Antiarrhythmic activity of 17.beta.-aminoestratrienes. Comparison of 3-ols and 3-acetates with the corresponding 3-(3-amino-2-hydroxypropyl) ethers

Campbell, John K.; Logan, Robert T.; Marshall, Richard; McGarry, George; Sleigh, Thomas; Winslow, E.

doi:10.1021/jm00152a013

Cited by 11 publications

(3 citation statements)

References 4 publications

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“…In preliminary studies, intraperitoneally administered Org 7797 was found 3 protect pentobarbital-anesthetized mice against arrhythmias induced by intravenous infusion of aconitine (1.27 p g h i n ) (5). These arrhythmias arise from prolongation of the open state of sodium ion channels culminating in high frequency focal automaticity, and are selectively sensitive to sodium channel blocking agents (1,38,49).…”

Section: Aconitine-induced Ventricular Arrhythmiasmentioning

confidence: 99%

Org 7797: A New and Unusual Antiarrhythmic Agent

Planellas¹,

Winslow²,

Yih³

et al. 1992

Cardiovascular Drug Reviews

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Key Words: Antifibrillatory drugs--Cardiac c y c l e a r g 7797.Pharmacological studies have shown that Org 7797 is a potent antifibrillatory agent with additional class Ic antiarrhythmic properties. Its antifibrillatory effects are manifested at the ventricular and supraventricular levels and can be explained by prolongation of wavelength at short cycle lengths leading to the prevention of deterioration of reentrant ventricular tachycardia (VT) to ventricular fibrillation (VF). This appears to result from drug-induced lengthening of refractoriness outweighing slowing of conduction which may, in turn, be a consequence of frequency-dependent prolongation of action potential duration. Org 7797 thus possesses an unusual and interesting electrophysiological profile. Higher doses of the drug are required to prevent or suppress arrhythmias of automatic origin in the dog. The dose required to suppress late ischemia-induced tachycardia, an arrhythmia dependent on sodium channel block for its termination, is four times higher than the dose required to prevent early ischemia-induced VF. Moreover, therapeutic plasma levels of the dose required for suppression of late VT are similar to concentrations required to reduce the maximum rate of depolarization of cardiac cells in vitro. By contrast, in rats plasma levels associated with antifibrillatory activity are much lower, suggesting that the mechanisms underlying the antifibrillatory and antiarrhythmic actions of Org 7797 may be different.In animals with normal hearts and in those with either established or developing infarcts, the hemodynamic effects of intravenous Org 7797 are minimal at antifibrillatory doses. The major effects of Org 7797 in normal animals are a very minor bradycardia (~4 % ) and a modest increase in peripheral vascular resistance, the latter of which was not seen in animals with myocardial infarction. Cardiac contractility and coronary blood flow ~~ ~_ _ _ _ _ _ _ _

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Section: Aconitine-induced Ventricular Arrhythmiasmentioning

confidence: 99%

Org 7797: A New and Unusual Antiarrhythmic Agent

Planellas¹,

Winslow²,

Yih³

et al. 1992

Cardiovascular Drug Reviews

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“…This compound has been shown to be effective against aconitineinduced and ischaemia-induced arrhythmias in rodents and to inhibit the fast inward sodium current in guinea-pig atria (Campbell et al, 1986). Org 7797 has been further subclassified as a Ic agent on the basis of the kinetics of onset of rate-dependent sodium channel block in porcine isolated cardiac tissue (Winslow et al, 1989a) and on its electrophysiological actions in vivo (Campbell et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Effects of Org 7797 on early, late and inducible arrythmias following coronary artery occlusion in rats and dogs

