Acute hemodynamic effects of a new inotropic agent,OPC-8212, on severe congestive heart failure

Summary The hemodynamic and clinical effects of OPC-8212, a newly synthesized, orally effective inotropic agent, were assessed for the first time in ten patients with severe congestive heart failure by means of right heart catheterization with a Swan-Ganz catheter. Cardiac output was determined by the thermodilution technique. Patients received a single oral dose of 6 mg/kg. To determine the magnitude and time-course of the effects of OPC-8212, measurements were made during an observation period before and 2, 4, 8, and 12 h after administration. Blood was also taken at these times for measurement of the concentration of plasma OPC-8212. No large meals were allowed during the first 4 h. After the single oral dose of OPC-8212, plasma concentrations increased rapidly, reaching an effective level after 8 h and peaking at 12 h. Hemodynamic performance improved as the mean OPC-8212 plasma level increased, with the maximum effect being observed between 8 and 12 h after acute administration of the drug. At 8 h, the cardiac index was increased from the baseline value of 2.4±0.2 (SEM) to 2.8±0.3 l/min/m² (P<0.01). The stroke work index rose from 26.2±5.1 to 31.7±60 g · m/m². The excessive pulmonary artery diastolic pressure fell from 22±2 to 17±3 mmHg at 8 h (P<0.001) and to 16±2 mmHg (P<0.001) at 12 h. The incidence of ventricular premature beats was not increased and no other side effects were observed. These changes were not associated with significant changes in heart rate or systolic blood pressure. Thus, this drug appears to be very promising for the long-term treatment of congestive heart failure.     

Oral OPC-8212 for the treatment of congestive heart failure: Hemodynamic improvement and increased exercise capacity

Summary The chronic effects of the oral administration of OPC-8212 (3,4-DIHYDRO-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone) on resting hemodynamics and exercise capacity were assessed in 15 patients with congestive heart failure (NYHA II–IV). Doses of 30 or 60 mg per day were given per os over 3.0 weeks on average (range 2–6 weeks). Multigated radionuclide ventriculography and multistage exercise testing were performed before and during OPC-8212 therapy to assess the changes in left ventricular volume and exercise capacity respectively. Systolic blood pressure showed a slight increase (from 123±3 to 129±4 mmHg) during OPC-8212 therapy, while heart rate was unchanged (69±3 vs 67±3 beats/min). The left ventricular end-diastolic volume index decreased from 127±9 to 107±7 ml/m², and ejection fraction and the P/V index (the ratio of peak systolic pressure to left ventricular end-systolic volume index) increased during OPC-8212 therapy (from 27%±3% to 30%±4% and from 1.5±0.2 to 2.0±0.3 mmHg/ml/m² respectively). NYHA functional class was improved in 9 of 15 patients, and the average peak work load achieved during exercise testing increased from 27±6 to 47±7 W. No significant adverse effect was observed in any patient. These results indicate that OPC-8212 enhances the inotropic state and, hence, reduces heart size with no change in heart rate. Moreover, it increases exercise capacity. Thus, OPC-8212 is an inotropic agent with promise for application in the long-term treatment of congestive heart failure.     

OPC-8212 in the treatment of congestive heart failure: Results of a pilot study

Summary To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invesive homodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83±8 beats/min), mean arterial pressure (70±15 mmHg), pulmonary wedge pressure (18±7 mmHg), or cardiac index (2.3±0.4 L/min/m²) following treatment with OPC-8212. Both exercise duration (5.3±1.6 min) and peak oxygen consumption (12.0±2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p<.05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p<0.05) and 11/1,000 beats to 2,4/1,000 beats (0.05<p<0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.     

Clinicopharmacological studies of a newly synthesized cardiotonic agent (TA-064) in patients with congestive heart failure

In animal experiments, a new inotropic agent, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenetyl)amino] ethanol, designated TA-064 was found to possess a more positive inotropic than chronotropic action. Its effectiveness and lack of significant toxicity make it beneficial for clinical use as a cardiotonic in human heart failure. The effects of TA-064 were investigated in patients with various types of heart disease (n = 29). Cardiac output increased, left ventricular end-systolic dimension decreased, and left ventricular fractional shortening increased for 15 minutes after a single intravenous dose (1 mg). The plasma level of TA-064 at the cessation of infusion was 61.1 +/- 49.6 ng/ml and thereafter declined biexponentially. After a single oral dose (10 mg), TA-064 appeared in the plasma at 30 minutes and reached its peak levels of 13.7 +/- 5.6 ng/ml at 60 minutes. Seven hours later, the plasma level was 5.9 +/- 3.1 ng/ml which was considered to be within the effective range according to the results after intravenous administration. In conclusion, minimal effective plasma levels of TA-064 are obtained by oral administration of 10 mg three times a day.     

