The GABA derivative TZ-50-2 exerted pronounced antiarrhythmic effects on a variety of arrhythmias (atrial, ventricular, and mixed). The drug was superior (or at least comparable) to quinidine, procainamide, lidocaine, verapamil, bonnecor, and other reference drugs in antiarrhythmic activity and therapeutic range, and showed no cardiotoxicity. The antiarrhythmic effects of TZ-50-2 were due to modulation of calcium and sodium channels. Key Words: GABA; cardiac arrhythmiasAntiarrhythmic potency of local anesthetics and anticonvulsants with similar mechanisms of action attracts now considerable attention [10]. The novel GABA derivative hemisuccinate 4-oxi-3-benzylamino-N-benzylbutan amide (laboratory code TZ-50-2) exhibits both local anesthetic [9] and anticonvulsant properties [6]. This work was aimed at investigation of antiarrhythmic activity (AA) of TZ-50-2 on different models of atrial, ventricular, and mixed arrhythmias. MATERIALS AND METHODSExperiments were carried out on 446 outbred male albino rats (175-220 g), 48 mongrel rabbits (2.8-3.6 kg), 98 cats (2.6-4.2 kg), and 31 dogs (14-22 kg) of both sexes, as well as on isolated atria (trabecular and auricular preparations) of frogs (n=36) and guinea pigs (n=20).Toxicity of TZ-50-2 and reference drugs (mean lethal dose, LDs0 ) was determined in experiments on rats with single intravenous injection followed by 48-h monitoring [3,7].The ECG (R, RR, QT, PQ, QRS) were recorded in standard lead II with EKIT-04 electrocardiograph in experiments on dogs under pentobarbital anesthesia (40 mg/kg, intrapleurally) with drug administration by biological titration (1 mg/kg/ml) until cardiac arrest. Drug effects on the myocardial reli;actory period were studied on isolated auricles of guinea pig heart [8]. The effects on action potentials and transmembrane ionic currents were studied on isolated atrial trabeculas from the heart of Rana ridibunda [ 12].The antiarrhythmic efficacy of the drugs was evaluated by comparing their potencies (mean effective doses, EDs0) and antiarrhythmic indices (LDs0/ED~0) characterizing the therapeutic window (TW) [3].The data were analyzed statistically [3]. RESULTSIntravenous inl~asion of TZ-50-2 had no effect on the ECG indices in the anesthetized dogs up to a total dose of 50 mg/kg (reached over 50 min). Further infusion (up to 60-120 mg/kg) caused respiration arrest

The antiarrhythmic rhythmidazol produces a cardiotoxic effect that can be corrected by suphan, befol, and their combinations, as evidenced by normalization of ultrastructural organization of cardiomyocytes and myocardial oxygen consumption by these drugs. Key Words: antiarrhythmics; cardiotoxic effect; rhythmidazol; suphan; befolAlong with nominal therapeutic effects, antiarrhythmic drugs produce cardiotoxic effects (CTE) that manifest themselves in the appearance of new and in many cases fatal cardiac rhythm disturbances and in the inhibition of myocardial contractility [3,7,11].Morphological basis of CTE of antiarrhythmic drugs is provided by changes in myocardial ultrastructural organization (MUSO) [7,11], which are conjugated with ionic imbalance and disturbance of oxygen consumption in cardiomyocytes [1].Both the nonglycoside cardiotonic suphan (Nsuccine-dl-tryptophan dipotassium salt) and the reversible monoamine oxidase inhibitor antidepressant befol have pronounced cardioprotective effect against CTE of such standard antiarrhythmic drugs as procainamide, lidocaine, bonnecor, Obsidan, and verapamil [71.Thus, it seems worthwhile to study CTE of the new antiarrhythmic drug rhythmidazol (dihydrochloDepartment of Pharmacoiogy, Department of Hospital Therapy and Clinical Pharmacology, Kuban Medical Academy, Krasnodar; Department of Hypoxia Research, A. A. Bogomolets Physiology Institute, Kiev ride-9-diethylaminoethyl-2-tertiarobytilimidazo(1,2-a) benzimidazole), which according to classification [12] belongs to classes I and III antiarrhythmic drugs [5]. It should be necessary to test the possibility of correcting CTE of this antiarrhythmic drug by suphan, befol, and their combinations and to examine the effects of these preparations on MUSO and myocardial oxygen consumption. MATERIALS AND METHODSThe study