Winslow¹,

Campbell²,

Barron³

et al. 1991

British J Pharmacology

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1 The class Ic steroidal antiarrhythmic agent, Org 7797, was compared with two other Ic agents, flecainide and propafenone for intravenous activity against ischaemia-related cardiac arrhythmias and for electrophysiological actions in vivo. In addition the haemodynamic effects of Org 7797 were assessed in greyhounds. 2 Org 7797 (0.5mgkg-1) significantly reduced the expected incidence of early ischaemia-induced ventricular fibrillation (VF) in rats and greyhound dogs and at doses of 0.5-1.0mgkg-1 antagonized reperfusion-induced arrhythmias. Comparative studies in rats showed Org 7797 to be 2-4 times more potent than flecainide or propafenone. 3 Org 7797 (0.5mg kg-1) slowed intracardiac conduction in anaesthetized beagles and again was at least 2-4 times more potent than flecainide or propafenone.4 Org 7797 (0.5 and 2.0mgkg-'), flecainide (1.0 and 2.0mgkg 1) or propafenone (0.5 and 2.0mgkg 1), did not significantly prevent induction of tachyarrhythmias (VT) in dogs with 5-6 day old myocardial infarcts although all 3 drugs appeared to prevent induced VF. All 3 drugs (notably fecainide) did however reduce the VT rate.5 All 3 drugs (1-2 mg kg 1) suppressed spontaneous tachyarrhythmias in conscious beagle dogs with 1-2 day old infarcts. Propafenone was the least effective.6 In an antifibrillatory dose (0.5mgkg-'), the major haemodynamic effect of Org 7797 was a 10% increase in peripheral vascular resistance. Stroke volume, cardiac output and coronary blood flow were unchanged. In therapeutic doses, Org 7797 was also less negatively chronotropic than flecainide. 7 It was concluded that Org 7797 is a potent antifibrillatory agent which is haemodynamically well tolerated. Higher doses are required to suppress late ischaemia-induced tachyarrhythmias which suggest that its antifibrillatory effects are the consequence of an action other than, or in addition to, sodium channel block.

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“…В качестве критерия при классификации использованы значения ED 50 , определённые по хлороформной модели на самцах белых мышей. Соединения, имеющие ED 50 £0,15 ммоль/кг, отнесли к высокоактивным, а ED 50 >0,20 ммоль/кг -к низкоактивным [10][11][12][13][14][15][16][17][18]. Основанием для выбора данных значений ED 50 в качестве граничных критериев между классами высоко-и средне-и низкоактивных соединений служит тот факт, что вошедший в экзаменационную выборку хинидин, общепринято считать антиаритмическим препаратом cредней силы, значение ED 50 для него составляет 0,22±0,04 ммоль/кг [19].…”

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Study "structure-anti-arrhythmic activity" relationship of n-phenil acetamide derivatives and amides of aromatic carbonic acids

AIa

et al. 2010

BIOMED KHIM

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С использованием компьютерной системы SARD-21 (Structure Activity Relationship & Design) выявлены структурные признаки, характерные для высоко-и низкоактивных антиаритмических средств, оценена степень их влияния на эффективность антиаритмического действия. На основании полученных данных сформирована математическая модель прогноза эффективности антиаритмического действия лекарственных средств с уровнем распознавания 82% по двум методам. Выявленные структурные закономерности могут быть использованы для конструирования новых высокоактивных антиаритмических лекарственных средств, а также для модификации известных антиаритмических препаратов с целью увеличения эффективности их антиаритмического действия.Ключевые слова: структура-свойство, антиаритмическая активность, теория распознавания образов.

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Antiarrhythmic activity of 17.beta.-aminoestratrienes. Comparison of 3-ols and 3-acetates with the corresponding 3-(3-amino-2-hydroxypropyl) ethers

Cited by 11 publications

References 4 publications

Org 7797: A New and Unusual Antiarrhythmic Agent

Org 7797: A New and Unusual Antiarrhythmic Agent

Effects of Org 7797 on early, late and inducible arrythmias following coronary artery occlusion in rats and dogs

Study "structure-anti-arrhythmic activity" relationship of n-phenil acetamide derivatives and amides of aromatic carbonic acids

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