[The role of vagal control in the action of propranolol on the chronotropic cardiac function].

The effects of propranolol on the heart rate variability was studied in anesthetized outbred male rats, to which the drug was administered as intracisternal and intraperitoneal injections. Propranolol was found to increase the power of low- and high-frequency components of the heart rate. In influencing the heart rate variability, propranolol has the central mode of action. It is suggested that the ability of propranolol to increase the power of the low and high frequency components of the heart rate is related to its enhancing effect on the central cardiac vagal control.

[Comparative study of the electrophysiological properties of class iii medicinals (cardiocyclide, nibentan, sotalol) and evaluation of their efficacy in atrial fibrillation produced by auricular and vagal stimulation].

The electrophysiological properties of cardiocyclide, nibentan and sotalol and their efficacy on a model of atrial fibrillation were compared in experiments in anaesthetized dogs. The electrophysiological parameters of drugs were investigated using the method of programmed electrical stimulation of myocardium on the background of excitation of the peripheral segment of the right vagus nerve with current pulses of increasing frequency. The atrial fibrillation was produced by short stimulation (10 pulses) of the right auriculum (10 Hz, 4 thresholds). Cardiocyclide was injected in a dose of 2.5-5.0 mg/kg; nibentan, 0.25 mg/kg; and sotalol, 2.5 mg/kg. Cardiocyclide was found to prevent vagotonic atrial fibrillation in 80% of cases; under vagal stimulation this drug maintained the electrophysiological attributes and exhibited the frequency-independent action inherent in this agent. Nibentan completely retained its ability to prolong the ventricular repolarization under vagal stimulation conditions, increased the effective atrial and ventricular refractory periods, and showed the ability to prevent and eliminate the vagotonic atrial fibrillation in 80-90% of cases. Under vagal stimulation, sotalol increased the repolarization and prolonged the effective refractory atrial and ventricular periods, reduced the heart rate, and suppressed the sinus node function. The action of sotalol was frequency-dependent. Sotalol was found to prevent the vagotonic atrial fibrillation in 60% of cases.

[Effect of the class III antiarrhythmic drug nibentan in vagotonic atrial fibrillation].

Nibentan, the class III antiarrhythmic drug, was experimentally investigated in anaesthetized dogs using the model of vagotonic atrial fibrillation. Under the conditions of vagus nerve stimulation, nibentan retained the ability to prolong the ventricular repolarization and increase the effective refractory periods and to maintain the frequency-independent action on the effective refractory periods of the atrium. At the same time, nibentan did not affect conduction via the His-Purkinje system and prevented bradycardia induced by vagus stimulation. The drug was found to depress the conduction in atrium, this effect being retained on the background of vagus nerve stimulation. Nibentan has proved to be effective in preventing the vagotonic atrial fibrillation.

[Comparative study of electrophysiological mechanisms of anti-arrhythmia III class agents, cardiocyclide, nibentan, and sotalol during experimental myocardial infarction and sympathetic stimulation]. / Sravnitel'noe izuchenie élektrofiziologicheskikh mekhanizmov antiaritmicheskikh preparatov III klassa kardiotsiklida, nibentana i sotalona na fone éksperimental'nogo infarkta miokarda i simpaticheskoi stimuliatsii.

Electrophysiological mechanisms of the action of cardiocyclide, nibentan, and sotalol--antiarrhythmic agents of class III--was studied in dogs with experimental myocardial infarction induced by a two-step occlusion of the coronary artery. Cardiocyclide exhibited the properties typical of the class III antiarrhythmics by prolonging the ventricular repolarization and increasing the effective refractory periods in the atrium and ventricles. The degree of manifestation of these antiarrhythmic effects of cardiocyclide is independent of the induced heart rate, which is related to the ability of this drug to block the slow activation component (IKs) of the delayed rectified potassium current. Nibentan elongates the QT interval and increases the effective atrial and ventricular refractory periods, but the effect was dependent of the stimulation frequency. Sotalol, which also exhibited the properties of a class III antiarrhythmogen possessing beta-blocking activity, produced more pronounced inhibiting action upon the sinus node function and conduction (in comparison with the analogous effects of cardiocyclide). This is probably related to the ability of sotalol to block the cardiac adrenoreceptors. The effect of sotalol is also frequency-dependent, which is related to the blocking of rapid activating component (IKr) of) of the delayed rectified potassium current. On the background of isoproterenol infusion, cardiocyclide completely retained the electrophysiological and antiarrhythmic effects. The efficacy of nibentan and sotalol with respect to the repolarization and refractoriness significantly decrease under the conditions of sympathetic nervous system activation. The ability of sotalol to suppress the sinus node function and conduction on the background of isoproterenol infusion is retained.

