ABSTRACT
The therapeutical procedure in case of acute cardio-circulatory failure due to intoxication by beta-blockers has gained great importance owing to suicidal and accidental poisonings with lethal outcome. The use of beta-adrenergic agonists is difficult because a not predeterminable overdosage has to be applied in consequence of the competitive inhibition of the beta-receptor. Cardiotonics with a non-adrenergic mechanism of action thus make expect a surer handling. A severe cardio-circulatory failure is provoked by talinolol in the anaesthetized dog. The therapeutical effect of 4 mg/kg Cordemcura, given i.v. is represented by comparing the parameters cardiac rate, dp/dtmax, filling pressure in the left ventricle, arterial pressure, cardiac output, total peripheral resistance, and PQ time with a control group. The results prove a sure therapeutical effect, which is compared with other cardiotonics. A clinical use is recommended. The aptitude of the intoxication by beta-receptor blokkers as a model for the cardiac insufficiency is discussed.
Subject(s)
Adrenergic beta-Antagonists/poisoning , Aminopyridines/therapeutic use , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Amrinone , Animals , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/physiopathology , Dogs , Hemodynamics/drug effects , Propanolamines/poisoningABSTRACT
In comparison with detajmium, prajmalium, ajmaline, quinidine, lidocaine, disopyramide, propranolol, and Ethmozin the substance GS 015 is tested on the aconitin-induced arrhythmia of the rat, the auricular fibrillation by aconitin of the dog, the ventricular arrhythmia induced by ouabaine of the dog, the arrhythmia caused by calcium chloride of the rat, and the arrhythmia induced by barium chloride of the rabbit. The particular qualities of effect in the special forms of arrhythmia are discussed in connection with the study of the antiarrhythmic action in case of coronary occlusion, with the increase of the electric fibrillatory threshold, and with the electrophysiologic tests.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Arrhythmias, Cardiac/chemically induced , Barium Compounds , Chlorides , Dibenzazepines/pharmacology , Aconitine , Animals , Barium , Calcium Chloride , Dogs , Heart Rate/drug effects , Ouabain , Rabbits , Rats , Strophanthidin/pharmacologyABSTRACT
The haemodynamic and cardiac effects of GS 015, a substance of the series of the novel 5-(dialkyl-aminoacyl)-3-carbalkoxyamino-10,11-dihydro-5H-dibenz-[b ,f]-azepines with very potent antifibrillatory and antiarrhythmic actions, are studied on anaesthetized dogs and cats by means of the catheter technique. The clinical symptoms and the therapeutic range were tested on conscious animals. On the strength of the present results it can be stated that GS 015, given at pharmacodynamically effective doses, does not cause any circulatory side effects. A negative inotropic effect appears only at increased doses. Like other antiarrhythmic drugs, GS 015 possesses a limited therapeutic range which should be taken into consideration particularly in case of cardiac insufficiency. But an application seems possible also in patients during the acute stage of myocardial infarction.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Dibenzazepines/pharmacology , Hemodynamics/drug effects , Anesthesia , Animals , Cats , Coronary Circulation/drug effects , Dogs , Injections, Intravenous , Myocardial Contraction/drug effects , Species SpecificityABSTRACT
The derivatives of a novel structure series of dibenzazepines dispose of intense antiarrhythmic properties. The relations between structure and effect in comparison with the antiarrhythmically active derivatives of phenothiazine (Ethmozine) are discussed. When substituting the beta-aminopropionyl chain with cyclic residue by means of a dimethylaminoacyl chain there appears a marked antifibrillatory action besides of the intense antiarrhythmic one. The compound 17, the 3-carbethoxyamino-5-dimethylaminoacetyl-dibenzazepine, proved to be the most efficacious compound in the course of the basic screening on two models: action on the effective refractory period in the rabbit's atrium and aconitin-induced arrhythmia in the conscious rat. In comparison with Ethmozin, an antiarrhythmic agent of the phenothiazine type, 17 shows a somewhat lower efficacy in case of i.v. application, but a distinctly intenser one was stated after oral administration. A profound test on the models: two-step coronary ligature in the dog according to Harris and electrofibrillation in the cat's heart, revealed an equally intense antiarrhythmic action but a considerably intenser antifibrillatory one. Therefore the compound 17 (abbreviated designation in the USSR: GS 015 or in the GDR: AWD 19-166) was provided for a thorough pharmacological and toxcological study.
