17-ketosteroids and amafolone

Several class I antiarrhythmic drugs were used in an intraindividual comparative study in 15 patients with chronic stable ventricular extrasystole of various origins. In a randomised sequence lidocaine, ajmalin and, in a cross-over double blind study with placebo, the new antiarrhythmic Org 6001 were tested. Propafenon was given as a final preparation. Each substance was administered parentally in therapeutic doses. A significant placebo effect could be excluded, baseline control values before administration of individual substances correlated well. Comparing mean values obtained over one hour before and after administration of the substance it was shown that the effectiveness of drugs decreased as follows: ajmalin, propafenon, lidocaine, Org 6001. Whereas suppression of extrasystole was most marked after ajmalin, propafenon showed the longest period of activity. After Org 6001 divergent activity of arrhythmia could be observed; in some patients good antiarrhythmic effects could be demonstrated. For evaluation of effectiveness and validity of new antiarrhythmic substances intraindividual comparison with placebo and well established standard antiarrhythmic drugs is advisable.

Topics: 17-Ketosteroids; Adult; Aged; Ajmaline; Androstanols; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Chronic Disease; Double-Blind Method; Female; Humans; Lidocaine; Male; Middle Aged; Placebos; Propiophenones

1 The electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, have been compared with those of lignocaine on the human ventricular action potential in vitro.2 Org 6001 (4 to 16 mg/l) greatly reduced the maximum rate of depolarization (MRD) of the human ventricular action potential but had no effect on resting membrane potential or action potential amplitude.3 The action potential duration at the 50% repolarization level, but not at the 90% repolarization level, was significantly reduced by Org 6001. The absolute refractory period was unchanged.4 Lignocaine, at a concentration (4 mg/l) within the therapeutic range, had no significant effect on any measured parameter, either in muscle exposed to a normal (4.0 mM) or high (5.4 mM) extracellular potassium concentration ([K(+)](o)).5 Higher concentrations of lignocaine (8 to 16 mg/l) did, however, reduce MRD at both [K(+)](o) without changing resting membrane potential or action potential amplitude. The action potential duration was decreased slightly by these higher concentrations of lignocaine whilst the absolute refractory period was lengthened.6 Org 6001 was found to be more potent than lignocaine in reducing MRD but, unlike lignocaine, the absolute refractory period was not prolonged. These compounds, therefore, differed in their electrophysiological effects on human ventricular muscle although both are characterized as being class 1 antidysrhythmic drugs.

Topics: 17-Ketosteroids; Action Potentials; Androstanols; Anti-Arrhythmia Agents; Electric Stimulation; Heart; Humans; In Vitro Techniques; Lidocaine; Potassium

1 The effect of the antidysrhythmic aminosteroid, ORG 6001, on hypothermia-induced ventricular fibrillation was investigated in cats anaesthetized with pentobarbitone. 2 ORG 6001 (total dose, 10 mg/kg, by intravenous injection) reduced both the incidence of fibrillation and the temperature at which it occurred. The number of animals that survived to 16 degrees C was increased. 3 This protective effect of ORG 6001 could not be explained by changes in respiratory acidosis, plasma concentrations of sodium and potassium, or by changes in the action potential of excised hypothermic ventricular muscle. The hypothermia-induced elevation of blood lactate was less in cats treated with the aminosteroid. 4 Over a limited temperature range, ORG 6001 prolonged the P wave and QRS duration and shortened the QTc interval. ST segment elevation was slightly reduced in the drug-treated group. J deflections were observed but were not correlated with the development of fibrillation. 5 The onset of fibrillation was not considered to be due to temperature differences between the myocardium and arterial blood or between localized areas of the left ventricular wall.

Topics: 17-Ketosteroids; Action Potentials; Androstanes; Androstanols; Animals; Blood Pressure; Body Temperature; Carbon Dioxide; Cats; Electrocardiography; Female; Heart; Heart Rate; Hypothermia; Lactates; Male; Oxygen; Partial Pressure; Potassium; Sodium; Ventricular Fibrillation

Topics: 17-Ketosteroids; Androstanols; Anti-Arrhythmia Agents; Chromatography, Thin Layer; Gas Chromatography-Mass Spectrometry; Humans; Kinetics; Spectrometry, Fluorescence

The aminosteroid ORG 6001 (3 alpha-amino-5 alpha-androstan-2 beta-ol-17-one hydrochloride) was shown to be a compound with a rather strong local anaesthetic action. Compound action potentials evoked in non-myelinated nerve fibres of the desheathed rat vagus with the single sucrose gap method showed, in presence of this drug, a decrease in amplitude and increase in conduction time comparable with the effect of lidocaine. Since the total membrane resistance represented by the amplitude of the electrotonic potential was not affected by ORG 6001, it is likely that ORG 6001 reduces the transient increase in sodium conductance during the action potential, a mechanism also postulated for lidocaine. This is confirmed by the decrease of the post-tetanic hyperpolarization in the presence of both ORG 6001 and lidocaine. Since neither sodium pump activity nor the Na/K coupling ratio was affected by ORG 6001, the increase of the potassium-activated response was explained by an increased sodium permeability during rest. The local anaesthetic action of these drugs was even seen with a concentration (20--40 micron) sufficient to produce antiarrhythmic effects in vivo in man if the nerve was stimulated frequently (1--4 c.p.s.).