[Electrophysiological effects of ethacizine in experimental myocardial infarction and stimulation of sympathetic heart innervation]. / Elektrofiziologicheskie éffekty étatsizina pri éksperimental'nom infarkte miokarda i stimuliatsii simpaticheskoi innervatsii serdtsa.

The electrophysiological effect of ethacizine, an antiarrhythmic agent of class IC, was studied in dogs with experimental myocardial infarction under the beta-adrenergic stimulation conditions. It was found that ethacizine (i) slows down the atrioventricular conduction and the AV-node conduction; (ii) increases the time of the sinus node function recovery; and (iii) increases the effective atrioventricular refractory periods. Under the conditions of isoproterenol-induced stimulation of the beta-adrenergic structures, some of the ethacizine effects (e.g., increased refractoriness) completely disappeared and the other (slowed down conduction) decreased. As the stimulation frequency was increased, the effect of ethacizine upon the conduction exhibited a decrease. Upon the isoproterenol injection, dependence of the QRS complex on the forced rhythm frequency disappeared.

[Effect of the novel III class anti-arrhythmia preparation (AL-275) in experimental myocardium and sympathetic stimulation]. / Deistvie novogo antiaritmicheskogo preparata III klassa (AL-275) pri éksperimental'nom infarkte miokarda i simpaticheskoi stimuliatsii.

AL-275, a new antiarrhythmic agent, exhibits the properties typical of the class III antiarrhythmogen: (i) prolongs the ventricular repolarization; (ii) inhibits the sinus node automatism; (iii) increases the effective refractory periods in atrium and ventricles; and (iv) does not modify AV and intraventricular conduction. AL-275 produces a pronounced antiarrhythmic and antifibrillatory action. The effect of AL-275 is independent of the heart rate, which is an advantage over the other class III agents. Both character and intensity of the electrophysiological and antiarrhythmic activity of AL-275 were fully retained upon the preliminary infusion of isoproterenol. Independence of the drug action of both the heart rate and the isoproterenol-induced changes in refractoriness are related to the ability of AL-275 to block a slow component (IKs) of the potassium current.

New aminocarboxamides with class III anti-arrhythmic activity.

In the search for new anti-arrhythmic substances we discovered the class III activity of aminocarboxamides. These compounds show a prolongation of the effective refractory period. With some of them the prolongation is more pronounced after faster than after slower stimulation of the guinea pig papillary muscle. They should therefore be of interest in the treatment of cardiac arrhythmias after myocardial infarction and atrial fibrillation. The chemical synthesis, the structure-activity relationships of the new derivatives, their efficacy on the action potential duration (APD) and the effective refractory period (ERP) in vitro of isolated guinea pig papillary muscles are described and discussed in this paper. Since AWD 160-275 (13) and AWD 23-111 (14) exerted a pronounced APD90 and ERP prolongation at faster stimulation, they were selected for further electrophysiological characterization in vitro and in vivo. Anti-arrhythmic and pro-arrhythmic effects were determined in several animal models in comparison with dofetilide, sematilide, and sotalol. 13 was found to be effective in preventing programmed electrical stimulation-induced arrhythmias in anaesthetized dogs and may therefore contribute to the therapy of dysrhythmias after myocardial infarction. The pro-arrhythmic effect of 14, investigated in a model of triggered activity in chloralose-anaesthetized rabbits under methoxamine infusion, is low in comparison with other class III anti-arrhythmics.

[The pharmacology of the new combined anti-arrhythmia preparation metatsizin]. / K farmakologii novogo kombinirovannogo antiaritmicheskogo preparata metatsizina.

The combined antiarrhythmic effect of ethmosin and ethacisin in various dose ratios was studied in conscious dogs with two-stage ligation of the coronary artery (after Harris). A 6:1 ratio was found to be optimal for manifestation of the antiarrhythmic effect. In such a ratio of the doses the antiarrhythmic effect of a combination of ethmosin and ethacisin is essentially higher than the activity of each component. On the grounds of these data a combined antiarrhythmic drug methacisin was developed. It possesses a broad spectrum of antiarrhythmic activity. The drug is effective on models of arrhythmias specific of class I, III, and IV antiarrhythmics. Metacisin does not change hemodynamics and activity of the heart. Study of metacisin pharmacokinetics showed that it possesses bioavailability twice that of ethmosin tablets taken separately and four times that of ethasicin.