Combination of positive inotropic and vasodilating substances in congestive heart failure

Summary Therapy combining vasodilators and inotropic agents is considered to be one of the most powerful means of improving cardiac function in patients with congestive heart failure (CHF). The vasodilators enhance the effectiveness of inotropic agents by providing a reduction in preload and/or afterload.Inotropic drugs with different mechanisms of action, such as digitalis glycosides, ephedrine, dopamine, dobutamine, ibopamine, terbutaline, salbutamol, pirbuterol, prenalterol, amrinone, and milrinone, have been tested in combination with vasodilators with a predominant effect on preload (nitrates, molsidomine), with a predominant effect on afterload (hydralazine, nifedipine), or with a balanced action on both arterial and venous beds (nitroprusside, prazosin, captopril), showing positive results.The problem of the combination of digitalis glycosides and vasodilators with different sites of action has been considered by our group. In 42 patients with CHF, digoxin (DIG, 0.01 mg/kg intravenously) was tested in combination with molsidomine (MLS, 4 mg sublingually) (12 patients), a nitrate-like agent with a predominant vasodilating action on the capacitance vessels, nifedipine (NFP, 10 mg sublingually) (22 patients), a Ca²⁺ antagonist drug with a predominant action on the resistance vessels, and captopril (CPT, 25 mg orally) (8 patients), an ACE inhibitor with a balanced effect on both preload and afterload. The combination DIG plus MLS caused a reduction in left ventricular filling pressure (LVFP) greater than that achieved with either agent alone. The hemodynamic improvement was obtained without side effects, in spite of the striking fall in preload. We stress that this investigation was performed on patients with CHF following acute myocardial infarction. The combination DIG plus NFP resulted in a higher output increase and a greater LVFP reduction when compared with DIG or NFP alone, indicating a shift to a more improved left ventricular function curve. The combination DIG plus CPT provoked a decrease in LVFP greater than that achieved with either agent alone, while the increase in cardiac index and stroke volume index was not significantly different from that obtained with DIG or CPT.The results obtained by the combination of digitalis and a vasodilator with a pronounced effect on the resistance vessels, such as NFP, appear to be more favorable, since the reduction in impedance to left ventricular ejection allows a better ventricular emptying, thus leading to an improved cardiac output.     

A placebo-controlled,randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure

Summary OPC-8212 is a newly synthesized, orally effective inotropic agent. Previous studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure. However, the long-term efficacy of this agent remains to be established. Eighty-three patients with chronic heart failure were randomly assigned to treatment with either OPC-8212 (n=45) or matching placebo (n-38).Of the placebo-treated patients, two patients died and another six patients were withdrawn from the study because of a deterioration of heart failure, while only 1 out of 45 OPC-8212-treated patients were withdrawn because of increased congestive symptoms.After 12 weeks of treatment, the OPC-8212 group showed a significant improvement in their numerical scores in sense of well-being as judged by the patients' subscale A (p<0.01) and their physician's general impression of the patients' status (p<0.01). The ejection fraction obtained from echocardiography increased from a mean (±SEM) baseline value of 42.8±2.6% to 46.6±2.9% (p<0.05) in the OPC-8212 group and 44.4±3.7% to 45.5±4.1% in the placebo group. These effects were not associated with an increase in the heart rate. The treatment was well tolerated without any limiting side effects.Thus, OPC-8212 is effective in patients with chronic heart failure, providing significant hemodynamic and symptomatic benefit in chronic treatment, together with a possible improvement of the prognosis of patients with heart failure.     

