A patch clamp study of the action of ethacyzine on the rapid inward sodium current in single rat heart muscle cells.

The effect of ethacyzine (a diethylamine analogue of ethmozine) on the rapid inward sodium current (INa) was studied in single rat ventricular muscle cells by a patch clamp technique. Extracellular application of 3 microM ethacyzine depressed the INa in a use-dependent fashion. Rest recovery from the use-dependent block by ethacyzine followed an exponential time course with a time constant of about 215 +/- 40 s (n = 4, mean +/- S.E.).

[Possibilities of correcting adverse effects of anti-arrhythmia agents]. / Vozmozhnosti korrektsiii neblagopriiatnykh éffektov antiaritmicheskikh preparatov.

A hundred and twenty two patients with premature ventricular contractions and paroxysmal tachycardias were comprehensively studied prior to and following treatment regimen with ethacizin, befol, sodium succinate and their combinations. Besides its significant antiarrhythmic activity, ethacizin displayed a number of adverse cardiac effects, such as excessive negative inotropic and dromotropic ones. Befol and sodium succinate in combination with ethacizin can reduce or even eliminate these side effects in rest and during simulated mental stress and graded exercise. The antiarrhythmic effect of the combined therapy preserved or even became stronger. This therapy may be long performed for arrhythmias even in patients with circulatory insufficiency and cardiac conduction disturbances caused or redoubled by ethacizin.

[Correlation between the anti-arrhythmia effect of ethacizin and pharmacokinetic parameters in a model of rhythm adoption by the heart]. / Korreliatsiia mezhdu antiaritmicheskim deistviem etatsizina i farmakokineticheskimi parametrami na modeli usvoeniia ritma serdtsa.

Pharmacokinetics and pharmacodynamics of ethacizin were studied in a model of rhythm adoption by the heart, with the drug administered intravenously to anesthetized cats. A relation was demonstrated between blood ethacizin pattern and the drug's biphasic effect on the adoption of stimulation-imposed pace by the heart and ventricular fibrillation threshold. The estimated correlation coefficients, reflecting the relationship between the development of ethacizin anti-arrhythmic and antifibrillation effects and variation of its plasma levels between 10 and 120 min after the administration, were rather high (-0.85 and +0.93, respectively). Ethacizin shows anti-arrhythmic and antifibrillation activity when its plasma levels are between 2400 and 200 ng/ml.

[Effectiveness of ethacizin in ventricular arrhythmias refractory to prior anti-arrhythmia drug therapy]. / Effektivnost' étatsizina pri zheludochkovykh aritmiiakh, refrakternykh k predshestvuiushchei antiaritmicheskoi medikamentoznoi terapii.

Using Holter ECG monitoring, the efficiency of the new drug ethacizin was assessed on an individual basis in 48 patients with ventricular arrhythmias refractory to past treatments (group 1) and in 46 patients who responded to at least one of the available antiarrhythmic drugs (group 2). Ethacizin proved effective in 63% of first-group patients and in all second-group patients, with an overall response rate of 81%. The efficiency of ethacizin, ethmozin, and disopyramide was 100, 73 and 69%, respectively, in the same patients. It is suggested that separate assessments of new antiarrhythmic drugs are preferable in patients with treatment-resistant ventricular arrhythmias and those responding to at least one of the drugs available.

[Comparison of the results of ethacizin pharmacodynamics and pharmacokinetics in a single intravenous administration]. / Sopostavlenie rezul'tatov farmakodinamiki i farmakokinetiki étatsizina pri razovom vnutrivennom vvedenii.

A single intravenous injection of 30-50 mg ethacizin produces a favourable antiarrhythmic effect in 80-85% of patients with ventricular disorders of cardiac rhythm. The drug's action already begins "on the needle", reaches its peak within 3-5 minutes and lasts for 1-2 hours. A two-compartment model adequately represents ethacizin pharmacokinetics. The average ethacizin half-distribution and half-elimination periods are 4.7 and 154.4 minutes, respectively, and its clearance rate is 0.99 1/min. Therapeutic plasma concentration of the drug varies between 30-50 and 300-400 ng/ml.

[Atherogenic properties of phenothiazine drugs manifesting in cultured cells of the human aortic intima]. / Aterogennye svoistva fenotiazinovykh preparatov, proiavliaemye v kul'ture kletok intimy aorty cheloveka.

