denopamine and Heart-Failure

The crucial issues in the management of congestive heart failure (CHF) are improvement of depressed myocardial contractility and reduction of excessive load. For this purpose, positive inotropic agents and vasodilators have been developed as new oral drugs. The former include Denopamine which possesses beta 1 stimulating effect, Xamoterol which is a unique agent acting as a beta 1-partial agonist, and Ibopamine, Docarpamine and Phosphodiesterase Inhibitors which possess both inotropic and vasodilating effects and are called "Inodilators". The latter include Angiotensin Converting Enzyme Inhibitors. In addition, new vasodilators, such as, Vasopressin Antagonist have also been developed. However, careful long-term clinical trials are required with regard to the efficacy and adverse effects before these agents are widely used with safety in the management of CHF.

Topics: Administration, Oral; Cardiotonic Agents; Deoxyepinephrine; Ethanolamines; Heart Failure; Humans; Phosphodiesterase Inhibitors; Piperidines; Propanolamines; Pyrazines; Quinolines; Quinolones; Vasodilator Agents; Xamoterol

Denopamine is a new, orally active, positive inotropic agent. We evaluated its clinical effects in 13 patients who had undergone cardiac operations, 8 were in early postoperative periods and 5 were in late postoperative periods. In the former, denopamine therapy (30 mg/day) were started on the 6-14 th postoperative day in 5 patients so that they might free from catecholamine drip infusion (2-14 micrograms/kg/min), and on the 14-24th postoperative day in 3 patients in order that pleural effusion might reduce. All 5 patients were weaned from catecholamine, and pleural effusion in 3 patients disappeared completely. In the latter, denopamine therapy were indicated so that they might get relief from the symptoms of chronic heart failure. Although they had undergone combined valvular operations, they still remained in NYHA class II or III postoperatively, associated with cardiomegaly, hepatomegaly and atrial fibrillation. Denopamine therapy (15-30 mg/day) were quite effective in improving subjective symptoms but not in reducing cardiomegaly or hepatomegaly. No clinically significant side effects were noticed during 9-14 months of denopamine therapy. We conclude that denopamine is a quite useful cardiotonic agent in the postoperative management of patients with cardiac surgery.

Topics: Adult; Aged; Cardiotonic Agents; Ethanolamines; Heart Diseases; Heart Failure; Humans; Middle Aged; Postoperative Care; Postoperative Complications

The hemodynamic effect of oral TA-064 (20 mg), a newly synthesized inotropic agent, was compared with that of intravenous dobutamine (5 micrograms/kg/min) in eight patients with congestive heart failure who had been treated with intravenous dobutamine, digitalis, diuretics, and prazosin. Hemodynamics was measured using a Swan-Ganz catheter during the pre-dobutamine control period, during dobutamine infusion period, during the pre-TA-064 control period and at 90 minutes after oral administration of TA-064. Stroke work index was increased and mean pulmonary capillary wedge pressure was decreased with TA-064 or dobutamine. Cardiac index and stroke index was increased by each drug, and pulmonary and systemic vascular resistances were decreased. Mean systemic arterial pressure, heart rate and pressure-rate product did not significantly change in comparison with the control level. In conclusion, TA-064 has a hemodynamic effect similar to that of dobutamine and may be useful as an oral substitute for dobutamine in patients with congestive heart failure after temporary management with dobutamine.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Cardiac Output, Low; Cardiotonic Agents; Chronic Disease; Clinical Trials as Topic; Dobutamine; Ethanolamines; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Time Factors