Is there a role for positive inotropic agents in congestive heart failure: Focus on mortality

Congestive heart failure (CHF) is a common clinical syndrome that may result from a variety of etiologies. Impaired contractility can lead to pump failure and a number of hemodynamic and neurohormonal alterations. Vasodilator therapy improves symptoms and survival in patients with CHF due to systolic dysfunction. Inotropic therapy, on the other hand, has not been shown to improve survival and may even worsen survival. This article reviews the mechanism of action and clinical trials of inotropic therapy in patients with CHF.     

Calcium-sensitizing inotropic agents in the treatment of heart failure: A critical view

Summary Interventions that augment the contractile state of the heart are associated with, or caused by, alterations in Ca²⁺ exchange in heart muscles. New inotropic agents have been developed that increase the sensitivity of the myofilaments to Ca²⁺. To examine the effect of calcium-sensitizing agents on force development, we measured systolic and diastolic intracellular Ca²⁺ concentration ([Ca²⁺]_i) and constructed [Ca²⁺]_i-force relationships in normal (n=6) and myopathic human hearts (n=10). Using the bioluminescent calcium indicator aequorin, we found that the diastolic [Ca²⁺]_i was 225±52 nM in normal muscles, whereas in myopathic muscles diastolic [Ca²⁺]_i was significantly higher at 361±68 nM. Calcium-sensitizing agents that shift the [Ca²⁺]_i-force relationship toward lower [Ca²⁺]_i increase the diastolic force of myopathic hearts significantly more than in normal human hearts. This leads us to the conclusion that inotropic agents that increase the sensitivity of the myofilaments to Ca²⁺ further impair relaxation in myopathic hearts, resulting in a reduced contractile reserve and diminished actice force production.     

倍他乐克治疗慢性充血性心力衰竭临床观察

目的 观察倍他乐克治疗慢性充血性心力衰竭的疗效与安全性。方法 入选71例心脏病伴轻、中度慢性充血性心力衰竭的患者，将其随机分为治疗组（n=36）和对照组（n=35）。对照组接受常规抗心力衰竭治疗；治疗组在常规治疗基础上加服倍他乐克，共治疗12周。治疗前后观察两组患者的心率、多普勒超声心动图检查左室射血分数（LVEF）、左室舒张末压内径（LVDd）及心功能情况。结果 治疗组显效28例，占77．8％；有效6例，占16．7％；无效2例，占6．5％；总有效率为94．4％。对照组显效16例，占45．7％；有效10例，占28．6％；无效9例，占25．7％；总有效率为74．3％。治疗后两组之间的总有效率、心率和心功能差异均有统计学意义（P〈0．05）。结论 在接受心力衰竭常规治疗基础上加服倍他乐克对改善心力衰竭症状具有良好效果。     

左西孟旦治疗心衰的临床研究进展

左西孟旦（levosimendan,LS）是一种新型钙增敏剂,其正性肌力作用主要通过增加心肌肌钙蛋白对Ca2＋的敏感性和开放细胞膜上ATP敏感的K＋通道,增加心肌收缩力,同时扩张外周血管和冠状动脉,减轻心脏前后负荷。LS目前主要用于治疗急性和顽固性心力衰竭（HF）。国内外指南已将其列为IIa类（B级证据）,为HF的药物治疗增加了选择。     

Pharmacologic treatment of congestive heart failure

Congestive heart failure is a clinical syndrome producing symptomatic deterioration, functional impairment, and shortened life span. The syndrome is complex in that it includes both peripheral and cardiac effects which contribute to the progression of heart failure. In the periphery, elevations in thesympathetic nervous system and renin-angiotensin system increase afterload and contribute to further salt and water retention. The central cardiac abnormalities include remodeling of the heart and downregulation of beta receptors. Traditional heart failure therapy has included treatment of fluid retention with diuretics, although their effect on mortality has never been addressed. The most proven therapy in heart failure is treatment with vasodilators, particularly angiotensin-converting enzyme (ACE) inhibitors. Improved survival with ACE-inhibitor therapy has been demonstrated in patients with severe heart failure (CONSENSUS), mild to moderate heart failure (SOLVD), and in comparison with vasodilator therapy with hydralazine isosorbide dinitrate (VHeFT II). Improved survival has also been noted in postmyocardial infarction when the ejection fraction is decreased (SAVE). The ACE inhibitors have now become standard therapy for heart failure regardless of severity. Additive vasodilator therapy with calcium-channel antagonists is under investigation. Inotropic therapy is controversial at present because of disappointing mortality results. The clinical mainstay digitalis remains without convincing mortality reduction data. Other inotropic agents, particularly phosphodiesterase inhibitors, have shown uniformly negative survival results. However, the new mixed action agents vesnarinone and pimobenden have shown favorable data, with vesnarinone demonstrating a mortality reduction effect. Beta-blocker therapy in heart failure has also found renewed interest, particularly with the new agents carvedolol and bucindolol which also have vasodilating properties.     