Topics: 17-Ketosteroids; Action Potentials; Androstanes; Androstanols; Animals; Anti-Arrhythmia Agents; Biological Transport, Active; In Vitro Techniques; Lidocaine; Male; Membrane Potentials; Nerve Fibers; Potassium; Rats; Sodium

ST-segment elevation following temporary coronary artery occlusion was measured from nine epicardial leads in open-chest anaesthetized dogs. This was greatly reduced by the prior administration of the anti-dysrhythmic aminosteroid, ORG 6001. It is suggested that this effect is related either to a reduction in the extent and degree of myocardial ischaemia or to prevention of K+ egress from ischaemic cells.

Topics: 17-Ketosteroids; Androstanes; Androstanols; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Female; Hemodynamics; Male

1 The compound Org 6001 (3alpha-amino-2beta-hydroxy-5alpha-androstan-17-one hydrochloride) was found in recent experiments to exhibit anti-arrhythmic activity. Evidence is presented in this paper concerning its mode of action. 2 Org 6001 was 1.8 times more potent than procaine as a local anaesthetic on desheathed frog nerve. 3 Org 6001 had no effect on the resting potential of isolated cardiac muscle of rabbit, but greatly reduced the maximum rate of depolarization tion (MRD). The action potential duration TAPD) WAS MARGINALLY PROLONGED IN ATRIAL AND VENTRICULAR MUSCLE. 4 Org 6001 preferentially shortened APD in that part of the Purkinje system in which APD is normally longer than elsewhere, so that APD

Topics: 17-Ketosteroids; Action Potentials; Adrenergic beta-Antagonists; Androstanes; Androstanols; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Calcium; Female; Heart Atria; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Male; Membrane Potentials; Myocardial Contraction; Neural Conduction; Potassium; Rabbits; Sciatic Nerve

Org 6001 (3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride) is an orally non-hormonal aminosteroid possessing antiarrhythmic activity. In 13 dogs the efficacy of the drug against ouabain-induced ventricular tachycardia (VT) was studied. VT was produced by a mean dose of 67.5 +/- 18.7 mug/kg ouabain, administered by continuous infusion of 25 mug/min. 20 min after the onset of VT an 0.125 mg/kg/min infusion of Org 6001 was initiated, doubling the dose every 10 min. In all dogs VT was reverted into normal sinus rhythm (NSR) by a dose of 9.72 +/- 7.07 mg/kg (0.87-20.75 mg/kg) Org 6001. The duration of VT ranged from 27-61 min (mean 47.1 +/- 11.4 min), including the 20 min waiting period. NSR persisted in 8 dogs until the experiment was terminated (90 min after onset of VT), while in 5 dogs VT returned after 3-23 min sufficient to revert VT into NSR. A bolus injection of Org 6001 (10 mg/kg) gave an immediate return to NSR in 3 dogs, in which VT was provoked again by administration of a second dose of ouabain after the 90 min period had elapsed. Though the interaction of ouabain makes a quantitative analysis of the negative inotropic effects difficult, it appeared that there uas no major hemodynamic deterioration during and after treatment with Org 6001. During digitalization there was a significant increase in the first derivative of left ventricular systolic pressure (peak LVdP/dt) from 2340 +/- 600 to 3650 +/- 1070 mm Hg/sec and in peripheral resistance, while heart rate decreased. During VT, left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dropped by approximately 20 mm Hg, while heart rate increased significantly. After treatment with Org 6001, LVSP and MAP further decreased to 128 +/- 30 mm Hg (p less than 0.05) areased to 128 +/- 30 mm Hg (p less than 0.05) and 112 +/- 20 mm Hg respectively. Peak LVdP/dt fell from 3650 +/- 1390 to 2780 +/- 970 mm Hg/sec (p less than 0.05). Heart rate had dropped to 126 +/- 22 beats/min (p less than 0.05). During the first 30 min after Org 6001 infusion was stopped none of the parameters showed significant changes, although peak LVdP/dt rose slightly. It is shown in the present investigation that Org 6001 has effective antiarrhythmic properties in controlling ouabain-induced VT with acceptable cardiodepressant actions.

Topics: 17-Ketosteroids; Androstanes; Androstanols; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Output; Depression, Chemical; Dogs; Electrocardiography; Heart Rate; Heart Ventricles; Hemodynamics; Ouabain; Tachycardia; Time Factors

Topics: 17-Ketosteroids; Aconitine; Androstanes; Androstanols; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Dogs; Heart Rate; Hydroxysteroids; Lidocaine; Ligation; Male; Myocardial Contraction; Ouabain; Rats