The effects of phenothiazine drugs on the levels of cholesterol in smooth cells of the human aortic intima. Two antiarrhythmics (ethacizin and ethmozine) and two neuroleptics (trifluoperazine and chlorpromazine) were evaluated. The three agents ethacizin, trifluoperazine, and chlorpromazine given in concentrations of 10(-7) to 10(-5) M were ascertained to cause intracellular cholesterol accumulation, whereas ethmozine produced no effects on the intracellular levels of cholesterol. Ethacizin failed to cause cholesterol accumulation when the cells were incubated with ethacizin in the culture medium supplemented with lipid-deficient serum. Ethacizin in a concentration o 10(-5) M was shown to inhibit the synthesis of cholesterol esters and had no action on the intracellular synthesis of steroids.

[Mechanism of action and the effectiveness of ethacizin in patients with paroxysmal atrioventricular nodal reciprocal tachycardia]. / Mekhanizm deistviia i effektivnost' etatsizina u bol'nykh s paroksizmal'noi atrioventrikuliarnoi uzlovoi retsiproknoi takhikardiei.

An electrophysiologic study of ethacizin's mechanisms of action was carried out in patients with paroxysmal atrioventricular nodal tachycardia. Tachycardia was controlled by 0.5 mg/kg ethacizin in all patients. No patients demonstrated induced tachycardia in the presence of the drug, and 55% developed a complete retrograde atrioventricular block. The assessment of the preventive effect of oral ethacizin administration showed that paroxysms of tachycardia could not be provoked by esophageal electrostimulation of the heart in 87% of the patients. In the same patients, stable antiarrhythmic effect was maintained by long-term treatment with this drug. The suppression of retrograde stimulus conduction along the quick path of the atrioventricular node is assumed to be the principal electrophysiological mechanism of ethacizin action. Ethacizin can be used to control or prevent paroxysms of atrioventricular nodal tachycardia.

[Initial results of clinical research on a tabletted form of ethacizin (the diethylamino analog of ethmozine) in ventricular arrhythmias]. / Pervye rezul'taty klinicheskogo izucheniia tabletirovannoi formy étatsizina (diétilaminovogo analoga étmozina) pri zheludochkovykh narusheniiakh ritma serdtsa.

The clinical effectiveness, pharmacodynamics and some pharmacokinetic aspects of a new antiarrhythmic drug ethacyzin (a diethylamine analogue of ethmozin) were studied, using diurnal electrocardiographic monitoring and exercise testing, in 50 patients with frequent and chronic ventricular heart rhythm disorders. The drug had positive antiarrhythmic effect in 87-90% of patients treated with single 100-150 mg oral doses and courses of 150-300 mg daily (the mean dose being 200 +/- 50 mg). With a single oral dose of 100 mg ethacyzin, the onset, peak and overall duration of its therapeutic effect were noted at 0.5-1, 1.5-2 and 6-8 hours, respectively. The minimal therapeutic plasma ethacyzine concentration was 40-70 ng/ml. Both in acute testing and during treatment courses, the drug significantly expanded the P wave, the P-Q interval and the QRS complex of the electrocardiogram, without affecting heart rate or Q-T duration, the magnitude of the resulting change in the said parameters depending on the dose administered and the antiarrhythmic effect of ethacyzin.

[Comparative analysis of antiarrhythmic action and electrophysiological effects of a new benzodiazepine derivative gidazepam and ethacizin in arrhythmias of various genesis]. / Sravnitel'nyi analiz antiaritmicheskogo deistviia i élektrofiziologicheskikh éffektov novogo proizvodnogo benzodiazepina gidazepama i étatsizina pri aritmiiakh serdtsa razlichnogo geneza.

The antiarrhythmic and electrophysiological effects of the new benzodiazepine tranquilizer gidazepam versus ethacizin were examined in patients with cardiac arrhythmias. The antiarrhythmic effect of the agent was found during 24-day monitoring and simulated psychoemotional stress in 81% of patients with neurocirculatory dystonia and in 61% of patients with coronary heart disease. The antiarrhythmic effects developed with gidazepam-induced changes in electrophysiological properties of the cardiac conduction system. The preventive antiarrhythmic effect of gidazepam was demonstrated to be higher than that of ethacizin during stress in patients with arrhythmias of extra-ischemic genesis.