This study was designed to examine the effects of denopamine, a selective beta1-adrenergic agonist, in a murine model of congestive heart failure (CHF) due to viral myocarditis.. Positive inotropic agents are used to treat severe heart failure due to myocarditis. However, sympathomimetic agents have not been found beneficial in animal models of myocarditis.. In vitro: The effects of denopamine on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) production was studied in murine spleen cells. In vivo: Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus (day 0). Denopamine (14 micromol/kg), denopamine (14 micromol/kg) with a selective beta1-blocker metoprolol (42 micromol/kg), or denopamine (14 micromol/kg) with metoprolol (84 micromol/kg) was given daily, and control mice received the vehicle only. Survival and myocardial histology on day 14 and TNF-alpha levels in the heart on day 6 were examined.. In the in vitro study, TNF-alpha levels in treated cells were significantly lower than in controls (p < 0.05). In the in vivo study treatment with denopamine significantly improved the survival of the animals (14 of 25 (56%) treated, vs 5 of 25 (20%) control mice), attenuated myocardial lesions, and suppressed TNF-alpha production (66.5+/-7.5 pg/mg of heart in treated mice vs 113.5+/-15.1 pg/mg of heart in control mice, mean+/-SE). There was a strong linear relationship between mortality and TNF-alpha levels (r=0.98, n=4, p < 0.05). These in vitro and in vivo effects of denopamine were significantly inhibited by metoprolol.. These results suggest that denopamine may exert its beneficial effects, in part, by suppressing the production of TNF-alpha via beta1-adrenoceptors.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Cardiotonic Agents; Cardiovirus Infections; Culture Techniques; Dose-Response Relationship, Drug; Encephalomyocarditis virus; Ethanolamines; Heart Failure; Male; Metoprolol; Mice; Mice, Inbred DBA; Myocarditis; Myocardium; Tumor Necrosis Factor-alpha

Denopamine was orally administered for more than 12 months to patients with chronic heart failure on maintenance hemodialysis. The plasma level in subjects treated with denopamine at 30 mg/day tended to be higher than that in subjects on 15 mg/day. There was no gradual increase in plasma level as the duration of therapy prolonged. Left ventricular end-diastolic and end-systolic diameters as well as ejection fraction on echocardiography showed a tendency to be improved by denopamine. Similarly, the cardiothoracic ratio was improved temporarily. No adverse effects were detected by electrocardiography and laboratory tests. These observations suggest that denopamine is safe and effective for hemodialysis patients with chronic heart failure.

Topics: Administration, Oral; Adult; Aged; Cardiotonic Agents; Chronic Disease; Echocardiography; Electrocardiography; Ethanolamines; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Renal Dialysis

The present study was undertaken to determine whether cardiac response to beta 1-adrenergic agonists is altered in rats with chronic heart failure (CHF), and whether this alteration is related to beta-adrenergic receptor down-regulation in the viable tissue of the left ventricle of these rats. For this purpose, the cardiac response to denopamine, a selective beta 1-adrenergic agonist, and the change in cardiac beta-adrenoceptor density were examined in rats with CHF. A non-selective beta-adrenergic agonist, isoprenaline, was also examined as a comparison. Cardiac output and stroke volume indices were reduced 12 weeks after left coronary artery ligation, suggesting that CHF had developed at this time. Denopamine (2, 4 and 8 micrograms/kg i.v.), and isoprenaline (0.01 microgram/kg i.v.) increased the cardiac output and stroke volume indices in sham-operated rats, whereas such increases were attenuated in the CHF rat. The cardiac beta-adrenergic receptor density, measured by [3H]CGP-12177 binding assay, was reduced in homogenates and microsomal membranes in the viable tissue of the left ventricle of the CHF rat (homogenates: 29% reduction, microsomal membrane: 23% reduction). These results suggest that the cardiac responsiveness to denopamine is diminished in the CHF rat and this alteration is accounted for, in part, by a decrease in cardiac beta-adrenoceptor density.

