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.     

Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure

OPC-8212 is a new positive inotrope with a unique mechanism of action. To assess its clinical utility we administered 60 mg/day for 30 days to 10 patients with overt congestive heart failure, who had substantial limitations in exercise performance despite treatment with conventional therapy. Patients were evaluated by simultaneous respiratory gas exchange and radionuclide ventriculography measurements during graded maximal exercise testing. Improvement was demonstrated in both peak oxygen uptake and radionuclide-determined cardiac index after 30 days of treatment with OPC-8212. These changes were not associated with alterations in heart rate at rest or during peak exercise. Furthermore OPC-8212 significantly decreased ventricular ectopy in our patients. However, two patients had possible hematologic toxicity with prolonged use. The results of the present phase II study suggest that a larger randomized double-blind placebo study to evaluate the safety and clinical efficacy of this drug is warranted.     

Sustained inotropic effects of a new cardiotonic agent. OPC-8212 in patients with chronic heart failure

OPC-8212, a newly synthesized noncatecholamine, nonglycosidic, orally effective inotropic agent, has been shown to exert a potent cardiotonic action in acute administration to patients with heart failure. However, its long-term effect has not yet been established. Eight patients with dilated cardiomyopathy (New York Heart Association functional class II-III) were given a single dose of 60 mg of OPC-8212 daily for 4 to 8 weeks. OPC-8212 produced symptomatic improvement in four patients. Though there were no detectable changes in arterial pressure and left ventricular end-diastolic dimension, heart rate and end-systolic dimension significantly decreased after administration of OPC-8212. Baseline fractional shortening rose significantly and depression of shortening in response to acute pressor stress (afterload mismatch) was corrected after OPC-8212. The end-systolic pressure-dimension relation was shifted to the left with a steeper slope. These findings indicate that the inotropic state was substantially enhanced by the drug. No adverse effects were observed in any patient. Thus, the drug appears to hold promise for the chronic treatment of patients with moderate congestive heart failure who are essentially asymptomatic at rest, but develop severe impairment of cardiac function in a stressed state.     

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.     

Beneficial effect of OPC-8212 (3,4-dihydro-6-(4-(3,4-dimethoxy benzoyl)-1-piperazinyl)-2(1H)-quinolinone on myocardial oxygen consumption in dogs with ischemic heart failure

The effect of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative), on myocardial oxygen consumption (MVO2) following intravenous administration (1 and 3 mg/kg/min) was studied in normal and ischemic failing hearts in open chest dogs. Ischemic failing heart was obtained by intracoronary injection of 15-micron microspheres and volume loading. OPC-8212 significantly increased LV max dP/dt and decreased mean aortic pressure, whereas heart rate was not altered in both normal and failing hearts. Despite the remarkable positive inotropic effect, this agent did not increase MVO2 in the normal hearts and even decreased MCO2 in the ischemic failing hearts associated with a decrease in LV end-diastolic pressure and hence, LV chamber size. These results indicate that OPC-8212 does not increase myocardial oxygen demand, probably because the increase in MVO2 by positive inotropic effect is offset by a decrease in MVO2 due to a decrease in chamber size. Thus, OPC-8212 may be promising for the treatment of congestive heart failure with reduced coronary flow reserve.     

Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), in the dog with and without beta-blocker and Ca++-antagonist pretreatment

Hemodynamic effects of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative) were studied in anesthetized open chest dogs pretreated with propranolol and diltiazem. Three doses (1, 3 and 10 mg/kg) of OPC-8212 were administered intravenously and the net hemodynamic effect (% change) was obtained by subtraction of the effect of the solvent from the gross effect, since the vehicle has a transient, but significant hemodynamic effect. The maximal inotropic effect occurred 3 minutes after administration: LV dP/dt max and cardiac output (CO) increased by 19 +/- 2.5% and 28 +/- 8.5%, respectively, at 3 mg/kg. These cardiotonic effects were dose-dependent, whereas heart rate, peak LV pressure (PLVP) and mean aortic pressure were minimally changed at any dose. Accordingly, systemic vascular resistance (SVR) decreased in a dose-dependent manner although the decrease was much less than that in administration of isoproterenol. The inotropic effect was not blocked by beta-adrenoceptor blockade (propranolol 1 mg/kg), indicating that the cardiotonic action of this agent is not due to beta-adrenergic stimulation. Thus, this agent could reverse beta-blocker-induced heart failure. During infusion of diltiazem (0.1 mg/kg/min following bolus intravenous administration of 0.5 mg/kg), the increases in LV dP/dt max and CO due to OPC-8212 were similar to those in the control study. In contrast to the effects under beta-adrenoceptor blockade, however, decreased PLVP was restored by OPC-8212. Neither chronotropic nor rrhythmogenic effects were observed in the control or with either pharmacological intervention. These results indicate that OPC-8212 has a potent inotropic action with modest vasodilatory effect even with propranolol or diltiazem pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