[Clinical effectiveness of cordarone in combination with other anti-arrhythmia agents in refractory atrial fibrillation and adverse effects of the drugs]. / Klinicheskaia éffektivnost' kordarona v sochetanii s drugimi antiaritmicheskimi preparatami pri refrakternoi k terapii forme mertsaniia predserdii i pobochnye deistviia primeniaemykh lekarstv.

The study was undertaken to examine 105 patients with various circulatory diseases complicated by atrial fibrillation. Patients with refractory atrial fibrillation who had taken combined antiarrhythmic therapy were found to be more responsive to the combinations of cordarone + kinilentin (quinidine disulphate) and cordarone + ethacizin. The combinations of cordarone+digoxin and cordarone + finoptin were demonstrated to be less beneficial.

[A new Soviet drug, ethacizine, in the treatment of ventricular rhythm disorders]. / Novyi otechestvennyi preparat étatsizin v lechenii zheludochkovykh narushenii ritma.

The intravenous form of the Soviet anti-arrhythmic pharmaceutical ethacizine has been studied clinically. The pharmaceutical was administered to 30 patients with ventricular rhythm disorders during 3 to 15 minutes, at an average dose of 0.63 mg per 1 kg body weight, under the Holter monitor control. On the average the effect became apparent 6.5 min, after the injection and lasted on the average 149 +/- 15 min. Etacizine was effective in 77% of cases. It was established that there was no pronounced negative effect on the heart rate and the arterial pressure. Uzineg the tetrapolar rheography method it was shown that there was no pronounced negative effect on the central hemodynamics. The observation was made that etacizine induced a moderate decrease of the conductivity in atria AV-system and ventricles. Etacisin could be successfully used for rapid suppression of the ventricle rhythm disorders in various forms of coronary disease of the heart.

[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.

[Action of ethacizin on normal and anomalous forms of Purkinje fiber automaticity in the dog]. / Deistvie étatsizina na normal'nuiu i anomal'nye formy avtomatii volokon Purkin'e sobaki.

The effect of a new anti-arrhythmic drug etacysin was studied in various forms of dog Purkinje's fibres automativity: normal and abnormal arising at a late stage of experimental myocardial infarction (24 hrs after coronary artery ligation) and induced by ions Ba2+. An average 57% decrease in the frequency of automaticity of normal Purkinje's fibres due to steepening the slope of slow diastolic depolarization and almost complete depression of an abnormal one was observed for the drug concentrations 5 X 10(-7) and 10(-6) g/ml. Reduced automaticity was also related to decreased slow diastolic depolarization. Maximal values of diastolic potential were found unchanged.

[Effect of ethacizin (diethylamine analog of ethmozine) on the efferent activity of the sympathetic and parasympathetic nerves of the heart]. / Vliianie etatsizina (dietilaminovogo analoga etmozina) na efferentnuiu aktivnost' v simpaticheskikh i parasimpaticheskikh nervakh serdtsa.

This study examined the effects of the diethylamino analogue of ethmozin (ethacizin) (1 mg/kg, i.v.) on the spontaneous and reflex elicited efferent activity in thoracic cardiac sympathetic and parasympathetic nerves. Nitroglycerin and phenylephrine (4 and 8 micrograms/kg, i.v.) were administered to 15 anesthetized mongrel dogs while monitoring blood pressure and heart rate. In each dog, two cardiac nerves were isolated and efferent neurograms were simultaneously recorded and analyzed by microprocessor. Ethacizin significantly attenuated the spontaneous sympathetic efferent activity in both left and right, preganglionic (n-8) and postganglionic (n-14) sympathetic nerves to the heart. In contrast, reflex changes in sympathetic activity elicited by baroreceptor challenges, were not affected by ethacizin. Also, ethacizin did not significantly affect either spontaneous or baroreceptor reflex-induced parasympathetic efferent activities in 8 preganglionic nerves. Thus, this new phenothiazine derivative may exert part of its antiarrhythmic action through a reduction of the spontaneous sympathetic tonic discharges to the heart. The fact that ethacizin did neither reduce the reflex-induced changes in sympathetic or parasympathetic activities nor influence the tonic vagal discharges further suggests that the compound is not likely to interfere with reflexly mediated cardiovascular adaptive changes.