Topics: Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Animals; Cardiac Output; Chronic Disease; DNA; Down-Regulation; Ethanolamines; Heart; Heart Failure; Hemodynamics; In Vitro Techniques; Isoproterenol; Male; Myocardial Infarction; Myocardium; Organ Size; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Stroke Volume

Topics: Cardiomyopathy, Dilated; Chemotherapy, Adjuvant; Ethanolamines; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Pyridazines; Vasodilator Agents

Topics: Animals; Blood Pressure; Calcium; Cardiomegaly; Cardiomyopathy, Dilated; Ethanolamines; Heart Failure; Humans; Myocardial Contraction; Myocardium; Myosins; Receptors, Muscarinic

To investigate whether effects of denopamine become weaker or not. Initial single dose (10 mg) effects, single dose effects after long-term treatment (30 mg per day, about 40 days), and chronic effects were studied by Doppler and echocardiography in 23 patients with heart failure (NYHA II-III). 1) Chronic effects: Blood pressure and heart rates didn't change significantly whether they were measured before or after long-term treatment. But left ventricular end-diastolic dimension decreased from 54.6 +/- 10.2 to 53.3 +/- 10.1 mm (p less than 0.01). Percent fractional shortening (%FS) increased from 22.6 +/- 7.8 to 25.3 +/- 8.6% (p less than 0.05). Mean velocity of circumferential fiber shortening (mVCF) tended to increase, and cardiac index (CI) increased from 2.71 +/- 0.47 to 2.98 +/- 0.57 l/min/m2 (p less than 0.01). 2) Initial single dose effects: Blood pressure and heart rates increased significantly. %FS increased from 25.0 +/- 7.7 to 25.9 +/- 7.8% (p less than 0.05), mVCF increased from 0.94 +/- 0.26 to 1.03 +/- 0.28 cir/sec (p less than 0.01), and CI increased from 2.81 +/- 0.49 to 3.09 +/- 0.49 l/min/m2 (p less than 0.01). 3) Single dose effects after long-term treatment: Blood pressure and heart rates increased significantly. %FS tended to increase, mVCF increased from 1.02 +/- 0.27 to 1.09 +/- 0.30 cir/sec (p less than 0.05), and CI increased from 3.05 +/- 0.62 to 3.37 +/- 0.54 l/min/m2 (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adrenergic beta-Agonists; Aged; Drug Tolerance; Echocardiography, Doppler; Ethanolamines; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged

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.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Cardiotonic Agents; Echocardiography; Ethanolamines; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged

Topics: Administration, Oral; Adult; Aged; Cardiotonic Agents; Ethanolamines; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged

Topics: Adult; Aged; Cardiotonic Agents; Electrocardiography; Ethanolamines; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged

Cardiovascular effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) were investigated in various experimental animals. An intravenous bolus injection of denopamine dose-dependently increased the contractile force or the maximum rate of rise of left ventricular pressure (LV dp/dtmax in cynomolgus monkeys, miniature pigs, cats and rats. In these animals, the doses of denopamine which increased the contractile force by 30% of the control (ED30) were found to be 2-3 micrograms/kg. On the other hand, ED30 values for dl-isoprenaline ranged from 0.005 to 0.04 micrograms/kg. Thus, the potency of denopamine for increasing the contractility was approximately 1/60-1/300 that of dl-isoprenaline. It is noteworthy that the positive inotropic effect of denopamine was more pronounced than the positive chronotropic effect compared with those of isoprenaline, as estimated at ED30 for positive inotropy. In general, denopamine produced little effect on the blood pressure, and only a slight increase or an increasing tendency was observed in all of these animals. An intravenous continuous infusion of denopamine to monkeys or pigs produced qualitatively similar cardiovascular effects to those following intravenous bolus injection. When examined with monkeys, the positive inotropic effect and plasma levels of denopamine were closely related. Denopamine increased cardiac output, and reduced total peripheral resistance in pigs and dogs. In dogs, common carotid, superior mesenteric and femoral arterial blood flow were increased concomitant with the increase in cardiac output, while the vascular resistance of the corresponding vascular bed was reduced. Denopamine had no significant influence on central venous pressure in monkeys and pulmonary arterial pressure in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bundle of His; Cardiotonic Agents; Cats; Electrocardiography; Ethanolamines; Female; Heart Failure; Hemodynamics; In Vitro Techniques; Macaca fascicularis; Male; Myocardial Contraction; Rats; Rats, Inbred Strains; Species Specificity; Swine; Swine, Miniature

