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PubMed1985

High-dose prenalterol in beta-blockade intoxication.

This study presents a case of beta-blocker intoxication due to massive overdose of metoprolol (7.5 g). Prenalterol in a dose of 420 mg was given as antidote, in combination with epinephrine in intermittent doses. Resuscitation was performed during 4 hours because of mechanical asystole. The patient regained health in 24 hours after further repeated doses of 30 mg prenalterol. Prenalterol is valuable in the management of toxic doses of beta-blocking drugs, and a titration to extremely high doses of prenalterol might be necessary.

Adult↗
PubMed1987

Effects of prenalterol on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced shock.

The hemodynamic and cardiometabolic effects of prenalterol were evaluated in propoxyphene-induced circulatory shock in 10 pentobarbital-anesthetized pigs. Circulatory shock (i.e. a systolic arterial blood pressure below 60 mmHg (8 kPa) and/or a cardiac index of less than 2.0 1 X min-1 X m-2) was induced by intravenous propoxyphene chloride 15 mg X min-1. Circulatory shock occurred after 26 +/- 3 mg X kg-1 of propoxyphene. During continuous infusion of propoxyphene, consecutive doses of prenalterol 0.5, 1.0, 2.0 and 4.0 mg i.v. were injected with an interval between increments of 8 min. The maximum effect of prenalterol was seen following the 2 mg dose. Increases were observed in mean arterial blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, right ventricular stroke work index, maximum rate of rise of ventricular pressure, and total body oxygen consumption. Decreases were observed in pulmonary artery occlusion pressure, mean right atrial pressure and systemic vascular resistance, whereas heart rate and pulmonary vascular resistance remained unchanged. The cardiometabolic parameters: coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and extraction, remained low. Due to profound vasodilation, normal perfusion pressures were not reestablished. In conclusion, prenalterol improved cardiac performance by a significant positive inotropic action. However, pure inotropic stimulation was not sufficient to counteract the circulatory shock state during severe propoxyphene intoxication.

Animals↗
PubMed1987

Analysis of the inotropic effect of prenalterol in papillary muscles from guinea-pig hearts.

The inotropic effects of prenalterol were studied in papillary muscles isolated from the right ventricle of guinea-pig hearts. Force production and action potential were recorded. The preparations were paced at 0.4 Hz (at 31-32 degrees C) under isometric conditions. Prenalterol, in concentration 0.1 microM did not change the action potential duration whereas the peak force and the maximum rate of force development increased by 40.3 and 36.3%, respectively. Time to peak force was slightly shortened (-3.0%) and so was the time from peak force to half relaxation (-5.2%). A predetermined stimulus protocol was used for assessment of the recirculation fraction of activator calcium. At selected times an extra contraction was introduced in order to obtain contractile potentiation. Force of the subsequent two test contractions (after fixed intervals) was analysed. Prenalterol slightly reduced the decay of the postextrasystolic potentiation measured in the two test contractions. It is suggested that the inotropic effect of prenalterol is due to an intensified calcium influx during the action potential, and to some extent to more efficient re-utilization of released calcium. There seems to be a more rapid release of calcium from troponin C giving rise to a shortened time to peak force and an enhanced relaxation.

Action Potentials↗
PubMed1981

beta 1-Adrenoceptors mediating relaxation of the guinea-pig trachea: experiments with prenalterol, a beta 1-selective adrenoceptor agonist.

In the presence of 17 beta-oestradiol, prenalterol, a beta-selective adrenoceptor agonist, caused a dose-dependent relaxation of the isolated, pilocarpine-contracted guinea-pig trachea. This effect was blocked by the antagonists propranolol (non-selective) and practolol (beta 1-selective) but not by IPS 339 [(t-butylamino-3-ol-2-propyl)oximino-9-fluorene HCl] (beta 2-selective). The relaxing effect of terbutaline, a beta 2-selective adrenoceptor agonist, was more efficiently blocked by IPS 339 than by practolol. These data support the hypothesis that the guinea-pig trachea contains both beta 1- and beta 2-adrenoceptors mediating relaxation and that the beta 1-adrenoceptors are selectively stimulated by prenalterol. The efficacy of prenalterol was less than that of terbutaline, thus confirming its partial agonistic activity. In the absence of 17 beta-oestradiol, the ability of prenalterol to relax the pilocarpine-contracted trachea was lost. It is suggested that 17 beta-oestradiol may act as a functional antagonist to pilocarpine as it caused a partial relaxation itself.