[Effect of the diethylamine analog of etmozin on myocardial function (a clinical and experimental study)]. / Vliianie diétilaminovogo analoga étmozina na funktsional'noe sostoianie miokarda (kliniko-éksperimental'noe issledovanie).

Diethylamine analogue of ethmozine (DAA ethmozine) administered intravenously in the doses of 0.5-1 mg/kg exerts marked antiarrhythmic effect both experimentally and clinically, slight effect on the arterial pressure and myocardial contractility and led to insignificant and to statistically insignificant depression of automatism of the sinus node and on the fibres of the conductive system. DAA ethmozine enhanced the duration of the refractory periods of atriae and of the atrio-ventricular node by 20-30%, increased the time of stimulation conduction at all the levels of the conductive system of the heart. Sensitivity of the rapid sodium channels to DAA ethmozine exceeded by one order their sensitivity to ethmozine proper. The sum total of the results and also the preliminary data on the high antiarrhythmic activity of DAA ethmozine justifies the conclusion that this drug may prove to be effective in the treatment of cardiac arrhythmias.

[Effect of the sympathetic nervous system activation on the antifibrillatory efficacy of various anti-arrhythmia agents]. / Vliianie aktivatsii simpaticheskoi nervnoi sistemy na antifibrilliatornoe deistvie protivoaritmicheskikh sredstv raznykh klassov.

Experiments with a 7-min occlusion followed by reperfusion of the left coronary artery in narcotized rats showed that antiarrhythmic drugs of various classes--ethacizin (class I), AL-275 (class III), and CM-345 (class V)--produce pronounced antifibrillatory and antiarrhythmic effects. AL-275 and CM-345, in contrast to ethacizin, retained their efficacy under the conditions of isoproterenol-induced stimulation of beta-adrenoceptors. This difference in behavior is probably explained by dissimilar effects of the antiarrhythmics on the ion channels of cardiomyocite membranes.

[First results of the clinical use of ethacizin in patients with paroxysmal atrial fibrillation]. / Pervye rezul'taty klinicheskogo primeneniia etatsizina u bol'nykh s paroksizmal'noi mertsatel'noi aritmiei.

Fifty-six patients with frequently occurring paroxysms of atrial fibrillation were examined for the clinical efficacy of a new antiarrhythmic drug etacyzine (a diethylamine analog of etmozin). The use of the drug in doses of 50 to 70 mg intravenously and in doses in 150 to 200 mg per os a day removed and prevented the occurrence of atrial fibrillation paroxysms in 60 to 65% of cases, whereas etmozin in doses of 50 mg intravenously and 600 to 800 mg per os day did not produce any positive anti-arrthythma effect in the patients. The prolonged use of etacyzine (up to 1 year and over) exerted a beneficial antiarrhythmic action almost in all the patients. The drug did not provoke any serious side effects. However, in some patients, the use of the drug promoted a substantial prolongation of the P-Q interval and widening of the QRS complex of the ECG. In one female patient, the drug caused a paradoxical repetition of the ventricular rhythm.

[Prospective course of therapy arresting attacks of atrial fibrillation in patients with preexcitation syndromes]. / Prospektivnaia évoliutsiia kupiruiushchei terapii pri pristupakh mertsiatel'noi aritmii u bol'nykh s sindromom prezhdevremennogo vozbuzhdeniia zheludochkov.

A comparative study of antiarrhythmic drugs was performed in 81 patients with atrial fibrillation attacks in the presence of preexcitation syndrome. The first intravenous administration of cordarone was effective in 84.06%, disopyramide--in 69%, ajmaline in 44.8, verapamil in 42.1, novocaine amide in 39.4 and ethacizin in 38.5% of the patients. The first oral administration of quinidine and kinilentin arrested 80.4% of arrhythmia attacks, disopyramide 66.7% propranolol and mexitil 37.5 and 33.3%, respectively. Prospective evolution of antiarrhythmic therapy manifested with decreased therapeutic efficacy of the drugs from 55.7 to 26.2% in the whole group during the period of 1-5 years.