A new hydroxybenzyl alcohol derivative TA-064 exerts a positive inotropic action in experimental preparations. To assess the acute effects in man, we made a cardiac catheterization study of the hemodynamic responses to TA-064 (20 mg and/or 40 mg given orally) in eleven patients with refractory heart failure due to cardiomyopathy (nine patients with dilated cardiomyopathy and one with amyloidosis). All patients were already receiving full digitalis and diuretics therapy. The following statistically significant (P less than 0.05-0.01) effects were noted: Upon administration of 20 mg of the drug, the cardiac index (CI) increased from a mean +/- 1 SD of 1.6 +/- 0.4 to 2.1 +/- 0.6 l/min/m2; pulmonary capillary wedge pressure (PCW) fell from 25 +/- 5 to 21 +/- 5 mm Hg; right atrial pressure (RA) fell from 12 +/- 3 to 10 +/- 4 mm Hg. In contrast, when 40 mg TA-064 were administered orally, the CI increased from 1.7 +/- 0.4 to 2.4 +/- 0.9 l/min/m2; PCW fell from 25 +/- 8 to 20 +/- 6 mm Hg; pulmonary arterial mean pressure fell from 35 +/- 11 to 29 +/- 9 mm Hg. Neither systemic arterial mean pressure nor heart rate increased. No toxicity was observed. The plasma concentration of TA-064 increased dose-dependently and reached a peak value 0.5-1.5 h after oral administration. Plasma catecholamine levels revealed no significant changes before and after use of the drug; therefore, the mechanism of action may not have been mediated by catecholamine.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiomyopathies; Cardiotonic Agents; Catecholamines; Dose-Response Relationship, Drug; Ethanolamines; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Pulmonary Wedge Pressure

According to investigations conducted in Japan, TA-064 is a new cardiotonic agent, which is also effective orally. We analyzed computer-assisted alterations of pressure-volume relations serially and of MVO2 online (Bretschneider) during TA-064 influence in 16 patients with congestive cardiomyopathy: LV-function of 7 patients was only moderately decreased (group A) and in 9 patients massively (group B).. 1) TA-064, 8 micrograms/kg/min, i.v. had positive inotropic effects in both groups and induced mean maximal delta% changes at about the 5th minute of infusion as follows: LVSWI + 65% and 47%; DP/DTmax + 61% and 59%; LV-efficiency + 62% and 53%; MVO2 + 31% and + 11% (p less than 0.05). 2) TA-064, 20 mg p.o. induced serum levels (A: 23.8 +/- 12 and B: 26.4 +/- 20 ng/ml) corresponding to the effects with the dosages 1-2 micrograms/kg/min, i.v. (p greater than 0.05), thus implying that significant changes in LV-function require higher p.o. dosages. 3) TA-064 i.v. on the 6th day of exposure to the medication produced less LV-function improvement than on day 1 (p greater than 0.05).. In both groups A and B TA-064 improves LV-function primarily via increased contractility, without toxic side effects. For a more complex definition of the efficiency and mechanism of cardiotonic agents, the validity and importance of using on-line MVO2 assessment and analysis of serial pressure-volume relations is stressed.

Topics: Adult; Blood Pressure; Blood Volume; Cardiac Output; Cardiomyopathy, Dilated; Cardiotonic Agents; Computers; Dose-Response Relationship, Drug; Ethanolamines; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Myocardial Contraction; Myocardium; Online Systems; Oxygen Consumption

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiotonic Agents; Echocardiography; Ethanolamines; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Stroke Volume