ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00832.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTThe cardiac selectivity of prenalterol as an agonist was demonstrated in the anaesthetised cat, in which the heart rate was dose dependently increased without any effect on peripheral vascular resistance. When doses of prenalterol, isoprenaline (non–selective) and terbutallne (β2–selective) were adjusted to give the same increase in heart rate, prenalterol displayed a significantly higher inotropic effect than the other two agonists.It is generally accepted that cAMP acts as a second messenger in β–mediated responses. Prenalterol induced an inotropic effect in the cat heart, which at its maximum was 80% of that of isoprenaline without, however, any significant increase in cAMP content. In tissue homogenate from cat left ventricle, prenalterol caused only a minor activation of the adenylate cyclase activity. These results may indicate that only a small increase of the adenylate cyclase activity and cAMP level is sufficient for a maximal inotropic response or that production of cAMP is not essential for the positive inotropism produced by prenalterol.In isolated electrically driven rabbit papillary muscle prenalterol induced a positive inotropic response, which was inhibited by the β1–antagonist metoprolol but not by the α–blocker phentolamine or the β2–blocker IPS 339. This indicates that the contractile effect of prenalterol in the heart is mediated via β1–adrenoceptors and that α– or β2–adrenoceptors are not involved. An interindividual variation in intrinsic activity of prenalterol in rabbit papillary muscle was found to be correlated to the sensitivity to isoprenaline.Binding experiments have shown that prenalterol binds with equal affinity to both β1– and β2–adrenoceptors. Prenalterol did not affect subtetanlc contractions in soleus muscle, which indicates a lack of β2–agonistic activity of prenalterol in the skeletal muscle. When the cardiostimulatory effect of prenalterol was compared with the β2–blocking effect in the anaesthetised dog, the results revealed that the β2–blocking effect of prenalterol is produced at doses higher

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00833.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00834.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTExperiments were performedon5 resting conscious dogs supplied with an electromagnetic flow probe on the ascending aorta and a chronic aortic catheter for pressure recording. The animals were used repeatedly in four different types of experiment involving i. v. administration of1.saline (controls),2.prenalterol 45 nmol/kg (∞ 10 μg/kg) followed by an additional dose of 135 nmol/kg 20 min later,3.ouabain 50 nmol/kg (∞30 μg/kg) and4.a combination of protocols2.and3.Ouabain and the low dose of prenalterol exerted clear–cut positive inotropic effects as reflected in increased stroke volume and max dF/dt without significant changes in heart rate or arterial pressure. The PQ interval increased with ouabain but decreased with prenalterol. The higher dose of prenalterol caused a further rise in max dF/dt, a further shortening of the PQ time, increased heart rate and reduction in systemic vascular resistance. Higher doses of ouabain could not be given due to side–effects (vomiting). The combined treatment with ouabain and prenalterol showed their inotropic responses to be additive. Arrhythmias did not occur in any of the animals at the applied dose levels of the drugs. The experiments show that prenalterol through its β1–adrenoceptor stimulating action exerts a positive inotropic effect which surpasses that of emetic doses of ouabain. The inotropic response at moderate doses occurs without a change in heart rate. This fact and the apparent lack of influence of prenalterol on vascular α– and β2–adrenoceptors make the substance potentially useful clinically as an inotropic agent in cardiac failure, particularly in view of its relatively long

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00835.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTPrenalterol (H 133/22) is an adrenergic β–receptor stimulator which unlike isoproterenol is both orally active and has a long duration of action. The inotropic, chronotropic and dromotropic effects of prenalterol were investigated in pentobarbital anaesthetized dogs. Prenalterol was found to increase left ventricular maximum dP/dt in a dose–dependent manner up to a dose level of 50 μg/kg. Additional doses resulted in only small further increases in cardiac contractility. Electrophysiological studies were done to compare the effects of prenalterol and isoproterenol on sinus node and ventricular pacemaker function. Complete AV block was produced by electrocauterization of the His bundle. Prenalterol accelerated both ventricular and sinus node pacemakers at doses up to 50 μg/kg. The increase in ventricular rate was greater than the increase in sinus rate following supramaximal inotropic doses of prenalterol, yet no ventricular extrasystoles were ever observed. Similar acceleration of the ventricular and sinus node pacemakers were observed by infusion of isoproterenol. Prenalterol and isoproterenol accelerated AV nodal conduction and ventricular conduction but had little effect upon His–Purkinje conduction. Sinus node reset time was abbreviated as was the functional and effective refractory periods of the atrium and