was carried out on 427 conscious male albino rats. Combined action of rhythmidazol, befol, and suphan was tested by the method [10,11] with modifications [4]. The mean cardiotoxic doses (CTDs0) of the drugs were determined by their intravenous administration in doses provoking arrhythmia in 50% of animals. Arrhythmias were estimated by ECG (standard lead II), Befol, suphan, and their combinations in different doses (1/4, 1/2, 3/4, and 1 CTDs0 ) were administered 5 min prior to rhythmidazol. The ratio of the new CTDs0value to the control was taken as the protection coefficient (PC).The effects of the drugs on oxygen consumption and MUSO were studied in rats under acute hypoxia

Intravenous injection of T3-146, a cyclic derivative of,/-aminobutyric acid (structural analog of piracetam), 5 min prior to reperfusion of the descendent branch of the left coronary artery prevents the development of serious rhythm disturbances and stabilizes hemodynamics and cardiac function. These effects are probably due to the inhibitory effect of this compound on lipid peroxidation in the myocardium. Key Words: ~[-aminobutyric acid; ischemia; reperfusion; disturbances of cardiac rhythm and hemodynamic; treatmentReperfusion of coronary vessels is the most effective approach to correcting myocardial ischemia [11]. However, this procedure can aggravate damage to the myocardium and cause the reperfusion syndrome characterized by high risk of cardiac rhythm disturbances (CRD), including ventricular fibrillation [1,4,12].Previous studies have demonstrated that drugs stimulating central and peripheral GABAergic stresslimiting systems possess antiarrhythmic and antifibrillatory activity under conditions of acute regional myocardial ischemia and reperfusion [5,7]. In light of this, it seems interesting to study antiarrhythmic and antifibrillatory effects of a new cyclic derivative of ~/-aminobutyric acid (laboratory code T3-146) under conditions of reperfusion in cats. This agent is a structural analog of piracetam and possesses cardioprotective properties. MATERIALS AND METHODSExperiments were carried out on 96 albino male rats (0.155-0.210 kg) and 60 nonpedigree cats (2.6-3.5Department of Pharmacology, Kuban Medical Academy, Krasnodar kg). Acute toxicity (mean lethal dose, LDs0 ) of the T3-146 and reference preparations was determined in rats as described previously [6].Reperfusion CRD were modeled on cats narcotized with Nembutal (40 rng/kg, intraperitoneally) and artificially ventilated [3]. After thoracotomy, the descendent branch of the left coronary artery was occluded near the lower edge of the auricle for 30 rain. Removal of the ligature induced reperfusion ventricular arrhythmias which in most cases transformed into ventricular fibrillation. T3-146 and reference preparations were injected intravenously slowly in isotoxic doses (5% LDs0 ) 5 min prior to coronary occlusion. The occurrence of repeffusion ventricular arrhythmias and fibrillation was recorded on an EKIT-04 electrocardiograph.The effect of T3-146 on the main hemodynamic and cardiac parameters (HCP) was studied on cats narcotized with Nembutal (40 mg/kg, intraperitoneally) and artificially ventilated as described previously [9]. Systemic arterial and left ventricular pressures as well as its first and second derivatives (dP/dt and (dP/dt)/P) characterizing myocardial contractility were recorded. Electrocardiogram in

The antiarrhythmic activity of befol (an isotoxic dose) is higher than (or comparable to) that of lidocaine and bonnecor in atrial and ventricular arrhythmias induced by acute ischemia, reperfusion, myocardial infarction, or ouabain treatment. In epinephrine-induced arrhythmia, befol is inferior to these drugs (except lidocaine) in activity and range of therapeutic action. Key Words: befol; lidocaine; bonnecor; arrhythmias; treatmentBefol [4-chloro-N-(3-morpholinopropyl)-benzamide hydrochloride], a Russian-manufactured antidepressant, is a reversible monoamine oxidase inhibitor selectively inhibiting serotonin deamination [3].This drug is effective against cardiac rhythm disturbances (CRD) of ischemic and nonischemic origin [10].The aim of the present study was to compare the antiarrhythmic