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Experiments on anesthetized cats and rats showed that 2-mercaptobenzimidazole derivatives, known as SM-266 and SM-345, induced marked and long-term bradycardia, increased the stroke output, and reduced the requirements of the heart of oxygen. The drugs had practically no effect on systemic arterial pressure, cardiac output, and heart contractility. Studies on isolated frog venous sinuses disclosed that bradycardia induced by the drugs under study was related to the decrease caused by them in the velocity of slow diastolic depolarization directly in the pacemaker cells on the sinus node. On grounds of the obtained results it is concluded that the drugs under study may be related to a new group of specific bradycardiac agents.

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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.

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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.

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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.

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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.

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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.

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During experiments on strips of the frog ventricular myocardium and venous sinuses it was shown that marcaine and its derivative suppress the spontaneous activity of pacemaker cells, increase the threshold of occurrence of potentials of action and the minimal period of assimilation of forced excitations. These effects are dose-dependent and increase at a rise of stimulation frequency. Its derivative was inferior by effect intensity as compared with marcaine, it failed to exert a strong suppressive effect on the amplitude and duration of potentials of action.

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A new dibenzepin derivative, bonnecor, showed marked antiarrhythmic and antifibrillation properties in anesthetized cats. One and 2 mg/kg doses of the drug reduce cardiac assimilation of imposed ventricular electric stimuli, increase ventricular fibrillation threshold with a strong and lasting effect and prevent arrhythmias and fibrillation due to 10-minute occlusion and subsequent reperfusion of the anterior descending branch of the left coronary artery. Experimental holding of atrial trabecular membrane potential in a frog, in conditions of a double saccharose bridge, showed bonnecor, in 5 X 10(-7) and 1 X 10(-6) g/ml concentrations, to inhibit rapid sodium inflow and slow calcium inflow. It is expected that bonnecor can be used clinically to control critical arrhythmias and prevent sudden cardiac death.

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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.

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It has been demonstrated in experimental arrhythmias of animals (aconitine one in rats, strophanthine in guinea-pigs, creation of an "ectopic focus of excitation" in cats by electric stimulation) that new compounds, the derivatives of piperidine carboxylic acids, possess antiarrhythmic activity. In doses of 6-23 mg/kg, the compounds under study prevented the development of the mixed type arrhythmia induced by intravenous injection of aconitine, prolonged the time of survival and prevented the animals' death during intravenous injection of the arrhythmogenic doses of strophanthine, prolonged the refractory period, and increased the threshold of ventricular fibrillation in cats. As regards the power of the antiarrhythmic effect, the compounds under study--hydrochlorides of arylamides of N-hydroxyalkly-alpha-piperidine carboxylic acids--approach lidocaine, yield to marcaine, and exhibit a broader range of therapeutic action.

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It has been demonstrated in experiments on anesthetized cats with heart rhythm abnormalities induced by the creation of an "ectopic focus" by high-frequency electric stimulation of the ventricles that lidocaine in a dose of 5.8 mg/kg is inferior to marcaine in a dose of 1.3 mg/kg as regards the ability to inhibit the sympathetic tone. Lidocaine and marcaine have been discovered to produce different effects: lidocaine produced a dose-dependent selective inhibition of C-components of reflex discharges, whereas marcaine a more prolonged and uniform suppression of both A- and C-components of evoked responses, inhibiting both excitatory and inhibitory components of reflex responses.

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Comparative study of antiarrhythmic properties of marcaine and lidocaine was made on aconitine- and strophanthine-induced experimental arrhythmias and in rhythm disorders induced by electrical stimulation of the ventricles. Marcaine (5 mg/kg) prevented the development of rhythm disorders induced in rats by intravenous injection of aconitine (40 micrograms/kg) and also raised the arrhythmogenic dose of strophanthine (ouabain) in guinea-pigs. Administration of marcaine to anesthetized cats in a dose of 2 mg/kg reduced the assimilation of the rhythm imposed on the heart ventricles at the expense of an increase in the effective refractory period and increased the threshold of electrical fibrillation of the ventricles more noticeably and for a longer time as compared with lidocaine administered in a dose of 5 mg/kg. Marcaine compares very favourably with lidocaine as regards the potency and duration of the antiarrhythmic effect. However, it is inferior to lidocaine from the standpoint of the therapeutic action range. Toxic effects of marcaine do not make clear the prospects of its clinical use as an antiarrhythmic drug. Nevertheless the search of new effective antiarrhythmic drugs among marcaine analogs holds promise.

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To reveal latent cardiac pathology in alcoholic patients'--the adaptation mechanisms adjusting the heart to the exercise test were quantitatively evaluated. The computer-made histograms of the cardiac rhythm of 30 practically healthy humans and 24 alcoholic patients showed before, during and after the exercise test that the variation range of the R-R interval was drastically decreased in alcoholic patients as compared to normal, while their mode was shifted towards shorter cardiointervals and had an increased amplitude. When the alcoholic patients were exposed to the exercise tests the shifts of the cardiointerval parameters in them were sharply different from those observed in the healthy subjects and after the test was over, the initial cardiac rhythm parameters failed to reappear within more than 3 min. Nonachlazin treatment of alcoholic cardiomyopathy increased the exercise tolerance estimated on the basis of the computer-processed cardiac rhythm, contributing to the reappearance of the normal clinical picture in the patients.

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Chronic experiments on rabbits have shown that microinjections of 30, 60 and 90 micrograms of petroleum hashish extract into the ventromedial hypothalamic nuclei and into the central gray matter of the midbrain depresses the negative motivated excitation (fear, pain) induced by electric stimulation of these structures or by electric shock. Injection of hashish into the lateral hypothalamic area facilitates the appearance of the digestive positive motivated excitation. Repeated injections of the preparation during 3--15 days contributed to the development of tolerance to analgesic, behavioral and hypothermic effects of hashish. Discontinuation of the injections (90 micrograms) at the 30th experimental day did not reveal any distinct picture of the withdrawal syndrome. A suggestion is made that the brain structures investigated may participate in the development of pathological motivation to hashish.

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