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00836.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTFourteen beagle dogs were treated with increasing doses of metoprolol. The first group (n=7) formed part of a preliminary study to establish a suitable dosage regimen. Two of these dogs recovered from plasma concentrations of about 50 000 nmol/1 metoprolol, when metoprolol infusion was stopped. Pour dogs died with plasma concentrations of about 80 000 nmol/1 metoprolol and one dog, in which AV block II developed, recovered from a CO of 300 ml/min after 10 mg/kg prenalterol.The second group consisted of a control group of three dogs and a prenalterol treated group of four dogs. Both groups were treated with increasing doses of metoprolol for 1.5 hours followed by a continuous infusion of metoprolol throughout the rest of the experiment, reaching plasma concentrations of 50 000 nmol/1 of metoprolol. In the prenalterol group, prenalterol was given i.v. in a dose of 0.5 mg/kg every 10 minutes starting 3 hours after the first dose of metoprolol up to a total dose of 5 mg/kg.Metoprolol caused an initial decrease in heart rate (HR) which remained stable at 115 beats/min despite increasing plasma concentrations. Blood pressure (BP) and cardiac output (CO) fell, the decrease being directly proportional to plasma concentrations of metoprolol. The central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) increased indicating reduced inotropic function of the heart. An initial increase in total peripheral resistance (TPR) was seen followed by a return to almost baseline levels with increasing metoprolol concentrations. The three control dogs died after 4–5 hours. Death was caused by low CO failure, preceded by nodal bradycardia followed by asystole. No characteristic ECG changes were seen until cardiac failure developed. Prenalterol reversed the effect of metoprolol on CO, stroke volume (SV), CVP and PCWP. BP and HR remained below the basal values. These basal values of BP and HR were, however, high because of increased sympathetic activity caused by the chloralose anaesthesia. The return of TPR to basal values was more pronounced in the prenalterol group than in the control group.The results suggest that neither HR nor ECG can be used to assess the severity of metoprolol poisoning. BP and CVP or PCWP and when possible CO are probably the best clinical aids in assessment.The present study shows that prenalterol by exerting a pronounced inotropic effect can completely reverse the low CO failure caused by massive doses of metoprolol. However, doses of prenalterol much higher than those normally used are necessar

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00837.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACT1. Prenalterol is rapidly and completely absorbed after oral administration with peak concentrations reached after 30 minutes.2. Prenalterol is rapidly distributed to extravascular tissues after intravenous administration.3. The extent of bioavailability after administration of prenalterol as a solution is about 25% of an intravenous dose. After administration of 20 mg prenalterol in a controlled release preparation the bioavailability is increased to about 45%.4. The half–life of the elimination phase is close to 2 hours.5. 60% of an intravenous dose and 15% of an oral dose is eliminated unchanged by renal excretion. The rest is mainly excreted as the sulphate ester of prenalterol.This presentation deals with the pharmacokinetic properties of prenalterol. The results have been obtained mainly from studies in healthy subjects after acute administration of the drug both intravenously and orally, but some preliminary data on the pharmacokinetics of prenalterol In patients with cardiac failure will also be presented.The studies were performed in six healthy male volunteers 22 to 25 years of age and with a mean weight of 78 kg. The subjects were in good health as judged from clinical and laboratory examinatlons. Prenalterol was administered on occasions separated by at least three days and was given in a randomised order. The subjects arrived at the laboratory after having fasted overnight. A standardised meal was given 3 and 6 hours after drug administration.Prenalterol was administered as prenalterol hydrochloride, a salt freely soluble In water. A single dose of 2.5 mg prenalterol was infused intravenously over 5 min. Oral prenalterol was given as a solution together with 100 ml of water in doses of 2.5, 5.0 and 10.0 mg. Three of the subjects received the intravenous dose and the oral dose of 2.5 mg as tritiated compoun

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00838.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTIn previous pharmacokinetic studies in healthy subjects the time course of plasma concentration of prenalterol was described by a short distribution phase (α–phase) with a mean half–life of about 8 minutes and an elimination phase (β–phase) with an average half–life of about two hours [1, 2]. The aim of this joint study was to check the pharmacokinetic data obtained after intravenous single dose administration with the computer program TOPFIT [3]using different compartment models and to test the predictive power of the chosen kinetic model for plasma concentration data after repetitive intravenous prenalter

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00839.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACT1. Prenalterol inducesa dose–dependent effecton different variables reflecting myocardial contractility and heart rate. A clear cut effect can be demonstrated after an oral dose of 2.5 mg. The duration of the effect increases considerably when prenalterol Is administered as a controlled release preparation partly due to an increased bioavailability.2. Prenalterol induces a lipolytic effect manifested as a rise in free fatty acids and glycerol. Also a slight increase of plasma insulin is recorded while plasma potassium decreases somewhat.3. When prenalterol is administered together with therapeutic doses of a selective or non–selective β–adrenoceptor blocker it induces the same haemodynamic effects as before the β–blocker but the dose has to be increased ten–fold. These results suggest that prenalterol might be a useful drug to counteract unwanted haemodynamic effects of a β–blocker.4. In animal studies It has been shown that prenalterol has affinity for both β1– and β2–adrenoceptors. However, it has a stimulating effect mainly on β1–adrenoceptors. Therefore, theoretically it might act as a β2–adrenoceptor antagonist. Preliminary results from studies in patients with chronic asthma indicate that prenalterol only has an insignificant β2–blocking effect when the drug is administered In doses which induce a significant β1

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00840.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY

摘要:

ABSTRACTElectrophysiological studies with prenalterol in 19 patients (6 women, 13 men, 5 with sinus node disease, 4 with AV node disease, 7 with double node disease, 2 with conduction disturbance below His bundle, 1 normal) showed that sinus node function (heart rate, sinus node recovery time) is uniformly improved by this β–stimulator.Also AV conduction is significantly and uniformly improved (shortening of AH interval and of the functional refractory period of AV conduction).There is no or little influence on intra–atrial conduction and on conduction below the His bundle. However, spontaneous depolarisation in His–Purkinje fibers – as tested in patients with complete AV block and ventricular demand pacemaker – is increased through β–stimulation with prenalterol as reflected by shorter escape intervals and higher frequency escape rhythm.Prenalterol may be of clinical use in patients with cardiomyopathies who developed bradycardia under digitalisation or patients with severe bradyarrhythmia either with or without digitalis.It might also be useful in rare emergency situations, when complete pacemaker fai

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1982.tb00841.x

出版商:Blackwell Publishing Ltd    

年代:1982

数据来源: WILEY