The hemodynamic effects of ibopamine, a dopamine congener, in patients with congestive heart failure

Ten patients with congestive heart failure underwent noninvasive and invasive hemodynamic testing before and sequentially after the administration of ibopamine to determine the cardiovascular effects of this oral dopamine congener. Single doses of 200, 400 and 600 mg were administered to all patients and 5 repeated doses of 200 or 400 mg were studied in 8. Hemodynamic effects occurred as early as 30 minutes and lasted up to 4 hours after dosing. In general, ibopamine elicited statistically significant dose-related increases in cardiac output and reductions in the derived resistance of the systemic and pulmonary circulations. A biphasic response in central and peripheral pressures was observed; up to 1 hour after administration, ibopamine elevated mean right and left atrial pressures and pulmonary and systemic arterial pressures with a significant reduction of these measurements beyond 1 hour. It did not alter heart rate. Repeated doses qualitatively affected hemodynamics similar to the initial dose and did not appear to be accompanied by short-term tolerance. While oral ibopamine elicits some favorable hemodynamic effects in humans with cardiac failure, the biphasic hemodynamic response is generally undesirable in the majority of these patients.     

Onset of cardiovascular action after oral ibopamine. Early hemodynamic effects of single and repeated doses in patients with idiopathic dilated myocardiopathy

The acute effects of ibopamine (active ingredient of Inopamil), an orally active dopaminergic agent, were invasively evaluated in 16 consecutive patients with idiopathic dilated cardiomyopathy (New York Heart Association Functional Class II and III) Single doses of 100 and 200 mg were administered to 7 and 9 patients, respectively, and two repeated doses of 100 mg were studied in 6 patients. In order to assess the onset of cardiovascular effect, control hemodynamic measurements were repeated 5, 10, 15, 20, 30, 60, 120, and 180 min after ibopamine 200 mg. Both the tested doses of ibopamine increased the mean pulmonary arterial pressure and the mean pulmonary wedge pressure, with a maximal effect 15 min after drug ingestion (+ 47.0 and + 65.4% in the 200 mg group, p less than 0.002). Pulmonary pressures returned to baseline or lower values beyond 60 min. Systemic arterial pressure showed a small transient increase (+ 7.9% in the 200 mg group at 15 min), but fell significantly below baseline after 120 min, a larger decrease occurring in the 100 mg group (p less than 0.05). Ibopamine had a slower but more prolonged effect on cardiac output (increase of up to 32.1% at 60 min) and systemic vascular resistances. Repeated doses (100 mg after an 8-h interval) elicited comparable cardiovascular effects. Oral ibopamine caused a significant increase in mean pulmonary arterial and capillary pressures as early as 5 min after drug ingestion, before cardiac output and peripheral vascular resistances were affected. A biphasic hemodynamic response was also observed after single and repeated low (100 mg) doses of ibopamine.     

Hemodynamic effects of ibopamine in patients with idiopathic congestive cardiomyopathy

We administered 150 mg of ibopamine orally to 10 patients suffering from idiopathic congestive cardiomyopathy. Hemodynamic function was evaluated by right heart catheterization and by measurement of cardiac output with the thermodilution technique. Ibopamine caused no significant change in heart rate or mean arterial pressure. Cardiac index, stroke volume index, and left ventricular work index all increased significantly by about 30%. Mean pulmonary arterial pressure decreased by about 30%, and systemic vascular resistance decreased by about 20%. The effects peaked at about 3 h and lasted 5-7 h. No side effects were noted. These findings with invasive techniques confirm those of others using noninvasive techniques, and suggest that ibopamine may be useful in the treatment of congestive heart failure.     

Acute haemodynamic effects of ibopamine and dopamine on isovolumic relaxation

The effects of intraduodenal ibopamine (a new orally active inotropic agent claimed to have haemodynamic effects similar to dopamine) on isovolumic relaxation were monitored for 90 min in eight closed-chest anaesthetized dogs. Dopamine and epinine (ibopamine active metabolite) were also infused at graded doses. After 15 min, ibopamine (12 mg/kg) shortened the time constant of isovolumic relaxation, and increased stroke volume and mean aortic pressure. Peak positive dP/dt increased significantly only 10 min later. Heart rate did not change. Dopamine (10 micrograms/kg per min) similarly reduced the time constant, and increased stroke volume, mean aortic pressure, peak positive dP/dt and heart rate. Epinine (10 micrograms/kg per min) caused similar changes in peak positive dP/dt, stroke volume, mean aortic pressure, and accelerated time constant without raising the heart rate. Ibopamine and epinine therefore significantly improved the isovolumic relaxation phase, like dopamine, without however affecting the heart rate.     

