[ANTIARRHYTHMIC EFFECTS OF 2-ETHYL-6-METHYL-3-HYDROXYPYRIDINE HEMISUCCINATE IN COMPARISON TO MEXIDOL.]

Based on the results of experiments on nonlinear white awake male rats it is established that 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate and mexidol exhibit a pronounced antiarrhythmic (antifibrillatory) activity on the calcium chloride arrhythmia model. The maximum effect was observed for hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine. This substaned; unlike mexidol, also showed high activity on the model of aconitine arrhythmia, which is typical of class I antiarrhytmics. Mexidol did not show this activity. Consequently, 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I (lidocaine, procainamide) and is comparable in this respect with class IV drug verapamil.

[GABAergic mechanism of cerebrovascular effect of the NMDA receptor antagonist MK-801].

NMDA receptor antagonist MK-801 (dizocilpine) increases the local blood flow in the cerebral cortex in rats under transient global ischemia (TGI) conditions to a greater degree than in intact animals. The GABA receptor blocker bicuculline in most experiments eliminates or reduces the MK-801 induced increase in the blood flow after TGI, which is indicative of the participation of GABAergic mechanism of cerebrovascular tone control in the observed MK-801 activity.

[Search for new drugs with antiarrhythmic properties among derivatives of adamant-2-ylamides of alkylamidocarbonic acids].

The experiments on white outbred awaken male rats have shown that derivatives of adamant-2-ylamides of alkylamidocarbonic acids exhibit prominent antiarrhythmic (antifibrillatory) effect on the model of calcium chloride arrhythmia. The most pronounced effect was demonstrated by N-[2(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide. This compound was also active on the model of aconitine arrhythmia, which is characteristic of class-I antiarrhythmic agents. It is established that N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide has prominent antiarrhythmic activity and is more safe than other antiarrhythmic drugs of class I (lidocaine, ethmosine, novocainamide), class IV (verapamil), and class III (cardiocyclide).

[Adamantane derivate enhances cerebral blood flow under conditions of ischemic brain damage].

Experiments have shown that adamantane derivate - 5-hydroxyadamantan-2-on (100 mg/kg, i.v.) enhances the local blood flow in the cerebral cortex of rats under global transient brain ischemia conditions, while not influencing the brain blood flow in intact rats. In the same dose, adamantane derivate significantly decreases mortality in rats under conditions of hypergravity ischemia. The cerebrovascular effect of adamantane derivate is abolished by bicuculline (GABA-A receptor blocker), which is evidence for a GABAergic component in the mechanism of the cerebrovascular action ofadamantane derivate.

[Cerebrovascular and antiserotoninergic activity of the combination of tropoxin and mexidol].

The results of experiments on narcotized rats showed that tropoxin substantially reduces the constrictor reactions of cerebral blood vessels to meta-chlorophenylpiperazine, while not increasing the blood flow in the carotid system of either intact rats or animals with model ischemic damage of brain. In contrast, mexidol increases the cerebral blood flow in rats under conditions of global transient ischemia of brain. A combination of tropoxin and mexidol retains both the anti-serotoninergic activity of tropoxin and the vasodilating effect of mexidol.

[Antiarrhythmic properties of afobazole and other 2-mercaptobensimidazole derivatives].

Experiments on conscious male rats have shown that, under conditions of the aconitine-induced arrhythmia model, afobazole and other 2-mercaptobensimidazole derivatives exhibit antiarrhythmic effect, i.e. possess properties of rapid Na+ channel antagonists. The effect of afobazole under these conditions was significantly more pronounced than that of the reference drugs lidocaine and procainamide. The antiarrhythmic (antifibrillatory) effect of afobazole was also detected under the conditions of arrhythmia caused by high doses of calcium chloride. This drug was 1.5 times more effective in its antifibrillatory action than lidocaine, but it was less effective than verapamil. It has been also found that afobazole possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I and IV (lidocaine, procainamide, ethmosine and verapamil).

