The anti-arrhythmia activity and effect on the heart conduction system of the new anti-arrhythmia preparation bonnecor

In 10 patients with frequent ventricular extrasystoles there were studied the antiarrhythmic effectiveness and side effects of a new drug bonnecor at a single intravenous administration in doses from 15 to 60 mg (0.17-0.91 mg/kg). It was found that the drug exerted the antiarrhythmic effect at dosages of over 0.4 mg/kg and side effects and toxic effects occurred at dosages of over 0.7 mg/kg. The optimal dose for a single intravenous administration was regarded to be the dose of 0.6 mg/kg. The mechanisms of action of bonnecor were studied during intracardiac electrophysiological investigation. The drug was shown to suppress the conduction of excitation along the atrioventricular node, the His-Purkinje system, the ventricular myocardium and the abnormal pathways of conduction. Thus, bonnecor may be referred to as an agent of class I according to the classification of Vaughan Williams. When administered intravenously (0.6 mg/kg) bonnecor was found to interrupt and prevent the recurrent development of atrioventricular tachycardia and also supraventricular tachycardias at the presence of the abnormal pathways of conduction.     

The pharmacokinetics and pharmacodynamics of the new Soviet anti-arrhythmia preparation allapinin

Pharmacokinetics and pharmacodynamics of a new antiarrhythmic drug allapinin was studied in patients with frequent ventricular and supraventricular extrasystoles. The technique of determining allapinin by high performance liquid chromatography is described. Intravenous administration of the drug in a dose of 20 mg was shown to be effective in 50% of patients.     

The anti-arrhythmia properties of bonnecor metabolites

The experiments on the model of aconitine-induced arrhythmia in anesthetized rats and awake dogs with cardiac rhythm disorders caused by the coronary artery occlusion showed that all four metabolites of bonnecor possessed the antiarrhythmic activity. Metabolite 4 proved to be the most active on both models of cardiac rhythm disorders.     

The pharmacodynamics and pharmacokinetics of bonnecor in patients with different disorders of the heart rhythm

The clinical pharmacokinetics and the effect of bonnecor on parameters of the pharmacodynamics were studied in 53 patients with cardiac rhythm disorders, including 23 patients in the acute period of myocardial infarction. At intravenous administration of bonnecor in a dose of 0.4-0.6 mg/kg there was noted a pronounced antiarrhythmic effect with respect to both ventricular and supraventricular cardiac rhythm disorders. Bonnecor exerted no significant effect on the hemodynamic parameters. The pharmacokinetic parameters of bonnecor possess a great variability, the mean values of the parameters are close to the corresponding ones for ethacizine. Along with the unchanged drug one can detect in the blood mono-N-demethylated metabolite. The ranges of effective concentrations and those inducing side effects of the drug are given.     

A comparative study of the pharmacokinetics and pharmacodynamics of bonnecor]

The pharmacokinetics and pharmacodynamics of bonnecor were studied simultaneously in animals with experimental arrhythmia. It was shown that irrespective of the animal species and individual features of the drug elimination kinetics the level of bonnecor concentration correlated with the antiarrhythmic effect. The data on the excretion of bonnecor and its metabolites in the urine in the dog and man were obtained. The decrease of bioavailability at oral administration of bonnecor was demonstrated to be related to its intensive conversion in metabolite M-I.     

Bonnecor--a new anti-arrhythmia preparation

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.     

The relationship between the physicochemical and pharmacokinetic parameters and the anti-arrhythmia activity of bonnecor and its metabolites

The antioxidant properties of a new antiarrhythmic drug bonnecor and its main metabolites were determined by using chemoluminescence. A significant correlation was revealed between the physicochemical properties, antiarrhythmic activity, pharmacokinetic parameters of bonnecor and its metabolites.     

The anti-arrhythmia action of combinations of N-propylajmaline bromide with anti-arrhythmia agents of different classes]

In experiments on 68 dogs with ventricular arrhythmia at the late stage of experimental myocardial infarction caused by the coronary artery branch occlusion it was shown that combinations of N-propylaimaline bromide (IA class of antiarrhythmic agents) with trimecaine (IB class) or anapriline (II class) or phynoptine (IV class) induce a significant increase of the antiarrhythmic effect that is not observed at combination of N-propylaimaline with ethmosine (the both antiarrhythmic drugs belong to IA class). This potentiating effect is thought to be related to differences in the molecular mechanisms of action of antiarrhythmic drugs.     

The anti-arrhythmia activity of new dicyclohexylamide derivatives of N-substituted alpha-aminocarboxylic acids]

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 metabolism of bonnecor

Bonnecor metabolism in the rat urine was studied. The main metabolites of bonnecor were identified by means of chromatography-mass-spectrometry.     