Assessment of the cardiohemodynamic effects of ibopamine, an orally-active dopamine analogue, in the anesthetized open-chest guinea pig and the isolated guinea pig atria

In the anesthetized open-chest guinea pig, ibopamine (10-300 micrograms/kg, i.v.), epinine (10-100 micrograms/kg, i.v.) and dopamine (10-300 micrograms/kg, i.v.) produced dose-related increases in heart rate (prevented by 20 micrograms/kg pindolol, i.v.), left ventricular dP/dt max and aortic flow. Ibopamine produced pressor effects (prevented by 0.5 mg/kg phentolamine, i.v.), while dopamine produced a slight depressor effect. A biphasic response (the pressor phase followed by a depressor) was observed after epinine, although the depressor phase was not significant. Calculated total peripheral resistance (TPR) tended to be increased after ibopamine and epinine (initial phase), while it was decreased after dopamine. Pindolol potentiated the increase in TPR produced by ibopamine and epinine, while the increase in TPR was converted to the decrease after phentolamine. Decreases in TPR produced by epinine and the highest dose of dopamine were inhibited by pindolol. In the isolated guinea pig atria, ibopamine (10(-6)-10(-4) M) increased the atrial rate and the developed tension in a concentration-related manner. The positive chronotropic and inotropic effects of ibopamine were of the same order as those of epinine.     

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute haemodynamic effects of ibopamine in patients with severe congestive heart failure.

Ten patients with congestive heart failure (CHF), in III and IV NYHA Class, were treated orally with a single dose of ibopamine ranging from 1.2-3.3 mg/kg, and were studied using the Swan-Ganz catheter and thermodilution technique. Cardiac index (CI) and stroke volume index (SVI) were increased, and mean pulmonary pressure (PAP), systemic vascular resistances (SVR) were lowered. Ibopamine increased CI (+33%) and SVI (+26%), and decreased PAP (-17%) and SVR (-24%). All changes were statistically significant. The maximum haemodynamic effect occurred 180 min after ibopamine administration. Blood pressure and heart rate were unaffected. Tolerability was good. This study shows that ibopamine when orally administered to human subjects improves cardiac performance and further investigations on its use as a therapeutic agent in the long term treatment of CHF are recommended.     

Ibopamine. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy

Ibopamine is an orally active derivative of dopamine which undergoes hydrolysis to the active moiety epinine. In single-dose and short term studies ibopamine demonstrated inotropic and vasodilating properties. It improved cardiac and systemic haemodynamics by increasing cardiac output and reducing afterload, both at rest and during exercise. In non-comparative clinical studies ibopamine produced benefits in functional class and clinical symptoms for up to 1 year in patients with moderate to severe congestive heart failure. Similarly, short term comparative studies with placebo have indicated ibopamine as a useful adjunct in the treatment of patients maintained on conventional therapy with digoxin, diuretics and vasodilators. Preliminary evidence also suggests that ibopamine is as effective as digoxin in the treatment of patients with moderate congestive heart failure. Should the results of long term comparative studies confirm these encouraging findings, ibopamine will be a useful addition to the drugs available or as an alternative to digoxin for the treatment of congestive heart failure.     

Intravenous nisoldipine in severe congestive heart failure

The acute hemodynamic effects of intravenous nisoldipine were studied in 10 patients with severe congestive heart failure. Nisoldipine was administered in three consecutive doses (1.5, 3.0, and 6.0 micrograms/kg) at least 150 min apart. Following the first dose, mean arterial pressure declined from 96 +/- 17 to 87 +/- 16 mm Hg (p less than 0.01), cardiac index increased from 2.1 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than 0.025), and systemic vascular resistance fell from 27 +/- 10 to 19 +/- 6 units (p less than 0.01). Maximal hemodynamic effects occurred by 2 to 5 min and gradually waned over the next 120 min. There were no significant changes in heart rate or filling pressures. The time course for the hemodynamic effects were similar with subsequent doses but the magnitude of change was significantly greater. There was a dose-dependent increase in peak arterial nisoldipine concentration. Baseline plasma norepinephrine and renin were high but did not change with nisoldipine administration. No significant changes were seen after nisoldipine administration. No major side effects were observed. These data suggest that nisoldipine is a potent arterial vasodilator that can be of benefit in patients with low output cardiac failure.     