Adrenergic beta-Agonists↗
PubMed1984

Regional myocardial contractile response to the beta-adrenergic stimulant prenalterol in the conscious dog following myocardial infarction. Mechanism of hemodynamic effect.

In order to assess regional myocardial contractile responses to the beta-adrenergic stimulant prenalterol after recent myocardial infarction, 9 male mongrel dogs underwent left circumflex coronary artery (LCX) occlusion after implantation of miniature subendocardial sonomicrometer crystals in normal, marginally ischemic (border) and central ischemic zones. 90-min LCX occlusion with reperfusion resulted in substantial infarction (mean +/- SEM 24 +/- 3% of total left ventricular area) and characteristic regional functional alterations. In conscious, unsedated animals 72 h after infarction, intravenous prenalterol (30 micrograms/kg) significantly decreased end-diastolic and end-systolic segment length and increased percent systolic shortening in normal and border zones, but did not alter ischemic zone function. Heart rate increased significantly with prenalterol. Regional myocardial function before drug administration correlated closely with response to the inotropic agent. These results indicate that the mechanism by which prenalterol improves cardiac function 72 h after myocardial infarction is stimulation of normal and marginally ischemic myocardium.

Animals↗
PubMed1981

Hemodynamic effects of atrial pacing and prenalterol infusion in patients taking beta-adrenergic blocking drugs.

Prenalterol, a beta-adrenergic agonist, was given to nine patients with angiographically proved coronary artery disease. Subjects were studied during chronic beta-adrenergic blockade. The adequacy of blockade was assessed by the exercise heart rate response and by plasma concentrations of blocking agents. After incremental doses of 2.5 mg, 5.0 mg and 7.5 mg of prenalterol, heart rate was increased by 20%, 24% and 38%, respectively, and left ventricular dP/dt max by 55%, 73% and 61%, respectively. Systolic and diastolic blood pressures did not change significantly; pulmonary artery wedge pressure fell from 10 +/- 0.5 mm Hg to 7.1 +/- 0.9 and 6.7 +/- 0.7 mm Hg after 2.5 mg and 5.0 mg, respectively (p less than 0.01 for both). The net inotropic response to prenalterol was assessed, independent of the chronotropic response, using incremental atrial pacing before and after drug infusion. At identical heart rates, left ventricular dP/dt max increased by 40%, 49% and 48% after 2.5 mg, 5.0 mg and 7.5 mg, respectively. Left ventricular cineangiography before and after infusion showed an increase in ejection fraction from 0.73 +/- 0.02 to 0.83 +/- 0.03 (p less than 0.001). Plasma prenalterol concentration estimations demonstrated a clear, dose-related inotropic response, the level of response in each patient being largely determined by the degree of beta-adrenergic blockade at the time of the study.

Adrenergic beta-Antagonists↗
PubMed1984

Beta-adrenergic stimulation of the failing ventricle: a double-blind, randomized trial of sustained oral therapy with prenalterol.

Eleven patients with severe left ventricular impairment (mean ejection fraction 24%) and moderate impairment of exercise tolerance underwent a double-blind, placebo-controlled, cross-over trial of the orally administered beta-agonist prenalterol. Exercise hemodynamics and tolerance were measured during bicycle and treadmill exercise after 2 weeks of therapy with placebo or prenalterol. Cardiac index, ejection fraction, and stroke work index were not improved and exercise duration and peak oxygen consumption were not significantly different during the two treatments. During prenalterol treatment heart rate during exercise was consistently reduced. These results show that prolonged therapy with prenalterol does not improve hemodynamics or exercise tolerance and is associated with a diminished heart rate response to exercise.

Administration, Oral↗
PubMed1987

Effects of clenbuterol and prenalterol on behavior maintained under a multiple fixed-interval, fixed-ratio schedule.

The results of a number of studies have implicated beta adrenergic receptors in the brain in the actions of proven antidepressant drugs. This suspected involvement of central beta adrenergic receptors made it of interest to characterize the behavioral effects of centrally acting beta adrenergic agonists. Clenbuterol and prenalterol, unlike most beta adrenergic agonists, penetrate into the central nervous system after peripheral administration. In the present study, the effects of these agonists on behavior maintained under a multiple fixed-interval 5-min, fixed-ratio 30-response schedule were determined. Both compounds, in a dose-dependent manner, reduced response rate under both components of the multiple schedule. Under the fixed-interval component, clenbuterol and prenalterol altered the temporal pattern of responding. At no dose tested was there evidence for any stimulant action of either of the drugs. The effects of clenbuterol and prenalterol on behavior maintained under the multiple schedule appeared to be a result of an interaction of the agonists with beta adrenergic receptors. This was evidenced by the ability of the beta adrenergic antagonist propranolol to block the effects of the agonists. The behavioral effects of clenbuterol and prenalterol appear, in general, to be similar to effects reported previously for tricyclic and monoamine oxidase inhibiting antidepressant drugs.