[Effects of afobazole on the stress protein HSP70 level in the brain tissue of rats with global transient ischemia].

Experiments in anesthetized rats showed that global transient brain ischemia caused a significant decrease in cerebral blood flow in rat cerebral cortex and reduced the stress protein HSP70 level in striatum. Afobazole administration restored the cerebral blood supply disturbed by ischemia and increased the stress protein HSP70 synthesis in striatum.

[Afobazole effect on cerebral circulation under hemorrhagic stroke model conditions].

Narcotized rats under hemorrhagic stroke model conditions exhibit a significant decrease in the cerebral flow in the region of contralateral cerebral hemisphere symmetric to the zone of lesion. Under these conditions, afobazole produced a significant increase in the local circulation in cerebral cortex, which was violated by hemorrhagic stroke. The cerebrovascular effect of afobazole was not manifested in cases of hemorrhagic stroke on the background of GABA receptor blocking by bicuculline. The obtained results demonstrate that afobazole increases the cerebral blood flow not only under conditions of global transient cerebral ischemia, but on the hemorrhagic stroke model as well, which is probably related to a mediated drug effect on the GABA receptor complex.

Antiarrhythmic properties of estrogens.

Estrone, estriol, and estradiol valerate exhibited antiarrhythmic activity in rats with aconitine-induced arrhythmia. Estrone was most effective in this respect.

[Anti-arrhythmia activity of estradiol valerate and estradiol nitrate]. / Issledovanie antiaritmicheskikh svoistv éstradiola valerata i nitrata éstradiola.

Estradiol valerate and estradiol nitrate exhibit significant antiarrhythmic activity of on the aconitine arrhythmia model in rats. In both cases, the maximum effect was observed in a dose of 0.5 mg/kg.

[The effect of novel class III anti-arrhythmia agents cardiocyclide and nibentan during activation of cardiac beta-adrenoreceptors]. / Deistvie novykh antiaritmicheskikh preparatov III klassa--kardiotsiklida i nibentana na fone aktivatsii beta-adrenoretseptorov serdtsa.

The effect of cardiocyclide and nibentan--class III antiarrhythmics--on the heart rate frequencies (HRF) and the EEG intervals (PQ, QRS, QT, and QTc) was experimentally studied on narcotized rats under conditions of the isoproterenol-induced activation of beta-adrenergic structures. It was established that cardiocyclide retains properties of the class III drug, as manifested by decreased HRF and increased QT duration in the absence of changes in the conductivity. In contrast, the activity of nibentan was decreased on the background of activation of the sympathetic system.

[The anti-arrhythmia activity of new dicyclohexylamide derivatives of N-substituted alpha-aminocarboxylic acids]. / Antiaritmicheskaia aktivnost' novykh proizvodnykh ditsiklogeksilamidov N-zameshchennykh al'fa-aminokarbonovykh kislot.

Experiments on arrhythmia models showed a high antiarrhythmic activity of new derivatives of dicyclohexylamides of N-replaced alpha-aminocarbonic acids. The new compounds surpassed in intensity and duration of the antiarrhythmic effect the standard agents with classes I and III antiarrhythmic activity. In doing so they raise myocardial electrical stability and prevent sudden development of ventricular fibrillation. According to the mechanism of the antiarrhythmic activity, the new compounds may be related to antiarrhythmic agents possessing the properties of classes I and III.

[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.

[Anti-arrhythmic properties of specific bradycardic agents from the group of 2-mercaptobenzimidazole derivatives]. / Antiaritmicheskie svoistva spetsificheskikh bradikardicheskikh sredstv iz gruppy proizvodnykh 2-merkaptobenzimidazola.

