Haemodynamic and tolerance studies in man of a new, orally active, selective? 1-adrenoceptor agonist H 80/62

Johnsson, G.; Jordö, L.; Lundborg, Per; Rönn, O.; Welin-Fogelberg, I; Wikstrand, John

doi:10.1007/bf00609978

Cited by 67 publications

(9 citation statements)

References 13 publications

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“…The two cases reported here illustrate that prenalterol is useful in treating severe cardiac failure due to massive overdosage with J3-adrenergic blocking drugs. Doses far exceeding the usual therapeutic ones may be necessary in these cases but no side effects were observed, a finding in agreement with previous tolerance studies of prenalterol (Johnsson et al, 1978). Reprint requests should be addressed to P. Kulling.…”

Section: Case Reportssupporting

confidence: 85%

?-adrenoceptor Blocker Intoxication: Epidemiological Data. Prenalterol as an Alternative in the Treatment of Cardiac Dysfunction

1983

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1 During the three years 1978-1980 the Swedish Poison Information Centre received reports of 184 patients hospitalized due to ?-adrenoceptor blocker overdosage. Of the 35 patients who developed signs of severe cardiac dysfunction (HR < 50 beats/min, systolic blood pressure < 80 mm Hg), 23 had ingested propranolol, 10 metoprolol and 2 alprenolol. 2 The mean value of the defined daily doses (DDD) per 1000 inhabitants per day in Sweden during these years were 11.97 for propranolol, 8.02 for alprenolol and 7.74 for metoprolol. The incidence of severe poisoning due to alprenolol overdosage is lower than expected according to DDD. 3 During 1979 19 persons died from overdosage with ?-adrenoceptor blockers in Sweden: 15 due to propranolol (non-selective, lacks intrinsic sympathomimetic activity), 2 to metoprolol (cardioselective, lacks intrinsic sympathomimetic activity) and 2 to alprenolol (non-selective, intrinsic sympathomimetic activity). These findings indicate that severe and even fatal poisoning may occur regardless of the type of ?-blocking agent. 4 The usefulness of prenalterol, a cardioselective ?-adrenoceptor partial agonist, in reversing unwanted cardiac effects of ?-adrenoceptor blocking agents is illustrated by two cases of massive propranolol intoxication (maximal plasma concentrations of propranolol 7.2 and 7.8 ?mol/l respectively). Prenalterol in high doses (130 and 280 mg/24 h respectively) restored cardiac function.

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Section: Case Reportssupporting

confidence: 85%

?-adrenoceptor Blocker Intoxication: Epidemiological Data. Prenalterol as an Alternative in the Treatment of Cardiac Dysfunction

1983

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“…Preliminary investigations of their haemodynamic effects, using non-invasive methods in healthy subjects (Johnsson et al, 1979), showed a significant shortening of the pre-ejection period (PEP), left ventricular ejection time (LVET), and electromechanical systole, and a rise in the systolic blood pressure. There were no great changes in heart rate or diastolic blood pressure when the racemic form was given as an intravenous infusion in doses up to 20 ,ug per kg body weight or in oral doses of 2-5 to 20 mg.…”

mentioning

confidence: 99%

Haemodynamic effects of a new beta 1-receptor agonist in acute myocardial infarction. A useful antidote to unwanted cardiac effects of beta-blocking agents.

Ariniego¹,

Waagstein²,

Mombay³

et al. 1979

Heart

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SUMMARYThe haemodynamic effects of a new pl-receptor agonist, 1-(4 hydroxyphenoxy) 3-isopropylamino-2-propanol, were studied in 25 patients after acute myocardial infarction using non-invasive methods. The drug caused an increase in systolic blood pressure and pulse pressure, without change in diastolic blood pressure, and a slight increase in heart rate and reduction in the pre-ejection period. These changes were greater in patients without a history of left heart failure. It is suggested that this cardioselective drug possesses positive inotropic activity but only slight positive chronotropic activity. The substance has been further investigated as a possible antidote to unwanted cardiac side effects of the cardioselective p-blocker, metoprolol. The changes in the cardiovascular dynamics caused by metoprolol in patients with acute myocardial infarction were promptly reversed by this new PA-agonist.With its positive inotropic properties and its efficacy in reversing the effects of a cardioselective p-blocker, the drug is a potentially useful pharmacological agent to support an acutely depressed myocardium in patients on p-blocking agents.Myocardial failure is an important if not a major cause of mortality in acute myocardial infarction, and is related to the size of the infarct (Bolooki et al., 1971) and to the severity of the coronary artery disease (Wackers et al., 1976). Until a definitive form of treatment becomes available, pharmacological support of the failing myocardium is necessary. Beregovich and co-workers (1972) reported that short-term administration of catecholamines improved myocardial contractility after myocardial infarction. The substance racemic 1-(4 hydroxyphenoxy)-3-isopropylamino-2 propanol3 and its laevo form4, new compounds with (l-selective agonist activity, were investigated in animals by Carlsson et al. (1977) and in healthy volunteers by Johnsson et al. (1979) and Knaus et al. (1978). Preliminary investigations of their haemodynamic effects, using non-invasive methods in healthy subjects (Johnsson et al., 1979), showed a significant shortening of the pre-ejection period (PEP), left ventricular ejection time (LVET), and electromechanical systole, and a rise in the systolic blood pressure. There were no great changes in heart rate or diastolic blood pressure when the racemic form was given as an intravenous infusion in doses up to 20 ,ug per kg body weight or in oral doses of 2-5 to 20 mg. These findings indicate a selective inotropic action, making the substance a useful pharmacological agent to support a myocardium whose function has been depressed 'H 80/62, AB Hassle