新型棕榈酰谷氨酸-顺铂纳米粒的制备及其体外药效研究

目的以棕榈酰谷氨酸为载体材料制备新型高载药顺铂纳米粒(palmoyl glutamic acid-cisplatin-nanoparticles,PG-CDDP-NPs),并对其体外抗肿瘤活性进行研究。方法采用肖顿-鲍曼缩合法合成棕榈酰谷氨酸两亲性材料,以所合成的材料为载体,利用其与顺铂的配位作用制备高载药新型顺铂纳米粒,并对所制备的PG-CDDP-NPs性质进行考察;以市售顺铂注射剂为对照,采用MTT法考察了PG-CDDP-NPs对人肝癌细胞HEPG2的体外抗肿瘤活性。结果合成了棕榈酰谷氨酸,并成功制备了高载药量的PG-CDDP-NPs,PG-CDDP-NPs粒径为(106.33±4.45)nm,粒度分布较均匀,包封率为(84.20±0.81)%,载药量质量分数高达(27.03±0.12)%。体外释放研究表明,PG-CDDP-NPs具有缓慢释药性质,24 h累积释放量质量分数仅为(28.74±1.37)%。体外药效学实验结果显示PG-CDDP-NPs和CDDP-S对高表达的人肝癌细胞HEPG2细胞的IC50值分别为3.54μmol·L-1和4.55μmol·L-1。结论以棕榈酰谷氨酸为载体材料可制备高载药量的顺铂纳米粒;PG-CDDP-NPs在体外对HEPG2细胞有杀伤作用,与顺铂注射剂相比,显示出较强的抑瘤效果,PG-CDDP-NPs是一种具有潜在应用价值的顺铂纳米制剂。     

An experimental study of the safety of the preparation bonnecor in trials on dogs

The preclinical study of safety of an antiarrhythmic drug bonnecor (GS-015) was carried out in the experiments on dogs. Administration of the drug in a dose of 5 mg/kg was found to exert no significant effect on functions of the vital organs. The dosage of 15 mg/kg can produce in dogs changes of the hematological and biochemical parameters and cause functional disorders of the cardiac muscle and death of the animals. The data obtained indicate that in dogs the drug possesses a little therapeutic range.     

The antifibrillatory properties of bonnecor

The preventive and therapeutic effects of bonnecor were shown in the experiments on awake and anesthetized rats under conditions of acute myocardial ischemia. It was concluded that the relieving influence of bonnecor on the course of acute myocardial ischemia was related to its antifibrillatory and antiarrhythmic properties.     

Effect of the novel III class anti-arrhythmia preparation (AL-275) in experimental myocardium and sympathetic stimulation]

AL-275, a new antiarrhythmic agent, exhibits the properties typical of the class III antiarrhythmogen: (i) prolongs the ventricular repolarization; (ii) inhibits the sinus node automatism; (iii) increases the effective refractory periods in atrium and ventricles; and (iv) does not modify AV and intraventricular conduction. AL-275 produces a pronounced antiarrhythmic and antifibrillatory action. The effect of AL-275 is independent of the heart rate, which is an advantage over the other class III agents. Both character and intensity of the electrophysiological and antiarrhythmic activity of AL-275 were fully retained upon the preliminary infusion of isoproterenol. Independence of the drug action of both the heart rate and the isoproterenol-induced changes in refractoriness are related to the ability of AL-275 to block a slow component (IKs) of the potassium current.     

The pharmacokinetics and metabolism of bonnecor in rats

The pharmacokinetics of 14C-bonnecor after intravenous and oral administration was studied. The bioavailability was 70%. It was shown that administration of doses in the range of from 3 to 43 mg/kg as well as the repeated use of bonnecor failed to influence the pharmacokinetic parameters.     

The effect of bonnecor on blood coagulability and thrombocyte aggregation in transient myocardial ischemia]

The experiments on conscious rabbits have indicated that bonnecor given in doses of 0.05 mg/kg and 0.5 mg/kg accelerates clot formation and platelet aggregation, without changing the density of a thrombus. In experimental transient myocardial ischemia, the agent decreases the hypercoagulative change associated with the damaging effect of occlusion and reperfusion.     

Experimental study of the anti-arrhythmia action of unithiol]

Tests conducted on 70 rabbits showed that cardiac rhythm disorders produced by introduction of a 10% calcium chloride solution was prevented by the administration of unithiol. With developing arrhythmia in the muscle of the rabbits' heart the level of sulfhydryl groups went down. The introduction of unithiol was followed by a rising content of sulfhydryl groups, especially in the myocardium of the left ventricle.     

The psychotropic properties of bonnecor and ethacizine

The comparative study of the psychotropic activity of new acyl derivatives of dibenzazepine and phenothiazine--bonnecor (chlorhydrate 3-carbethoxyamino-5(dimethylaminoacetyl) dibenzazepine and ethacizine (chlorhydrate 2-carbethoxyamino-10-(beta-diethyl-aminopropionyl)phenothiazine)--in the experiments on small laboratory animals showed the presence of the antidepressive, anxiolytic, antiamnesic and antihypoxic effects. The drugs exerted the psychotropic effects at administration in the doses exceeding those which influence the cardiovascular system. By the degree of the anxiolytic action bonnecor and ethacizine are inferior to diazepam, are as potent as trioxasine and are superior to meprobamat. The noted psychotropic action by its character and degree can serve as a beneficial supplement to the spectrum of the pharmacological activity of the studied compounds.