A dose response study with oral prenalterol in patients with chronic congestive cardiac failure

Prenalterol is an orally active cardioselective beta agonist, with a long half-life. Previous studies have confirmed its inotropic activity following intravenous infusion in patients with heart failure. It has little chronotropic activity and no significant arrhythmogenicity. We have studied the response to sustained-release oral prenalterol given over four weeks at doses of 20, 40, 100, and 200 mg daily in 10 patients with New York Heart Association class II and III heart failure due to ischemic heart disease. All were in sinus rhythm and already receiving diuretics and digoxin. The drug was well tolerated and without side effects. Nine patients showed a dose-related improvement in their exercise tolerance as measured on the treadmill, up to a dose of 100 mg daily, with a significant increase in estimated oxygen uptake. There was a dose-related reduction in maximum heart rate, systolic blood pressure, and rate-pressure product during exercise, which is suggestive of a reduction in myocardial oxygen consumption. We conclude that prenalterol improves exercise tolerance without any significant cardiovascular or other side effects, and produces a clinically relevant and sustained improvement in patients with chronic heart failure. M-mode echocardiographic measurements of left ventricular dimension and function at rest did not show any change during the study.     

Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure

The acute effects of OPC-8212, a newly synthesized orally effective inotropic agent, were assessed clinically. Eleven patients with moderate congestive heart failure received a single mean dose of 6.5 mg/kg body weight of the drug. Eight hours after administration, the cardiac and stroke work indexes increased by 11% (p less than 0.01) and 20% (p less than 0.005), respectively, with concomitant decreases in the diastolic pulmonary artery (25%, p less than 0.005) and right atrial pressures (33%, p less than 0.01). There were no significant changes in blood pressure or heart rate. The contractile state of the left ventricle was also assessed by the shift of the Starling curve. To construct the function curve, lower body negative pressure was used to regulate the venous return to the heart. An inotropic effect of the agent was confirmed by the shift of this function curve upward and to the left, even when an augmentation of the cardiac output was masked by the marked reduction in preload. The hemodynamic and clinical effects of OPC-8212 were encouraging and the drug appears to be promising for the treatment of congestive heart failure.     

左旋卡尼汀治疗慢性充血性心力衰竭的临床观察

目的　研究左旋卡尼汀对慢性充血性心力衰竭急性期的治疗作用。方法　选择慢性充血性心力衰竭病人 76例 ,随机分为常规治疗的 A组 (n=38)和在常规治疗基础上加用左旋卡尼汀的 B组 (n=38) ,分别比较两组病人治疗前后及两组间治疗后心功能变化情况。结果　两组病人治疗前后心功能变化均有显著差异 (P<0 .0 5 ) ,同时治疗后 B组较 A组的心功能变化亦有显著差异 (P<0 .0 5 )。结论　左旋卡尼汀对慢性充血性心力衰竭急性期有治疗作用     

缬沙坦联合倍他乐克治疗慢性充血性心力衰竭的疗效观察

目的探讨研究缬沙坦联合倍他乐克治疗慢性充血性心力衰竭的临床效果。方法选取2013年2月~2014年2月来我院治疗的慢性充血性心力衰竭患者52例,随机分为观察组与对照组,每组26人,对照组实施常规内科治疗,观察组在此基础上实施缬沙坦联合倍他乐克治疗,对两组患者的临床疗效进行比较。结果经治疗后观察组的总有效率为88.5%,明显高于对照组73.1%,差异具有统计学意义(P0.05);治疗后观察组的HR、SBP以及DBP均比对照组降低明显,差异具有统计学意义(P0.05);治疗后观察组的心功能指标LVEF的提高明显高于对照组,并且差异具有统计学意义(P0.05)。结论采用缬沙坦联合倍他乐克治疗慢性充血性心力衰竭效果明显,能够明显改善患者心功能,值得在临床上推广应用。     

