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.

Renal and humoral effects of ibopamine, a dopamine agonist, in patients with liver cirrhosis.

We investigated the renal and humoral effects of short-term administration of ibopamine, an orally active dopamine agonist, in patients with liver cirrhosis. The patients were divided into two groups on the basis of sodium excretion with a constant sodium intake of 40 mEq/d. We also compared the effects of ibopamine with those induced by intravenous infusion of dopamine hydrochloride (3 micrograms/kg per minute) in similar patients. Ibopamine caused significant increases in urine output, glomerular filtration rate, and sodium excretion throughout the 4 hours of the trial in patients with basal sodium excretion rate greater than 20 mmol/d. These renal effects were associated with a significant reduction in plasma aldosterone concentration. In contrast, only a transient increase in glomerular filtration rate and a diminution in plasma aldosterone concentration were observed after ibopamine in the patients with a basal sodium excretion rate less than 20 mmol/d. The infusion of dopamine had renal effects similar to those of ibopamine in both groups of patients. These results indicate that in cirrhotic patients with normal sodium excretion, ibopamine exerts a diuretic and natriuretic effect similar to that of dopamine infusion. However, these properties of dopaminergic agents are apparently lost in patients with avid sodium retention.

Peripheral hemodynamic effects of ibopamine in patients with congestive heart failure. A placebo-controlled, double-blind study.

Under double-blind conditions, 150 mg of ibopamine (di-isobutyric ester of N-methyldopamine) or placebo were given orally to 11 patients with congestive heart failure; after 3 hours, 50 mg of sulpiride were administered intramuscularly. Peripheral hemodynamics were evaluated at the level of the forearm using strain-gauge plethysmography. Ibopamine increased arterial blood flow and venous capacity and decreased arterial peripheral resistance; these effects were counteracted by sulpiride. No significant changes were observed after placebo and sulpiride. These findings confirm the vasodilating effects of ibopamine on peripheral hemodynamics and its utility in patients for the treatment of congestive heart failure.

Long-term therapy of chronic congestive heart failure with ibopamine: a multicenter trial.

The present multicenter open investigation was designed to provide information on the adverse reaction rate, drug interaction, and survival in a group of 544 cardiac patients treated for 1 year with ibopamine either alone or in association with digitalis, diuretics, and other drugs. Some efficacy parameters were also considered. Heart failure was due to idiopathic dilated cardiomyopathy (21%), ischemic heart disease (32%), hypertensive heart disease (31%), and others (16%). Ibopamine was given alone to 39 patients; the others were given the drug in association with digitalis, diuretics, and vasodilators. One hundred forty patients did not complete the trial (25.7%). The most common causes of discontinuation were death (12.5%), noncompliance with the protocol (5%), and adverse events (3.9%). The clinical conditions and NYHA functional class improved in most patients. The cardiothoracic ratio decreased on average. The 1-year mortality rates associated with NYHA class II, III, and IV were 4.4, 13.8, and 37.2%, respectively. Survival tended to be shorter in a small group of 22 patients with hyponatremia, thus confirming some previous reports. Adverse experiences were mainly related to cardiovascular and gastrointestinal systems; the symptoms were considered severe only in 1 of 544 patients enrolled. Ibopamine seems not to induce dangerous arrhythmias. Blood pressure and heart rate did not change over time during ibopamine treatment. Laboratory tests were not significantly affected; fluctuations observed in some tests were related to concomitant variations in the severity of the primary disease. No tolerance to ibopamine seems to be observed during this long-term therapeutic trial.

Treatment of heart failure following chronic cor pulmonale with ibopamine.

A group of 36 patients with cor pulmonale chronicum were treated for 12 months with ibopamine, a dopamine-related drug, orally active, suitable for the long-term therapy of congestive heart failure. In heart failure due to chronic pulmonary disease other drugs such as digitalis are hardly effective. The results obtained indicate that ibopamine, given alone or associated to other drugs, is clinically efficient in the treatment of cor pulmonale chronicum while very few side effects definitely related to ibopamine were reported. In particular no increase in arrhythmias or significant augmentation of anginal episodes was noted.