activities (AAA) of befol, lidocaine, and bonnecor in experiments on animals with various CRD. MATERIALS AND METHODSExperiments were performed on 205 male Wistar rats (0.170-0.240 kg), 9 rabbits (2.4-3.6 kg), 107 cats (2.8-4.4 kg), and 25 dogs (7-25 kg).Acute toxicity (mean lethal dose, LDE0) of befol, lidocaine, and bonnecor was determined in experiments on rats (intravenous injections).The antiarrhythmic activities of the drugs were studied in atrial [16] [14] in rabbits and ouabaininduced arrhythmia in cats (0.05 mg/kg with successive injection of 0.01 mg/kg each 10 min until extrasystole and ventricular tachycardia appeared). Atrioventricular arrhythmia was induced by aconitine [5] in rats. Antiarrhythmic activity was evaluated by biological titration [17] in atrial arrhythmias, by the difference in CRD incidence in experimental and control animals with ventricular CRD induced by acute ischemia and reperfusion, and by the per, centage of ectopic ventricular contractions recorded 24 h after occlusion of descending branch of the left coronary artery in CRD induced by myocardial infarction. The AAAs of the drugs were compared by the isotoxic dose. In chemically-induced CRD, AAA was assessed by the mean effective dose (EDE0), mean lethal dose (LDE0), and antiarrhythmic index (LDJEDE0), which characterizes the range of therapeutic action [2]. Befol, lidocaine, and bonnecor were injected intravenously in ascending doses. The data were processed statistically by the methods described previously [2,8]. out of 5 cases bonnecor induced conduction disturbances of various intensities. Lidocaine was not tested in atrial CRD, since in therapeutic doses it is ineffective against these arrhythmias [6]. As Table 1 shows, occlusion arrhythmia did not develop in 40% of the control cats, while reperfusion arrhythmia occurred in all cases and in 67% cats it turned into ventricular fibrillation. Befol (11.7 mg/kg, 5% LDs0) did not prevent these CRD. Higher doses of befol (23.4 and 35.0 mg/kg, 10 and 15% LDs0, respectively) prevented the early occlusion and reperfusion arrhythmias in 85.7% (23.4 mg/kg) or 100% (35.0 mg/kg) of the cats; none of the animals developed ventricular fibrillation. At 1.4 mg/kg (5% LDs0) lidocaine exhibited no appr...

Dimebon, an antihistamine agent, exerts a moderate antianginal effect, improving the function of ischemic focus in the myocardium and decreasing the necrotic zone in experimental myocardial infarction. Dimebon is less active than obsidan, finoptin (except for the size of the necrotic zone), and cordaron. Key Words: dimebon; obsidan; .finoptin; cordaron; ischemia; myocardial infarction; treatmentThe Hx-receptor blocker dimebon exhibits antiarrhythmic activity in a wide dose range (0.1-10.8 mg/kg), being effective against cardiac rhythm disturbances of different origins, including those induced by experimental myocardial infarction [2].At 5 and 7.5 mg/kg dimebon increases the rate of coronary blood flow and decreases oxygen consumption by the myocardium, creating an oxygen reserve in the heart in local acute myocardial ischemia.In this study we compared the effects of dimebon with those of obsidan (propranolol), finoptin (verapamil), and cordaron (amiodarone) on the functional state of ischemic focus in the myocardium and on the size of the necrotic zone (NZ) in experimental myocardial infarction. MATERIALS AND METHODSExperiments were performed on 20 cats weighing 2.5-4.2 kg. The animals were anesthetized with Nembutal (40 mg/kg intraperitoneally), and local myo- The effects of the drugs on the size of NZ in experimental myocardial infarction were studied on 40 cats weighing 2.8-4.2 kg. The animals were anesthetized with Nembutal (40 mg/kg intraperitoneally). Myocardial infarction was produced by occlusion of the DBLCA between the upper and middle third. The size of NZ was determined as described elsewhere [3]. The drugs were injected intravenously 30 min before and 120 min after ligation of DBLCA.The results were statistically processed as described previously [ 1,7]. RESULTSDepression of the ST segment was observed after administration of dimebon in a dose of 7.5 mg/kg.The greatest decrease in EST (40.3%) was recorded