It was shown in experiments on aconitine, calcium chloride, and epinephrine models of heart rhythm disorders that derivatives of 2-mercaptobenzimidasole possessing the properties of specific bradycardiac agents coded as SM-251, SM-266, and SM-345 cause a marked antiarrhythmic effect. SM-266 and SM-345 reduce considerably the number of ventricular fibrillations and the life-hazardous arrhythmia occurring during 7-min occlusion and subsequent reperfusion of the coronary artery in anesthetized rats. The agents under study reduced the ectopic heart rate in Harris' conscious dogs. It is concluded that the studied 2-mercaptobenzimidasole derivatives exert a marked antiarrhythmic and antifibrillatory effect.

[A comparative study of the antiarrhythmic action of bonnecor and the mesidide derivatives of alpha-azacycloalkane carboxylic acids]. / Sravnitel'noe izuchenie antiaritmicheskogo deistviia bonnekora i nekotorykh proizvodnykh mezididov al'fa-azatsikloalkankarbonovyykh kislot.

The antiarrhythmic properties of the dibenzazepine derivative bonnecor and derivatives of mesidides of alpha-azacycloalkanocarboxylic acids were studied in various experimental arrhythmia models. The comparative study revealed different antiarrhythmic effects in different arrhythmia models. Bonnecor was found to have a higher antiarrhythmic activity in most arrhythmic models. Tertiary salts were demonstrated to be more potent than quaternary ones.

[The anti-arrhythmic activity of the arylamides of alpha-hexamethyleneiminocarboxylic acids]. / Antiaritmicheskaia aktivnost' arilamidov al'fa-geksametileniminokarbonovykh kislot.

A high antiarrhythmic activity of arylamides of alpha-hexamethyleniminocarbonic acids was found on different experimental models of arrhythmias. It was shown that the lengthening of the carbonic chain in carbonic acids (R) as well as the change from ortho-toluidides to xylidides or mesidides in the aromatic fragment of the molecule increased the antiarrhythmic activity of the studied compounds, their toxicity also increased. The choice of compounds with optimal properties is determined by the combination of all investigated factors: intensity and duration and also the specific features of the spectrum of the antiarrhythmic effect, toxicity and therapeutic range.

[The relationship between the chemical structure and the antiarrhythmic action of ethacizine and its analogs]. / Sviaz' mezhdu khimicheskoi strukturoi i antiaritmicheskim deistviem étatsizina i ego analov.

The relationship between the chemical structure and the antiarrhythmic activity of phenothiazine derivatives--ethacizine and its analogues--was estimated quantitatively by the value of the antiarrhythmic effect on aconitine model in conscious rats. The lengthening of the side chain of nitrogen atom in position 10 of phenothiazine cycle by one methylene group as well as the substitution of demethylamine radical for diethylamine one increased the antiarrhythmic activity; the toxicity of the compound being also increased. Ethacizine was found to possess the highest antiarrhythmic activity and the greatest antiarrhythmic index.

[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.

[Characteristics of the protective action of ethacizin on the ischemic myocardium]. / Kharakteristika zashchitnogo deistviia étatsizina na ishemizirovannyi miokard.

A study was made of the effect of ethacizine, a new antiarrhythmic phenothiazint derivative, on the size of experimental myocardial infarction in rabbits 7 days after ligation of the coronary artery. Ethmozine was used as reference. Ethacizine diminished the extent of necrosis by 22.8% (P less than 0.05) when injected intravenously in divided doses beginning from the 30th minute of 2-hour ligation, the total dose being 1.5 mg/kg. The six-day cycle of ethacizine treatment instituted 24 h after coronary artery ligation (daily dose 1.2 mg/kg) provoked a more considerable reduction of the myocardial infarction size (by 44.9%). The effect of ethmozine was less pronounced though statistically significant. Ethacizine increased ATP content in both the ischemic and "intact" myocardium and minimized the impairment of membrane permeability in the occlusion zone 3 h after ligation when injected according to the first above-described scheme. It is assumed that these effects may contribute to the drug protective action on the ischemic myocardium.