A multicenter study of a new inotropic agent,piperanometozine (opc-8212) in congestive heart failure: Clinical improvement during short-term treatment

Summary Piperanometozine (OPC-8212) is a new, orally effective inotropic agent. To evaluate the efficacy of this agent on systemic hemodynamics and clinical symptoms in patients with congestive heart failure, a multicenter study was performed. Thirty four patients with New York Heart Association (NYHA) functional classes II to IV and initially treated with digitalis were enrolled from ten centers. After a washout period of one or two weeks (placebo period), digitalis was replaced by piperanometozine (30 or 60 mg/day) for four weeks, while other drugs were continued. Clinical symptoms, routine physical findings, electrocardiogram, chest roentgenogram, echocardiogram, exercise tolerance time, and routine laboratory data were obtained in 34 patients. Four patients were withdrawn from the study before completion. After the withdrawal of digitalis, heart rate was increased and ejection fraction was decreased. Exercise tolerance time was increased while other parameters were unchanged. At the end of the treatment period with piperanometozine, ejection fraction significantly (p<0.05) increased with a decrease in LV end-systolic volume (p<0.05), whereas heart rate and blood pressure remained unchanged. Systolic blood pressure/LV end-systolic volume (P/V index) tended to decrease after the withdrawal of digitalis and increase during piperanometozine therapy. Exercise tolerance time was further increased (p<0.01) and NYHA functional class was improved in 11 patients, whereas it worsened in only one patient. No major adverse effects were observed. These results indicate that a short-term therapy of oral piperanometozine restored the depressed cardiac performance of the heart and improved clinical symptoms in patients with congestive heart failure. Thus, this promising agent deserves further clinical study in long-term trials.     

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p less than 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p less than 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.     

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.     

A new cardiotonic agent,OPC-8212, elevates the myocardial oxygen consumption versus pressure-volume area (PVA) relation in a similar manner to catecholamines and calcium in canine hearts

Summary We studied the effect of a new positive inotropic agent, OPC-8212 (3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-l-piperazinyl]-2(1H)-quinolinone), on the relation between left ventricular oxygen consumption (VO₂) and pressure-volume area (PVA) in excised cross-circulated dog hearts. PVA represents the total mechanical energy generated by ventricular contraction. OPC-8212 increased the contractility index, Emax, by 59%±36% from 7.6±4.3 to 11.1±4.6 mmHg/(ml/100 g LV [leftventricle]). OPC-8212 elevated the VO₂-PVA relation without a significant change in its slope. Namely, OPC-8212 did not affect the mechanical efficiency of the contractile machinery from the PVA-dependent fraction of VO₂ to PVA, but increased the PVA-independent fraction of VO₂ which is related with non-mechanical processes of contraction. This effect suggested an increased energy expenditure for excitation-contraction coupling. These results associated with the enhanced contractile state by OPC-8212 were both qualitatively and quantitatively similar to those obtained with catecholamines and calcium in our previous study. This suggests that OPC-8212, catecholamines, and calcium have similar effects on intracellular Ca²⁺ concentration and enhanced ventricular contractility.Partly supported by a Grant-in-Aid (61480102) for Scientific Research from the Ministry of Education, Science, and Culture, and a Research Grant (60C-3) for Cardiovascular Diseases from the Ministry of Health and Welfare of Japan.     

Beta adrenergic blockade Hemodynamics and myocardial energy metabolism in patients with ischemic heart disease

Systemic and coronary hemodynamics and myocardial intermediary metabolism were studied before and after beta adrenergic blockade with propranolol in 9 patients with ischemic heart disease.