The oral dopamine agonist, ibopamine, in normal man: effects on rhythm, heart rate, blood pressure and catecholamines.

To evaluate the effects of the oral aselective dopamine congener ibopamine, heart rate, blood pressure, cardiac rhythm, electrocardiographic (ECG) parameters and plasma catecholamines were studied in ten healthy subjects on three occasions: without medication, after 100 mg oral ibopamine and after combined treatment of ibopamine and the dopamine antagonist metoclopramide. Ibopamine was well tolerated by all subjects. No significant changes in heart rate or blood pressure were seen during either ibopamine alone or during concomitant metoclopramide administration. In addition, there were no differences in PR-, QRS- and QTc- intervals on the ECG and plasma norepinephrine, epinephrine and dopamine levels were unchanged. None of the ten volunteers showed proarrhythmia from ibopamine. However, in one subject, episodes of accelerated idioventricular rhythm were observed after ibopamine, which were asymptomatic and did not exceed a rate of 51 beats/minute. During concomitant metoclopramide infusion, ibopamine did not induce accelerated idioventricular rhythm. In conclusion, in healthy subjects ibopamine appears to be a safe drug and causes neither proarrhythmia, nor changes in heart rate, blood pressure, ECG-parameters, or plasma catecholamines.     

Use of intermittent dobutamine infusion in congestive heart failure

Dobutamine is a cardiac inotrope useful in the acute treatment of congestive heart failure. Dobutamine improves cardiac output, decreases pulmonary wedge pressure, and decreases total systemic vascular resistance with little effect on heart rate or systemic arterial pressure. Clinical benefit has been observed to continue for weeks to months following the discontinuation of dobutamine. In addition, tolerance to dobutamine has been observed when infusions last 72 hours or longer. This has led investigators to study the effectiveness of chronic intermittent infusions of dobutamine. Studies utilizing dobutamine doses ranging from 1.5 to 15 micrograms/kg/min for 4-48 h/wk have shown sustained clinical and hemodynamic improvement in patients suffering from congestive heart failure. The mechanism by which dobutamine creates this effect is not entirely known; however, studies suggest dobutamine exerts a physical conditioning effect similar to exercise. Dobutamine infusions have also been associated with morphological and metabolic changes in myocardial tissue consistent with improved myocardial structure and function. The intermittent use of dobutamine may be beneficial in the chronic treatment of congestive heart failure in patients who fail to respond to conventional therapy.     

Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous epinine administration on left ventricular systolic performance, coronary hemodynamics, and circulating catecholamines in patients with heart failure.

Twenty-six patients with mild to moderate heart failure were studied to determine the effects of epinine infusion (at a rate producing plasma levels similar to those measured after oral administration of 100 mg of the prodrug ibopamine) on left ventricular (LV) function (14 patients), and coronary flow and circulating catecholamines (12 patients). The only significant hemodynamic change at an infusion rate of 0.5 microgram/kg/min was a 9% (p less than 0.05) decrease in systemic vascular resistance (SVR). At an infusion rate of 1 microgram/kg/min (mean free epinine plasma levels 14.3 +/- 3.7 ng/ml), heart rate (HR), dP/dtmax (1,405 +/- 255 to 1,490 +/- 320 mm Hg, NS), (dP/dt)/DP40, and the relaxation rate remained unchanged, but the ejection fraction (EF) increased from 32 to 38% (p less than 0.001), cardiac output (CO) increased, and SVR decreased by 22% (p less than 0.05). In a separate group of 12 patients, epinine infusion at rates of 0.5-1 microgram/kg/min produced no significant changes in coronary blood flow or myocardial oxygen uptake. At these infusion rates, arterial norepinephrine (NE) and dopamine (DA) levels decreased slightly and arterial and coronary sinus epinephrine increased. In conclusion, epinine, at concentrations similar to those achieved during therapeutic use of ibopamine, had negligible effect on myocardial contractility and relaxation rate in heart failure patients. Cardiac pump function was improved by a decrease in SVR rather than by inotropic stimulation. The data also suggest that these low concentrations of epinine may modulate the sympathetic nervous system, but further studies are needed to determine whether this effect could have clinical significance.     