Adrenergic beta-Agonists↗
PubMed1988

Prenalterol in severe congestive heart failure. I. The immediate haemodynamic effects as compared to nitroglycerine.

The immediate haemodynamic effects of prenalterol and nitroglycerine were examined in 15 patients, with severe chronic heart failure. Prenalterol was given intravenously in increasing doses of 2, 4, and 8 mg. Cardiac index increased significantly by 16%, 24%, and 32%, respectively. Heart rate increased by 16%, 19%, and 24%. Stroke volume index, systemic artery pressure, pulmonary artery pressure, and right atrial pressure did not change. Prenalterol reduced systemic vascular resistance by 15%, 17%, and 24%, respectively. Forearm blood flow and forearm vascular resistance was unchanged. Cardiac index and heart rate were not changed by 0.5 mg nitroglycerine, administered sublingually. Systolic and diastolic blood pressure were on average reduced by 14% and 12%, respectively. Systolic and diastolic pulmonary artery pressure and right atrial pressure were similarly reduced by 17%, 31%, and 39%, respectively. Nitroglycerine lowered calculated systemic vascular resistance by 11%, whereas forearm blood flow and forearm vascular resistance was unchanged. The conclusion is that prenalterol acutely increased cardiac index and improved haemodynamics in 14 out of 15 patients, mainly due to an increased heart rate. Nitroglycerine did not change cardiac index in the same group of patients.

Aged↗
PubMed1987

Effects of clenbuterol and prenalterol on performance during differential reinforcement of low response rate in the rat.

Evidence obtained to date indicates that beta adrenergic receptors in the brain may be involved in the effects of antidepressant drugs. Furthermore, it has been suggested that centrally acting beta adrenergic agonists might possess antidepressant activity. However, preclinical as well as clinical studies of the effects of beta adrenergic agonists have been limited due to the lack of compounds that penetrate into the central nervous system after peripheral administration. Recent results indicate that the beta adrenergic agonists clenbuterol and prenalterol are active centrally. For this reason, it was of interest to begin to assess their behavioral effects. It was found that clenbuterol and prenalterol, in a dose-dependent manner, reduced response rate and increased reinforcement rate under a differential-reinforcement-of-low-rate 72-sec schedule. The effects of these agonists were very similar to those of proven antidepressant drugs. The effects of the agonists clenbuterol and prenalterol, as well as the effects of the tricyclic antidepressant desipramine, on response and reinforcement rate were antagonized by the beta adrenergic antagonist propranolol. The present results indicate that clenbuterol and prenalterol are active behaviorally and that their effects appear to be mediated by beta adrenergic receptors. The similarity between the behavioral effects of the beta adrenergic agonists and those of proven antidepressant drugs provides evidence consistent with the contention that centrally acting beta adrenergic agonists might possess antidepressant activity.

Animals↗
PubMed1981

[Prenalterol (CGP 7760 B), a new cardioselective beta 1-adrenoceptor-agonist (author's transl)].

The haemodynamic effects of the new selective beta 1-receptor-agonist prenalterol were investigated in two groups each of 8 patients. Dosages of 500 microgram/5 min and 100 microgram/1 min were given after direct closure of atrial septal defect under neuroleptanalgesia. Prenalterol 500 microgram/5 min increased cardiac index (37.5%), heart rate (19%), stroke index (16.2%), mean arterial pressure (26.5%) and dp/dtmax (84.5%) significantly. Total systemic resistance, total pulmonary vascular resistance and mean pulmonary pressure remained constant. Filling pressures of both ventricles decreased slightly but significantly. Maximal hemodynamic changes after infusion of 100 microgram/1 min prenalterol were half as great as with 500 microgram/5 min and occurred 3 min earlier. The haemodynamic action of prenalterol was rather long lasting. One hour after cessation of the drug-infusion there were still detectable haemodynamic effects. In contrast to investigations in awake patients there was a greater increase in heart rate, which is referred to influences on the vagal reflex caused by anaesthesia.

Adrenergic beta-Antagonists↗
PubMed1983

[Effects of Prenalterol on left ventricular function of coronary patients].