Effects of ibopamine on heart performance: a radionuclide ventriculography study in patients with idiopathic dilatative cardiomyopathy.

The effects of ibopamine (SB-7505, Ib), a new orally active 3,4-diisobutyryl ester of N-methyldopamine, were studied in 8 patients aged between 34-56 years with idiopathic dilatative cardiomyopathy (II-III New York Heart Association Class) diagnosed by means of right and left heart catheterization and selective coronary angiography. Equilibrium radionuclide ventriculography (RVG) was performed in baseline conditions and 1, 2, and 3 h after the administration of a single oral dose of 200-300 mg of Ib. After 2 h Ib increased cardiac output (CO) (+16%, p less than 0.05), stroke volume (SV) (+12%, p less than 0.05) and ejection fraction (EF) (+10%, p less than 0.01). Patients were then randomly treated with placebo or Ib 100 mg t.i.d. according to a double-blind cross-over design for two periods of 15 days each. At the end of each period a RVG was repeated in baseline conditions and 1, 2, and 3 h thereafter. The mean values of the four determinations where higher after Ib than after placebo (CO: +10.1%, p less than 0.01; SV: +14.1%, p less than 0.01; EF: +10.8%, p less than 0.05). Patients subsequently started a long-term treatment with Ib 100 mg t.i.d.; after 6 months patients underwent RVG 3 h after the last dose of Ib: compared with the values recorded at the same time after the short-term treatment. CO further increased by 17% (NS), SV by 22% (p less than 0.05) and EF by 24% (p less than 0.05). The treatment was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Humoral and renal effects of ibopamine in normal subjects.

The acute effects of 50 mg of ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine, were investigated after oral administration to 10 adult subjects without evidence of renal, hepatic or cardiovascular disease. Blood pressure and heart rate did not change while diuresis and urinary electrolyte excretion increased significantly during the 240 min of the study. Glomerular filtration rate (GFR) was also increased at 80 min after ibopamine, whereas plasma aldosterone and prolactin were slightly decreased. In contrast to dopamine, ibopamine did not stimulate plasma renin activity. These results are attributable to the ability of ibopamine to be rapidly deesterified to N-methyldopamine (epinine) which has been previously shown to exert peripheral effects similar to those of dopamine. Therefore, the increased GFR can be ascribed to an enhanced renal blood flow. On the contrary, taking into account the significant increase of the fractional excretion of sodium (FeNa) the rise in sodium excretion seems to be the consequence of a direct tubular effect of epinine, even though the slight decrease in peripheral aldosterone concentration would have been a contributing factor. Urinary flow rate might be enhanced by the high sodium delivery to the distal nephron, rather than by a postulated dopaminergic inhibition of arginine-vasopressin release.

Effects of ibopamine on systemic, pulmonary and regional hemodynamics. Experimental investigations in anesthetized dogs.

The effects of a new orally effective dopamine-like derivative, ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine, on the cardiovascular system were investigated in anesthetized dogs. Ibopamine increased dose-dependently stroke volume index, cardiac index, left ventricular pressure, its first derivative: dP/dt, peak velocity left ventricular ejection and renal blood flow. After beta-blockade the positive inotropic effect of ibopamine is inhibited. Total peripheral resistance and renal vascular resistance decreased after ibopamine. Urine output was increased dose-dependently, reaching 115% after ibopamine 8 mg/kg intraduodenally. Coronary and femoral flows and resistance did not change after administration of 4 and 8 mg/kg. Only very high doses (24 mg/kg) caused an increase in flow and resistance. Mesenteric flow decreased transiently and then returned to the previous level or increased considerably over the basal figures when a high dose was used. No significant changes or fall in heart rate were observed with doses up to 16 mg/kg and no significant changes in pulmonary resistance were noted. The data obtained from the present investigation show, however, that oral ibopamine is capable of producing most of the effects induced by intravenously given dopamine in anesthetized dogs. Ibopamine's cardiac and renal effects may open new prospects for the long-term treatment of chronic heart failure in human subjects.

