Biomedical subjects
Publications and source records attributed to A P Rodionov.
1. The major metabolites of ethacizin (ethyl 10-[3-diethylaminopropionyl]phenothiazine-2-carbamate) have been isolated from human urine by h.p.l.c. and identified by determination of u.v., i.r., n.m.r. and mass spectra and comparison with spectra of synthetic standard compounds. 2. The pathways of metabolism of ethacizin include N-de-ethylation, sulphoxidation, N-10 amide hydrolysis, aromatic hydroxylation and conjugation.
Ethanol pharmacokinetics was studied after its intraperitoneal and intravenous administration in rats with different initial level of alcohol motivation using gas chromatography. It was shown that in general pharmacokinetic pattern studied upon both intraperitoneal and intravenous ethanol administration (with respect to resorption and/or distribution), the rate of ethanol elimination including a number of processes leading to a decreased drug content may be an important criterion for the selection of animals with distinct initial levels of alcohol motivation.
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.
To describe the pharmaceutical behaviour of Bonnecor methods and results of testing identity, purity, content and stability are presented. Spectroscopical analyses are needed for costitutionel examination of the molecule and of some possible metabolites.
Excretion, blood level, distribution, and metabolite samples were studied on the rat after application of GS 015 marked by 14C. The compound is quickly and completely absorbed and metabolized from an aqueous solution. The marked substances form a broad blood level maximum, at the occasion of which a main metabolite distinguishes itself apart from the initial compound at first provable yet. The elimination half-life from the blood is 6 h. An intense influx of radioactive substance into the tissues takes place. The excretion of the marked metabolites occurs mainly renally making appear a second main metabolite. Striking sex differences are partly observed in the parameters tested.
The antiarrhythmic action of GS 015 was studied proportionally to its plasma concentrations ascertained in parallel, using the model of the electrofibrillation of the cat's heart. Blood levels of about 1.3 micrograms/ml after i.v. injection of 2 mg/kg caused a marked short-term increase of the fibrillation threshold which then remained at the increased level for a longer period yet, observing GS 015 concentrations between 0.8 and 0.5 micrograms/ml. Individual differences existed in the height of the blood level as well as in its proportion to the effect.
The antiarrhythmic action of GS 015 was studied in proportion to its plasma concentrations ascertained in parallel, making use of the model of the two-step coronary ligature in the conscious dog. Blood levels of 1.0 microgram/ml (2 mg/kg i.v.) or of 0.8 microgram/ml (5 mg/kg orally) brought about a complete suppression of ectopic arrhythmias. The limit concentration for this effect is about 0.5 microgram/ml.
Head space chromatography was used to study the rate of ethanol excretion as criterion of the activity of the ethanol-oxidizing enzymatic system. Isolational stress was shown to be one of the factors determining induction of the ethanol-oxidizing erzymatic systems. The isolation-induced activity of these systems was reduced by diazepam administration. This fact may evidence the existence of central regulation of the activity of the enzymatic systems that metabolize ethanol.
Trials with patients suffering from stage II chronic alcoholism and normal test subjects as well as experiments made on male C57BL mice (with genetically determined alcoholic motivation) and CBA mice (with genetically determined alcoholic aversion) and random-bred male rats with different levels of initial alcoholic motivation have shown the presence of reverse proportional dependence between blood plasma endogenous ethanol and alcoholic motivation.
Gas liquid chromatography was used to study the kinetics of ethanol in the blood of rats during alcohol dependence and withdrawal. Chronic alcoholization was shown to lead to a considerable increase in the activity of the ethanol-oxidizing enzymatic systems. These systems were revealed to be hyperactive during alcohol withdrawal after 8-month consumption. It is concluded that hyperactivity of the ethanol-oxidizing systems during alcohol withdrawal may play an important role in the formation of alcohol abstinence symptoms.
1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.
Experimental study of pharmacokinetics of transdermal system with cytisin in rabbits showed a possibility of controlled intake of the drug over a 4-day period. The two stages of attaining the stationary levels of cytisin concentrations are revealed. The first stage lasted during first 24h and the second stage during succeeding 3 days. Using the data on intravenous cytisin injection we found that the stationary concentrations and the rate of cytisin intake in the first stage is twice as large as in the second stage. Thus cytisin can be classed as a short-living drug.
Dynamics of distribution of 3[H]-labeled himantane (N-(adamant-2-yl) hexamethyleneimine hydrochloride), a new drug possessing antiparkinsonian and immunostimulant activity, was monitored over a time period of 10 days after single injection (10 mg/kg, i.v.) in rats. It is show that himantane exhibits a selective affinity with respect to the tissues of striatum, where up to 10(-5) M of the radioactive drug equivalent is absorbed. This is significantly greater as compared to the relative amounts of drug in the whole brain, hippocampus, cerebellum, or thymus. The accumulation of radioactive himantane in striatum increased upon oral administration, which is indicative of the formation of drug metabolites possessing higher lipophilicity.
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.
The pharmacokinetics of befol at different routes of administration to animals and humans was studied. The therapeutic level of the drug concentration was established.
Bonnecor metabolism in the rat urine was studied. The main metabolites of bonnecor were identified by means of chromatography-mass-spectrometry.
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.
Kinetics of ethanol content, as a criterion of tolerance to the substance, was studied in rat blood at various steps of experimental alcoholism by means of gas-liquid chromatographic analysis. Initial addiction to alcohol was associated with its increased metabolism in the animals. Activation of ethanol-oxidizing enzymatic systems was observed in chronic alcoholization under conditions of free choice. This activation became statistically distinct after 10 days of the contact with alcohol. The activation of ethanol metabolism was maintained within 4 months and decreased after 8 months of alcoholization.