[A new class-III antiarrhythmic preparation among the dicyclohexylamides of aminocarboxylic acids]. / Novyi antiaritmicheskii preparat III klassa sredi ditsiklogeksilamidov aminokarbonovykh kislot.

The Institute of Pharmacology, Academy of Medical Sciences, jointly with AWD (Germany) has synthesized and tested a novel class III antiarrhythmic coded AWD-160-275, a derivative of dicyclohexylamides of aminocarboxylic acids. The compound was shown to prolong cardiac repolarization, to increase atrial and ventricular refractory periods, to decrease sinus nodal automatism, and to unchange intraventricular conduction. The compound proved to be superior to the reference drugs in the rate and duration of antiarrhythmic and antifibrillatory action. In therapeutical doses it has no antiarrhythmic effect. The specific feature of the agent is that there is no relation of longer effective refractory periods to the frequency of stimulation. This property may be useful in treating tachyarrhythmias.

[Sotahexal pharmacodynamics in patients with ischemic heart disease]. / Farmakodinamika sotageksala u bol'nykh ishemicheskoi bolezn'iu serdtsa.

Therapeutic and prophylactic antiarrhythmic efficacy of sotalol hydrochloride (Sotahexal, "Hexal", Germany) and its effects in intracardiac hemodynamics and ECG parameters were evaluated in 95 patients with ischemic heart disease (IHD). The highest response to the drug was observed in ventricular extrasystoles, arterial flutter and fibrillation. Acute episodes of arrhythmia are managed by bolus administration of Sotahexal [correction of Hexal]. In this case greater risk of side effects exists. It is desirable to decide on the drug dose, mode of administration on the individual basis with due consideration of the risks and dangers which could be avoided in case of adequate instrumental control.

[The relationship between the chemical structure and anti-arrhythmia action of a number of omega-aminoacyl-3-carbalcoxyaminodibenzazepines]. / Izuchenie zavisimosti mezhdu khimicheskim stroeniem i antiaritmicheskim deistviem v riadu omega-aminoatsil-3-karbalkoksiaminodibenzazepinov.

The antiarrhythmic activity of 20 derivatives of dibenzazepine (the effects on the maximal effective rabbit heart auricle contraction rate, aconitine-induced arrhythmia in rats under or without anesthesia) was studied. It was shown that the most active compounds are those with carbethoxyamine group in position 3 in combination with dimethylamino- or diethylamino-acetyl groups in position 5 of dibenzazepine ring. 5-dimethyl-aminoacetyl-10,11-dihydro-5H-dibenz b, f azepine (GS-015, bonnecor) was selected for the further detailed investigation.

[The effect of bonnecor on cardiac hemodynamics, blood supply and function in experimental myocardial ischemia]. / Vliianie bonnekora na gemodinamiku, krovoobrashchenie i funktsiiu serdtsa pri éksperimental'noi ishemii miokarda.

The effect of a new antiarrhythmic drug bonnecor on the hemodynamics, blood supply and function of the ischemic heart as compared with the famous antiarrhythmic drugs lidocaine and ethacizine was studied in the experiments on anesthetized animals (rats, dogs) under artificial respiration. It was shown that bonnecor administered in a dose of 0.5 mg/kg was able of relieving disturbances of the cardiac hemodynamics and function produced by occlusion of the coronary artery. The drug exerted no significant effect on the blood supply to the focus of acute and chronic myocardial ischemia.

[Bonnecor--a new anti-arrhythmia preparation]. / Bonnekor--novyi antiaritmicheskii preparat.

The antiarrhythmic properties of a new drug bonnecor being a derivative of dibenzazepine were studied on different models of arrhythmias. Bonnecor proved to be effective in the treatment of both atrial and ventricular arrhythmias of various genesis except rhythm disorders induced by ouabain intoxication. The drug was shown to exert a pronounced antifibrillatory effect and to increase the electrical stability of the intact and ischemic myocardium.

[The relationship between the physicochemical and pharmacokinetic parameters and the anti-arrhythmia activity of bonnecor and its metabolites]. / Vzaimosviaz' mezhdu nekotorymi fiziko-khimicheskimi, farmakokineticheskimi parametrami i antiaritmicheskoi aktivnost'iu bonnekora i ego metabolitov.