Early cardiovascular changes with ibopamine: evidence for a biphasic haemodynamic action.

1. The haemodynamic effects of ibopamine, an oral dopamine derivative, were studied in eight patients with left ventricular dysfunction using invasive catheterisation techniques. 2. An early rise was seen in the mean right atrial pressure (P less than 0.05), the mean capillary wedge pressure (P less than 0.01) and the mean pulmonary arterial pressure (P less than 0.001) which occurred at 15 min and persisted for 30 min. 3. A second, later, positive chronotropic effect was seen as an increase in the heart rate (P less than 0.05) at 45 min with an increased cardiac output (P less than 0.05) persisting above baseline values at 1 h, but with no change in stroke volume. 4. These results support a biphasic mode of action for ibopamine which may be explained by a time phase difference in alpha- and beta-adrenoceptor stimulatory effects.     

Hemodynamic effects of intravenous administration of olprinone hydrochloride on experimental pulmonary hypertension

To examine acute effects of olprinone hydrochloride (CAS 106730-54-0, Coretec) on pulmonary hypertension, hypoxic pulmonary hypertension was produced in 6 adult Beagle dogs. Using this pulmonary hypertension model, single intravenous bolus injections of olprinone at doses of 10, 30 and 100 micrograms/kg were administered at 5-min intervals and hemodynamic parameters were evaluated. Heart rate increased at doses of 30 and 100 micrograms/kg, but did not change at a dose of 10 micrograms/kg. Mean aortic pressure, mean pulmonary arterial pressure, pulmonary vascular resistance and systemic vascular resistance and right ventricular stroke work index did not change at doses of 10 and 30 micrograms/kg, but they decreased significantly at a dose of 100 micrograms/kg. On the other hand, cardiac index and the first derivative value of the left ventricular pressure did not show significant change at all doses. These results indicate the vasodilating effects on peripheral and pulmonary vessels in hypoxic model at high doses of olprinone. Its application in right heart failure accompanied by pulmonary hypertension therefore is expected to yield promising results.     

Evaluation of intravenous amrinone: the first of a new class of positive inotropic agents with vasodilator properties

Amrinone is the first noncatecholamine inotropic agent with substantial vasodilating properties to be approved by the Food and Drug Administration. Its use in acute congestive heart failure (CHF) is associated with significant increases in cardiac index, reductions in pulmonary capillary wedge pressure and systemic vascular resistance and little or no change in mean arterial pressure. Pharmacokinetic studies of amrinone report an elimination half-life of 2.6-8.3 hours, with slower elimination more likely in patients with compromised renal or hepatic function. Intravenous bolus doses of 0.75-3.5 mg/kg followed by infusions of 5-20 micrograms/kg/min produce hemodynamic improvements similar to those with dobutamine. Side effects with amrinone therapy are usually mild, but thrombocytopenia occurs in 2.4% of patients. Amrinone appears equally as efficacious as dobutamine in the management of acute CHF, but its role in therapy depends on efficacy and side effect data in greater numbers of patients.     

Invasive Pharmacodynamic Characterization of Combined Ibopamine and Calcium Blocker Therapy for Heart Failure

Study Objective . To determine the acute hemodynamic response of single-dose coadministration of ibopamine plus nifedipine or diltiazem in patients with New York Heart Association functional class (NYHA FC) II—III congestive heart failure. Design . A single-blind, placebo-controlled, two-paired, crossover study. Setting . Cardiology clinics at two large teaching hospitals. Patients . Eight patients with NYHA FC II—III congestive heart failure who met the inclusion criteria were selected randomly. Interventions . All patients underwent right heart catheterization. Day 1 consisted of concomitant calcium channel blocker plus placebo, with cardiac and peripheral hemodynamic recordings from 30 minutes–24 hours. The design was equivalent on day 2, with single-dose administration of ibopamine plus calcium channel blocker. Measurements and Main Results . Single-dose nifedipine-diltiazem augmented cardiac output and stroke volume secondary to decreasing systemic vascular resistance. The nifedipine-ibopamine and diltiazem-ibopamine subgroups demonstrated relatively equal hemodynamics, augmenting cardiac index (nifedipine 43%, p<0.05; diltiazem 40%, p<0.05 vs baseline) while decreasing systemic vascular resistance (nifedipine 41%, p<0.05; diltiazem 28%, p NS vs baseline) 30 minutes after the dose. In contrast to single-dose diltiazem, the diltiazem-ibopamine subgroup exhibited an increased left ventricular filling pressure (122%, p<0.05 vs baseline) and mean pulmonary artery pressure (43%, p<0.05 vs baseline) at 30 minutes after the dose. One patient experienced a transient episode of chest pain associated with increased heart rate and blood pressure with diltiazem-ibopamine. Conclusion . Diltiazem and ibopamine should be coadministered with caution in patients with coronary artery disease and left ventricular dysfunction.     

Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action

Compound LY195115 is a novel cardiotonic with both inotropic and vasodilator activities. In cat papillary muscles, LY195115 increased contractility in a concentration-dependent manner; its actions were not blocked by either prazosin or propranolol. An intravenous dose of 7.0 micrograms/kg LY195115 resulted in a 50% increase in contractility in anesthetized dogs; comparable inotropic responses were observed in anesthetized cats receiving 10 micrograms/kg i.v. These doses of LY195115 increased heart rates of both dogs and cats by less than 10%. Oral administration of 25 micrograms/kg to conscious dogs was associated with a selective inotropic response that was maximal at 3 h and maintained in excess of 23 h. This effect was not accompanied by gross behavioral changes or emesis. The hemodynamic profile of LY195115 was evaluated in anesthetized beagle dogs. A 60-min infusion of 1.0 microgram/kg/min LY195115 followed by a 5-min infusion of 10 micrograms/kg/min resulted in dose-dependent increases in contractility (LV dP/dt60) and heart rate; doses that increased LV dP/dt60 by 50% increased heart rate by less than 10%. Doses of greater than 5.0 micrograms/kg decreased left ventricular end-diastolic pressure and systemic vascular resistance; mean arterial blood pressure and cardiac output were unchanged. Estimated myocardial oxygen consumption (heart rate times either systolic or mean arterial blood pressure) was not altered by doses as high as 110 micrograms/kg. This balance of inotropic/vasodilator activities may provide a means of improving cardiac function while maintaining myocardial oxygen supply/demand.     

The acute hemodynamic, hormonal, and pharmacokinetic properties of oral spirapril in patients with moderate to severe heart failure.

The acute hemodynamic, hormonal, and pharmacokinetic responses to the oral angiotensin-converting enzyme (ACE) inhibitor spirapril were studied in 15 patients with moderate to severe congestive heart failure in a baseline controlled dose-ranging study. Doses of 0.3, 1.0, 1.5, 3.125, and 6.25 mg were investigated for 24 h in three groups of five patients each. All doses demonstrated a significant reduction in serum ACE, even after 24 h. Significant reductions in mean arterial pressure, systemic vascular resistance, and pulmonary capillary wedge pressure were observed with doses greater than 1.0 mg spirapril. Maximal significant hemodynamic effects occurred approximately 4-6 h after drug administration. The plasma concentrations of spirapril and its metabolite spiraprilate were dose-dependent. After administration of spirapril, the quick rise to the peak level of spiraprilate suggests rapid metabolism of spirapril into spiraprilate and a slow elimination of this metabolite. No severe hypotension or other serious side effects occurred in the patients studied. The results indicate that spirapril may be expected to be an effective drug in the treatment of congestive heart failure. From our findings we conclude that 1.5 mg spirapril is an optimal starting dose in patients with moderate to severe congestive heart failure.     

Hemodynamic action of verapamil in dogs with controlled aortic pressure--influence of sympathetic activation

Verapamil was given to 18 anesthetized dogs (alpha-chloralose 100 mg/kg) as a bolus injection (200 micrograms/kg) followed by constant rate infusion (10 micrograms/kg per min). Hemodynamic parameters were evaluated before and during verapamil administration. After a suitable period of time for complete reversal of hemodynamic effects, verapamil administration as well as hemodynamic measurements were repeated during graded aortic occlusion. This technique stabilized central aortic pressure so that the level of reflex baroreceptor stimulation could be kept constant. Atrio-ventricular conduction disturbances observed in 5 dogs during balloon occlusion are attributed to lack of sympathetic stimulation. Without balloon occlusion, verapamil produced significant decreases in peripheral systemic vascular resistance and pressure and marked increases in cardiac output. Heart rate, pulmonary arterial and pulmonary wedge pressures did not change significantly. During graded aortic occlusion, systemic resistance and cardiac output were less markedly affected but there was an increase in both pulmonary arterial and wedge pressures.