A significant reduction was produced in heart rate, left ventricular isometric tension development (dp/dt) and pressure-time per minute, whereas left ventricular end-diastolic pressure rose. Cardiac output and left ventricular mean systolic pressure and mechanical work did not change consistently.

Myocardial oxygen consumption was influenced by left ventricular external work and pressure-time per min., the latter having the predominant effect. Myocardial oxygen consumption was not closely related to the consistent reduction of dp/dt, presumably because of wide variations in stroke volume.

Coronary blood flow was reduced in 5 of 8 patients, changes in coronary diastolic vascular resistance in most cases favoring the preservation of an autoregulatory mechanism. A constant or reduced coronary arteriovenous oxygen extraction in 6 of 9 patients suggested that changes in perfusion rather than in extraction accommodated the altered myocardial oxygen needs. Propranolol appeared to have no direct action on vasomotor tone but probably reduced extravascular compression resistance.

Myocardial efficiency did not change consistently. External efficiency was generally reduced, but internal efficiency rose in 3 patients. When a reduction in efficiency indexes resulted from decreased cardiac work but increased coronary flow and myocardial oxygen consumption, the overstressed myocardium may have benefited.

Total myocardial substrate oxygen extraction ratios exceeded 100 per cent under control conditions and after beta blockade; therefore the respective energy contributions of carbohydrates and fatty acids were obscure, and conversion and storage seemed likely.

The NAD⁺/NADH redox potential gradient was consistently changed to a more positive value. Arterial levels of inorganic phosphate and creatine phosphokinase activity rose, and the myocardial balance of creatine phosphokinase became positive after propranolol.

The antianginal action of propranolol may be related to the following mechanisms: (1) myocardial work is reduced, thus lessening the disparity between oxygen demand and supply; (2) a relative or absolute improvement in coronary perfusion and myocardial oxygen delivery may result, subject to arteriolosclerotic limitations; (3) changes in myocardial intermediary metabolism and enzyme systems favor lessened cellular hypoxia and enhanced aerobiosis.     

Effects of amrinone, a new non-digitalic positive inotropic agent, on the efficiency and coronary circulation of the heart

It has been reported recently that 5-amino-34,4'-bipyridine-6(1H)-one is a new positive inotropic agent that appears to offer significant advantages over the cardiac glycosides. The effects of this agent were studied in a modified heart-lung preparation which allows the measurement of coronary flow and oxygen consumption in addition to a controlled study of cardiac contractility. In two models of cardiac insufficiency the administration of 5 mg amrinone caused a marked increase in cardiac output and a considerable decrease in left atrial pressure with complete reversal of the failure. In addition, the drug produces a 78% increase in coronary flow. Amrinone produces in these preparations a proportionally larger increase in cardiac output than in oxygen consumption, thus this agent increases cardiac efficiency. These results suggest that this new compound could be very useful in the treatment of cardiac insufficiency in congestive heart failure.     

Hemodynamic effects of sulmazol (ARL-115 BS), a new vasodilator and positive inotropic agent, in patients with cardiogenic shock

The imidazol-pyridine ARL-115 BS (sulmazol) has both positive inotropic and vasodilatory effects. Its hemodynamic effects were studied in 13 patients with shock after myocardial infarction. All patients required dobutamine or dopamine, while nine were treated with intra-aortic balloon counterpulsation. After a loading dose of 50 mg, sulmazol was administered at 50 mg/h followed by 100 mg/h during 30 or 60 minutes. At the highest dose of sulmazol, cardiac output increased from 4.3 +/- 1.1 to 4.9 +/- 1.5 1/min; systemic vascular resistance decreased from 1405 +/- 473 to 1228 +/- 439 dynes . s . cm-5, while pulmonary capillary wedge pressure decreased from 22 +/- 6 to 17 +/- 7 mm Hg. No changes occurred in heart rate or mean arterial pressure. The effect of sulmazol was greater than the effect of an increased dosage of dobutamine in five patients in whom this was studied. Episodes of supraventricular tachycardia occurred in two patients. No other side effects were observed. The hemodynamic changes caused by sulmazol favour its use in the treatment of acute cardiac failure, and cardiogenic shock.