The aim of the study was to assess the effect of Prenalterol on cardiovascular beta adrenergic system of 12 coronary artery disease patients with a previous myocardial infarction. For this purpose, left ventricular function was assessed before and after intravenous administration of 30 gamma/Kg of Prenalterol, under a constant heart rate, provided by atrial pacing. Prenalterol induced a significant improvement of left ventricular contractility (dp/dt pos.-VCEmax-Vmax d), relaxation (dp/dt neg.-T constant), ventricular compliance (total diastolic compliance-modulus of chamber stiffness-end-diastolic compliance) and pump (ejection fraction) indices. These results suggest the potential usefulness of Prenalterol in severe acute cardiac failure.

Adrenergic beta-Agonists↗
PubMed1979

Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man.

The haemodynamic effects of the selective beta1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selective beta1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/l) prenalterol had to be administered in doses that were twelve times higher than before the beta-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Hemodynamic assessment of prenalterol: a cardioselective beta agonist in patients with imparied left ventricular function.

The hemodynamic effects of a new cardioselective beta agonist, prenalterol, were evaluated in 12 patients with moderate or severe impairment of left ventricular function due to coronary heart disease or primary cardiomyopathy. In doses up to 7 mg the drug led to a substantial increase of left ventricular pressure rise (+55%) and mean circumferential fiber shortening (+59%) and a decrease of left ventricular end-diastolic pressure (-52%), mean pulmonary artery pressure (-24%) and pulmonary vascular resistance (-37%) indicating augmented myocardial contractility and reduced left ventricular preload. Cardiac output was increased only in 4 of 12 patients, heart rate, left ventricular systolic and mean right atrial pressures and the pressure-rate product as an index for myocardial oxygen demand remained essentially unchanged. The same is true for stroke index, stroke work index, total peripheral resistance, left ventricular end-diastolic and end-systolic volume and ejection fraction. The positive inotropic effect was achieved with good tolerance and without arrhythmogenic or other side effects. Prenalterol may be especially useful in patients with low sympathetic activity and hypotension. In patients with diffuse congestive cardiomyopathy, high sympathetic activity, pronounced peripheral vasoconstriction and normal blood pressure, vasodilator therapy alone or in combination with prenalterol should be considered.

Adrenergic beta-Agonists↗
PubMed1984

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.

Administration, Oral↗
PubMed1987

Microbiological systems in organic synthesis: preparation of racemic prenalterol utilizing Cunninghamella echinulata.

The fungal microorganism Cunninghamella echinulata was utilized to para-hydroxylate the synthetic substrate (+/-)-1-isopropylamino-3-phenoxy-propan-2-ol (1). The resulting product, (+/-)-1-(4-hydroxyphenoxy)-3-isopropylamino-propan-2-ol, or (+/-)-prenalterol, (2) was formed in greater than 85% yield. Extracts from incubates were derivatized with trifluoroacetic anhydride and the concentrations of 1 and 2 were determined by GC on a fused silica methyl silicone capillary column with nitrogen-phosphorus detection. At substrate concentrations of 100 and 200 mg/L, the biotransformation proceeds with apparent first-order kinetics. With higher concentrations, the kinetics of prenalterol formation and substrate uptake appear to be nonlinear with a Km value of 427.8 micrograms/mL and a Vmax value of 232.3 micrograms/mL/d. This suggests that the biotransformation may proceed through a single-capacity limited pathway. The microbial product was isolated and identified as (+/-)-prenalterol by comparison (mp, IR, MS, 1H NMR) with an authentic specimen.

Biotransformation↗
PubMed1983

Cardiovascular malformations associated with administration of prenalterol to young chick embryos.

Prenalterol (levo-1-[4-hydroxyphenoxy]-3-isopropyl-amino-2-propanol), a new stimulant of cardiac beta-adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2 1/2- through 5 1/2-day chick embryos (Hamburger-Hamilton stages 17-27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched-out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger-Hamilton stages 17 and 26-27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50-1/20) epinephrine (P = .035 at concentrations of 8-10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5-1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac beta-adrenergic receptors in the chick embryo produces cardiovascular malformations.

Abnormalities, Drug-Induced↗
PubMed1984

Inotropic effect of prenalterol in amitriptyline poisoning.

A case of severe amitriptyline poisoning with grade IV coma, seizures, bradycardia and hypotension who did not respond to dopamine was successfully treated with prenalterol, a new cardioselective beta-agonist. The case is discussed with respect to plasma concentrations of dopamine, prenalterol and amitriptyline. Prenalterol, hydrocortisone and insulin may be useful as inotropic agents in tricyclic poisoning where dopamine fails to provide an adequate response.

Adrenergic beta-Agonists↗