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“…Such views were based on the data obtained in man or in conscious animals in which reflex autonomic compensation to the heart was fully intact [Carlsson et al, 1977;Knaus et al, 1978;Ek et al, 19821. In the present study, autonomic innervation to the heart was surgically eliminated, and prenalterol produced marked increases in heart rate as well as in contractility. Hence, these observations would support the view that the tachycardia produced by this agent in vivo is attenuated by baroreceptor reflexes triggered in response to increases in arterial pressure induced by a positive inotropic effect [Johnson et al, 1978;Ronn et al, 19791. Following prenalterol administration there was an immediate reduction in the left atrial pressure, and that is also consistent with enhanced myocardial contractility.…”

Section: Discussionmentioning

confidence: 54%

“…The overall hemodynamic profile of prenalterol in animals and man indicates that this agent may be useful in the treatment of heart failure [Ronn et al, 1979;Kenakin and Beek, 19821. Furthermore, unlike other inotropic agents such as dobutamine and dopamine, prenalterol is orally effective and has an average half-life of 2 hr in man [Johnson, et al, 1978;Ronn, et al, 19791. The present studies are designed to test whether the duration of the inotropic effects of prenalterol in anesthetized dogs correlate with the reported longer half-life of this agent.…”

Section: Introductionmentioning

confidence: 99%

Effects of prenalterol, a partial beta adrenoceptor agonist, on the left ventricular function in anesthetized cardiac denervated beagle dogs

Ek¹,

Bjökman²,

Jandhyala

1985

Drug Development Research

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Ek, L., J-A. Bjorkrnan, and B.S. Jandhyala: Effects of prenalterol, a partial beta adrenoceptor agonist, on the left ventricular function in anesthetized cardiac denervated beagle dogs. Drug Dev. Res. 5:371-378, 1985. Cardiovascular effects of prenalterol, a partial beta adrenoceptor agonist, were investigated in pentobarbital anesthetized dogs. In these preparations, in which the heart was acutely denervated, intravenous administration of prenalterol significantly enhanced contractility (left ventricular max dPldt) as well as heart rate, and reduced left atrial pressure. Hence the data confirmed that this agent is an effective inotropic as well as a chronotropic agent. Ventricular function curves were determined in these studies to establish the efficacy of the myocardium in handling volume loads at various filling pressures. In order to relate the increased output directly to increases in inotropy, heart rate was kept constant by electrical pacing. Prenalterol significantly shifted these curves upward and to the left, indicating enhanced contractility. In a separate series, it was demonstrated that the inotropic effect of prenalterol persists for longer durations as indicated by the significant shift that occurred in left ventricular function curves 70 min after administration of a single dose of the drug. The data collectively suggest that prenalterol, an orally effective inotropic agent, possesses prolonged duration of action; hence, this drug may be more preferable than dopamine or dobutamine in the treatment of heart failure since the effects of these two agents are transient and are subjected to tolerance during continuous intravenous infusions.

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Haemodynamic and tolerance studies in man of a new, orally active, selective? 1-adrenoceptor agonist H 80/62

Cited by 67 publications

References 13 publications

?-adrenoceptor Blocker Intoxication: Epidemiological Data. Prenalterol as an Alternative in the Treatment of Cardiac Dysfunction

?-adrenoceptor Blocker Intoxication: Epidemiological Data. Prenalterol as an Alternative in the Treatment of Cardiac Dysfunction

Haemodynamic effects of a new beta 1-receptor agonist in acute myocardial infarction. A useful antidote to unwanted cardiac effects of beta-blocking agents.

Effects of prenalterol, a partial beta adrenoceptor agonist, on the left ventricular function in anesthetized cardiac denervated beagle dogs

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