[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.

[The combined effect of 2 first-line anti-arrhythmia drugs on the conduction velocity of myocardial stimulation]. / Deistvie kombinatsii dvukh antiaritmicheskikh preparatov I klassa na skorost' provedeniia vozbuzhdeniia po miokardu.

Experiments with recording the time of intraventricular reentry of the canine heart by a special protocol of stimulation showed that the first-line antiarrhythmic agents having various kinetics, ethacizine and lidocaine, compete for their binding to the Na+ channels of cardiac fibers. As a result of this competition, additivity was not found in the effects of ethacizine, 1.5 mg/kg, and lidocaine, 12 mg/kg, on the rate of intraventricular conduction at heart rate under 180/min. At higher cardiac rhythm values, the total effects of the two agents on the conduction were observed. The experimental evidence confirm the results of mathematical modelling of the combined effects of ethacizine and lidocaine on the intraventricular conduction velocity, which were calculated on the basis of kinetic constants for binding and dissociation of the agents to Na+ channels. The findings show that when the two first-line antiarrhythmics having a substantially different kinetics were used in combination, their antiarrhythmic effect may be enhanced without their total effects on the rate of normal intraventricular conduction velocity reentry.

[Calcium metabolism and transmembrane potential of thrombocytes in patients with frequent ventricular extrasystole treated with anti-arrhythmia drugs]. / Obmen ca'ltsiia i transmembrannyi potentsial trombotsitov u bo'lnykh s chastoi zheludochkovoi ekstrasistoliei na fone lecheniia antiaritmicheskimi preparatami.

The effect of antiarrhythmic drugs on platelet calcium metabolism in peripheral blood has been examined. Anti-arrhythmic agents (ethmozine, ethacizine, quinidine, disopyramide, amiodarone), used extensively for the control of various heart rhythm disorders, as well as calcium antagonists (verapamil were shown to have a calcium-blocking property. It is demonstrated that the rate of reduction in the total number of extrasystoles in the presence of antiarrhythmic drugs is correlated to the magnitude of their in vitro calcium-blocking effect. It can be assumed that the action of antiarrhythmic drugs is in part mediated by their effect on calcium currents; at the same time, disorders of Ca2+ transport in myocardial cells are a cause of developing arrhythmias. The ability of antiarrhythmic drugs to affect platelet calcium ion currents may be used for preliminary assessment of the efficiency of antiarrhythmic drugs, used clinically to control heart rhythm disorders.

[Calcium metabolism of the thrombocytes in ischemic heart disease]. / Sostoianie kal'tsievogo obmena v trombotsitakh pri ishemicheskoi bolezni serdtsa.

Changes in Ca++ concentration were studied in platelets of patients with acute myocardial infarction, unstable or stable angina pectoris and those of healthy donors by means of fluorescent probe Quin-2 AM. Influence of aggregation inductors on the process of Ca++ level increase in these cells was also investigated. Intracellular Ca++ concentration increased in patients with acute myocardial infarction in the presence of PAF 2.10(-7) M (1337 +/- 255 nM) and in the presence of ADP 10(-5) M (1767 +/- 296 nM). A certain increase in calcium responses to stimulators was observed also in patients with unstable or stable angina pectoris. Dynamic follow up of patients with acute myocardial infarction starting from the 14th day demonstrated significant fall in intracellular Ca++ concentration (from 1767 +/- 296 nM to 834 +/- 186 nM, p less than 0.01). Platelet sensitivity to inductors during the course of therapy did not change significantly in patients with stable angina pectoris and tended to decrease in those with unstable angina pectoris (from 707 +/- 274 nM to 410 +/- 95 nM, p greater than 0.05). Increase in platelet aggregability and in calcium responses to stimulators in patients with IHD is an evidence of calcium metabolism disturbances which play an important role in the pathogenesis of the disease.

[Comparative study of the effectiveness of several anti-arrhythmia preparations in patients with a frequent extrasystole]. / Sravnitel'noe izuchenie éffektivnosti neskol'kikh antiaritmicheskikh oreparatov u bol'nykh s chastoi ékstrasistoliei.

The efficiency and side effect rates of 7 antiarrhythmic drugs: mexitil, rhytmilen, propranolol, ethmosine, cordarone, finoptin, digoxin, were compared in 80 patients. Their heart rhythm was controlled by continuous Holter ECG monitoring. The efficacy of oral doses of the drugs was assessed both in acute pharmacologic tests and in short-term clinical courses. The smallest side-effect rates and the highest efficiency were shown by cordarone (in all clinical samples) and ethmosine (particularly in coronary patients), hence both can be recommended for long-term clinical use.

[Blockade of thrombocyte calcium channels by cardiotropic compounds]. / Blokirovanie kal'tsevykh kanalov trombotsitov kardiotropnymi soedineniiami.

The effect of calcium antagonists (verapamil, nicardipine, nifedipine), nitrates (glycerin trinitrate, isosorbide dinitrate and sodium nitroprusside) and of antiarrhythmic drugs (ethmozin, ethacizin) on the increase of platelet Ca2+ concentration brought about by aggregation inductors was studied. All the analyzed substances produced an inhibitory effect on the induction of cellular Ca2+ level increase due to the action of platelet aggregation factor, ADP, vasopressin and endoperoxide PGH2 stable analogue. The degree of this inhibitory effect of calcium antagonists and nitrates was independent of the nature of the stimulator used. Calcium-blocking action of calcium antagonists and nitrates was due to suppression of the entry of Ca2+ into the cells. The action of nitrates on platelets was accompanied by an acceleration of cGMP and cAMP synthesis. Unlike nitrates, antiarrhythmic drugs did not influence the intracellular level of cyclic nucleotides. On the basis of the data obtained it is suggested that calcium-blocking action of different types of compounds can be mediated by different intracellular mechanisms.

[Comparative evaluation of the anti-arrhythmia effectiveness of mezotrin and izoptin]. / Sravnitel'naia otsenka antiaritmicheskoi éffektivnosti mezotrina i izoptina.

Isoptin and mesotrin (a new hypothetical calcium antagonist) were administered to 30 patients with frequent and persistent premature beats (22 patients with premature ventricular beats and 8 patients with premature supraventricular beats). The antiarrhythmic activity of mesotrin was nearly twice as high as that of isoptin, the antiarrhythmic effect being achieved in 63 and 33% of patients, respectively, which was especially distinct in ventricular rhythm disturbances (64 and 27%, respectively). The effective dose of mesotrin was approximately 2.5 mg/kg. Isoptin produced the greatest effect on atrio-ventricular conduction, while mesotrin to a great extent influenced atrial and ventricular conduction. Certain side effects of mesotrin were observed, consisting in slight euphoria, ventigo and heavyheadedness subduing spontaneously 10-15 minutes after administering the drug. Care should be taken when administering the drug to patients with sick sinus syndrome because of the possibility of its arrest.

[Optimization of the use of etmozin in treating patients suffering from frequent ventricular extrasystole]. / Optimizatsiia ispol'zovaniia étmozina pri lechenii bol'nykh, stradaiushchikh chastoi zheludochkovoi ékstrasistoliei.

Fifteen patients with frequent and stably recordable ventricular premature heart beat received etmozine treatment (the priming dose 500 mg, the maintenance dose 200 mg). Of these, 3 patients presented with coronary heart disease, 1 with mitral valve prolapse, and 11 with the idiopathic pattern of heart rhythm disorders. The drug was found to be highly effective. The 90% decrease in the number of ventricular premature heart beats during 2 h after administration of the priming dose can be used as criterion in predicting the efficacy of etmozine treatment.