Subject(s)
Anti-Arrhythmia Agents/chemical synthesis , Dibenzazepines/chemical synthesis , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/toxicity , Chemical Phenomena , Chemistry , Dibenzazepines/pharmacology , Dibenzazepines/toxicity , In Vitro Techniques , Lethal Dose 50 , Myocardial Contraction/drug effects , Rabbits , RatsABSTRACT
In the framework of a screening test of new phenoxyalkanolamines the authors tested derivatives with the basic structure Ph1--NHCH2CH2NHCH2CH(OH)CH2--OPh2 for beta-adrenergic blocking activity and sympathicomimetic action on the spontaneously beating atrial preparation from the guinea-pig and on the circulation of the cat. Derivatives with the substituents 2,5-dimethyl, 2-nitro, 3-nitro, 2,6-dimethyl and 2-chloro at Ph1 produced in the atrial preparation a some 3- to 10fold stronger beta 1-adrenergic blockade than propranolol. In in vivo experiments on the cat, all of these compounds had a potent sympathicomimetic effect on the heart, so that they may be classified as specific beta-adrenergic antagonists. The addition of 4-nitro, 3-methyl and 4-ureido at Ph2 reduces the beta-adrenergic blockade and suppresses the sympathicomimetic action. 1-(3',4'-Dimethoxyphenylethylamino)-2-hydroxy-3-phenoxypropane and its derivates showed a similar behaviour as described by Hoefle [8]. 1-[beta-(3-Nitrophenylamino)ethylamino]-2-hydroxy-3-phenoxypropane hydrochloride exhibited a particularly strong and long-lasting sympathicomimetic effect. Studies on the dog revealed a specific beta 1-mimetic action; in the effective dose range of 10-30 micrograms/kg i.v., a positive inotropic effect prevailed, and the effect on heart rate was but small. No beta-adrenergic blockade or mimetic action on the peripheral vascular system was observed.
Subject(s)
Adrenergic beta-Agonists , Adrenergic beta-Antagonists , Phenyl Ethers/pharmacology , Propanolamines/pharmacology , Animals , Blood Pressure/drug effects , Cats , Dobutamine/pharmacology , Dogs , Drug Interactions , Guinea Pigs , Heart Rate/drug effects , Hemodynamics/drug effects , In Vitro Techniques , Myocardial Contraction/drug effects , Oxyfedrine/pharmacologyABSTRACT
Clenbuterol was tested for cardiac and haemodynamic side-effects by administering cumulative broncholytically efficient doses (continuous infusion) to anaesthetized dogs. The application of a dose of 1.25 micrograms/kg produced increased heart rate (+ 18%), increased maximum pressure-rise rate dp/dt max (+ 44%), increased heart time volume (+ 43%) and decreased total peripheral resistance (- 30%). The circulatory action of an isoprenaline dose of equivalent broncholytic efficacy (0.1875 micrograms/kg/min) led to more considerably marked changes of + 75%, - 117%, + 51% and - 33%, respectively. Parallel to the cardiovascular changes, Clenbuterol causes only a slight and non-significant increase of free fatty acids in the serum (+ 23%), whereas isoprenaline (with + 107%) has a strong beta 1-mimetic effect. In contrast to this, Clenbuterol stimulates the mobilization of glucose to a greater extent than isoprenaline. These findings show that Clenbuterol must be considered as a broncholytic agent of great beta 2-specificity; due to its long duration of action and its easy enteral absorption, it constitutes a true enrichment of therapeutics.
Subject(s)
Clenbuterol/adverse effects , Ethanolamines/adverse effects , Heart/drug effects , Hemodynamics/drug effects , Animals , Blood Glucose/metabolism , Dogs , Female , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Isoproterenol/pharmacology , Rats , Uterine Contraction/drug effects , Vascular Resistance/drug effectsABSTRACT
In view of its application to human beings, the authors tested 3-[3'-diethylaminopropyl-(1')-carbamoyl]-6,7-dimethoxy-1-thiasiochroman-1,1-dio xide ("16-252"), which is a potential antidepressant by its basic neuropharmacological activities, for circulatory side-effects on the rat, the cat and the awake carotid-ligated dog and compared them with those of imipramine. "16-252" differs from imipramine in principle. Whereas imipramine exerts above all a sympathiocomimetic circulatory effect (characterized by tachycardia, increased cardiac output and increased arterial pressure), "16-252" induces bradycardia, a decrease in cardiac output and a reactive increase of the total peripheral resistance. The doses of "16-252" required to bring about more marked circulatory side-effects are about 3-fold higher than those of imipramine. Medium doses of "16-252" do not produce the cardiodepressant effects typical of imipramine and they do not potentiate the action of administered noradrenaline typical of tricyclic antidepressants. The results obtained are discussed from the aspects of cardiotoxic properties in case of long-term therapy.