心阻抗血流图在充血性心力衰竭治疗初期的临床价值

目的：探讨应用心阻抗法无创心功能检测仪监测充血性心力衰竭（CHF）时血流动力学变化,指导下一步治疗的应用价值。方法：入选67例CHF患者,应用无创心功能检测仪监测心率、基础阻抗、每搏输出量、心排血量、心缩力指数、收缩功能指数、舒张功能指数、外周血管阻力和血管顺应性指标,统计分析其用药前、用药后3h和用药后3d的患者的症状和以上指标的变化,分析无创心功能检测仪的应用价值。结果：用药前、用药后3h和用药后3d统计学分析显示心率和外周血管阻力下降,基础阻抗、每搏输出量、心排血量、心缩力指数、收缩功能指数、舒张功能指数和血管顺应性升高,有统计学差异（（均P〈0．01）。结论：无创心功能检测仪能反映CHF时血流动力学变化的过程,对CHF的治疗有一定的指导意义。     

Novel use of a short-acting intravenous beta blocker in combination with inotropic therapy as a bridge to chronic oral beta blockade in patients with advanced heart failure

The role for beta blockers in advanced heart failure (New York Heart Association class IV) remains undefined because of concerns about tolerability and uncertainty about efficacy. We report the use of a short-acting intravenous beta blocker in combination with inotropic therapy as a means to bridge five patients with advanced heart failure to chronic oral beta blockade; two of these patients had been chronically managed with intravenous inotrope. At 4 months' follow-up, all patients remained on beta-blocker therapy and none was hospitalized for heart failure or had received intravenous diuretics. Given the early separation of survival curves in the randomized clinical trials of beta blockers in heart failure, it is possible that these patients will accrue a survival benefit. We conclude that some patients with advanced heart failure can be offered oral beta-blocker therapy by bridging with a combination of intravenous inotrope and short-acting intravenous beta blocker.     

Neurohumoral activation in congestive heart failure: A double-edged sword?

The search for the basic mechanism(s) responsible for the progressive and frequently irreversible deterioration of left ventricular pump function in congestive heart failure has been quite extensive; nonetheless, no single explanation has been forthcoming. Indeed, given the complexity of this disease process, it is becoming increasingly unlikely that a single pathogenetic mechanism will ever be uncovered for congestive heart failure. This review will examine recent experimental and clinical evidence which suggests that excessive adrenergic stimulation of the heart is double-edged. That is, while increased adrenergic input to the heart may initially enable the failing myocardium to function adequately for a period of months to years, continued excessive adrenergic stimulation of the heart through both local neural and circulating catecholamines may lead to frank myopathic effects on the heart, with resultant worsening of left ventricular function and the development of intractable congestive heart failure. While we do not mean to suggest that excessive sympathetic stimulation of the heart is the only, or even the major mechanism responsible for the development of irreversible congestive heart failure, the data reviewed herein do suggest that adrenergic stimulation may play a primary role in the pathogenesis of congestive heart failure.     

盐酸乌拉地尔和多巴酚丁胺联用治疗慢性充血性心力衰竭的临床观察

目的观察盐酸乌拉地尔和多巴酚丁胺治疗慢性充血性心力衰竭（CHF）的临床疗效。方法将62例心功能（NYHA）Ⅲ～Ⅳ级的CHF患者,随机分为乌拉地尔治疗组和硝普钠对照组各31例。在常规加多巴酚丁胺治疗的基础上,治疗组给予乌拉地尔25～100mg泵入;对照组给予硝普钠25～50mg泵入。结果两组治疗后心功能均有改善,乌拉地尔组有效率97%,硝普钠组有效率100%;两组用药后血压、心率、呼吸均明显下降,左室射血分数（LVEF）分别为（46±6）%（P<0.01）和（46±5）%（P<0.01）。两组均未见明显不良反应。结论盐酸乌拉地尔和多巴酚丁胺联合治疗CHF疗效确切,安全可靠。