epinephrine (0.1 gg/kg/min) or only epinephrine (same dosage) was randomly selected. Weaning was successful in both groups, but the combined therapy produced a larger increase in CI and a more pronounced decrease of the elevated filling pressure (PCWP). PAP was not changed in the combined therapy group, but increased in the patients receiving epinephrine alone. It is concluded that enoximone has beneficial hemodynamic effects in the perioperative period, and that potentiation of the effects of epinephrine in severe heart failure may be one of the drug's most useful features.     

A preliminary report of the effects of orally administered enoximone on regional hemodynamics in congestive heart failure

Twelve patients with moderately severe congestive heart failure underwent the simultaneous determination of central and regional hemodynamics after administration of placebo and enoximone. The regions examined hemodynamically included renal, hepatic-splanchnic and upper limb. Enoximone was studied in 2 doses, 1 and 2 mg/kg, and administered in a double-blind, placebo-controlled, crossover design. At these doses enoximone elicited a significantly greater increase in cardiac output and a greater decrease in systemic vascular resistance than placebo. Systemic blood pressure was not significantly altered. Enoximone did not significantly change the flow or resistance of renal or hepatic-splanchnic vascular beds. Limb vascular resistance decreased modestly after enoximone with a significant augmentation (+12% to 17%) of limb blood flow compared with placebo. The initial oral administration of the 1 and 2 mg/kg doses of enoximone improved central hemodynamic parameters with apparent preferential reduction of limb vascular resistance and augmentation of blood flow to the limb region (peripheral musculoskeletal system).