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.

Correlation between digoxin plasma levels and arterial blood pH.

The correlation between arterial blood pH and digoxin plasma levels was studied after digoxin (Eudigox) administration a) in a single p.o. dose, b) in a steady state p.o. regimen, or c) i.v. The clinical trial was carried out on 26 male hospitalized patients selected and divided into groups according to their arterial blood pH values, which ranged between 7.20 and 7.53. Arterial blood pH proved to be directly correlated with digoxin plasma levels and with the corresponding AUC and inversely with the total plasma clearance of the drug. The data may explain the strongly reduced activity shown by digoxin in patients suffering from respiratory acidosis in clinical practice.

[Preliminary evaluation of the effect of ibopamine on the secretion of prolactin]. / Valutazione preliminare dell'effetto della ibopamina sulla secrezione di prolattina.

Ibopamine, diisobutyric ester of N-methyl dopamine, is an orally active dopaminergic agonist. The prolactin-lowering activity of Ibopamine was studied in 8 subjects with normal prolactine levels given the drug in a single dose of 100 mg. Prolactin levels measured by radioimmuno assay were evaluated before and within 2, 4 and 8 h of administration. Afterwards prolactin levels were evaluated after 4 and 8 days of treatment with Ibopamine administered at a dose of 50 mg three times daily. Ibopamine was shown to decrease prolactin to a statistically significant extent at the 2nd h after administration. At the 4th h prolactin returned to baseline values. After 4 and 8 treatment days prolactin levels did not differ significantly from baseline values. These results provide further evidence for the dopaminergic activity of Ibopamine and suggest a more through investigation in hyperprolactinemic subjects.

Effect of ibopamine on peripheral haemodynamics.

Peripheral haemodynamics was studied in healthy volunteers by strain gauge plethysmography after administration of ibopamine (IB), diisobutyric ester of N-methyl-dopamine, an orally active dopaminergic agonist. Seven subjects received a single oral dose of ibopamine of 150 mg and 6 received a daily dose of 150 mg (50 mg t.i.d.) for 5 consecutive days. Arterial resting blood flow and venous capacity increased and peripheral resistance decreased significantly. Six further subjects were then studied; 3 h after an oral dose of ibopamine 150 mg, the parenteral administration of Sulpiride 50 mg, a specific vascular dopaminergic antagonist, was found significantly to counteract its peripheral activity. Heart rate and arterial blood pressure were never affected and tolerability was good.

Effectiveness of ibopamine in the management of ascitic liver cirrhosis--a controlled study v placebo and frusemide.

1 Thirty in-patients of both sexes suffering from ascitic liver cirrhosis were divided into three groups treated with (a) a placebo, (b) ibopamine (SB 7505, a new oral dopaminergic drug) and (c) frusemide, for 10 days. 2 Body weight decreased with both frusemide and ibopamine, diuresis and urinary excretion of Na+ and Cl- increased with both drugs; whereas urinary excretion of K+ increased only with frusemide. 3 An important difference between the frusemide and ibopamine treatment was encountered in creatinine clearance, which increased only with ibopamine, and in blood uric acid which increased only with frusemide. 4 The antidiuretic hormone (ADH) in the plasma of cirrhotic patients was lower than the sensitivity limit of the radioimmunoassay method, whereas in a group of healthy subjects it could be clearly measured. 5 The treatments did not affect systolic or diastolic blood pressure, heart rate, or a series of haematochemical parameters. 6 The increase in diuresis and creatinine clearance and the very good tolerability encountered with ibopamine highlight this new oral dopamine agonist as a useful drug in the management of liver cirrhosis.

Renal effect of SB 7505: a double-blind study.

Two groups of 20 patients with no evidence of cardiovascular, hepatic, renal or gastrointestinal failure were treated orally for five days with placebo or SB 7505 100 mg/day. No change was observed in heart rate or blood pressure. Urine output, the excretion of Na, K and Cl, and creatinine clearance were significantly increased.