The antioxidant properties of a new antiarrhythmic drug bonnecor and its main metabolites were determined by using chemoluminescence. A significant correlation was revealed between the physicochemical properties, antiarrhythmic activity, pharmacokinetic parameters of bonnecor and its metabolites.

[A first trial in the clinical study of bonnecor]. / Pervyi opyt klinicheskogo izucheniia bonnekora.

The brief data on the results of the clinical trials of a new antiarrhythmic drug bonnecor at intravenous administration performed in six clinical institutions of the country are presented. A high effectiveness and a good tolerance of the drug in VT, VE, ST, SE and WPW syndrome were revealed.

[A comparative study of the pharmacokinetics and pharmacodynamics of bonnecor]. / Sravnitel'noe izuchenie farmakokinetiki i farmakodinamiki bonnekora.

The pharmacokinetics and pharmacodynamics of bonnecor were studied simultaneously in animals with experimental arrhythmia. It was shown that irrespective of the animal species and individual features of the drug elimination kinetics the level of bonnecor concentration correlated with the antiarrhythmic effect. The data on the excretion of bonnecor and its metabolites in the urine in the dog and man were obtained. The decrease of bioavailability at oral administration of bonnecor was demonstrated to be related to its intensive conversion in metabolite M-I.

[Quantitative assessment of the blood supply to the focus of myocardial ischemia in dogs in pharmacological research]. / Kolichestvennaia otsenka krovosnabzheniia ochaga ishemii miokarda u sobak v farmakologicheskikh issledovaniiakh.

The method of quantitative evaluation of blood supply of ischemic myocardial focus was suggested, it consists in measuring the venous blood outflow from the ischemic area with the help of ultrasonic technique. In experiments on anaesthetized dogs with coronary artery occlusion the rate of blood flow and dynamics of its changes in the ischemic focus were determined. It was shown that sodium oxybutyrate improves the blood supply of myocardial ischemic area.

[Anti-arrhythmia and antifibrillatory properties of dibenzazepine derivatives]. / Antiaritmicheskie i antifibrilliatornye svoistva proizvodnykh dibenzazepina.

Antiarrhythmic and antifibrillation properties of bonnecor, a derivative of dibenzepin, were studied in comparison with ethmozine, quinidine and novocainamide, using various experimental arrhythmia models. Bonnecor activity was somewhat smaller than that of ethmozine, and much greater than that of quinidine and novocainamide in the mixed atrioventricular arrhythmia model simulated in aconitin-treated rats and the ventricular arrhythmia model simulated by two-degree coronary occlusion in dogs. Intravenous 1 mg/kg and oral 6 mg/kg bonnecor doses prevented ventricular fibrillation caused by acute coronary occlusion in rats, while ethmozine showed no such effect.

[Pharmacology of ethacizin]. / K farmakologii etatsizina.

Study of the relationship between the chemical structure and pharmacological action in the series of dialkylaminoacyl derivatives of phenothiazines made it possible to discover etacyzine (a diethylamine analog of etmozine). Comparison of the pharmacological action of etacyzine with that of etmozine demonstrated that the replacement of the morpholine radical of the side chain of the phenothiazine ring by the diethylamine one leads to the potentiation and increase of the duration of the antiarrhythmic effect, emergence of anti-fibrillary activity, antiischemic properties and to the ability to restrict the size of experimental myocardial infarction.

[Ethacizin: pharmacologic properties and prospects for clinical application]. / Etatsizin: farmakologicheskie svoistva i perspektivy klinicheskogo primeneniia.

The study of the regularities between the chemical structure and pharmacologic action of phenathiazine dialkylaminoacyl derivatives led to the identification and investigation of a new drug called ethacizine-phenothiazin-2-carbethoxyamino-10 (beta-diethylamino-propionyl) hydrochloride. Ethacizine exceeds its structural analogue ethmozin by two times in terms of intensity and by 4-5 times in terms of the duration of antiarrhythmic effect. Ethacizine has marked antianginal properties. It shows a prolonged inhibitory effect on the average elevation of the ST interval at multiple leads of the epicardial electrogram during coronary occlusion, increases the threshold of myocardial ischemia development, and reduces the size of experimental infarction. The combination of potent antiarrhythmic activity, already confirmed by clinical observations, with antianginal properties and a capacity to limit the size of infarction makes in possible to consider ethacizine a promising means for treating coronary heart disease.