O. V. Zhuk

The pharmacodynamics of anticonvulsant and subconvulsant effects of ethanol in CBA and C57BL/6 mice

A method of determination of minimal effective doses (MEDs) of bicuculline causing clonic-tonic convulsions (CTC) and tonic extension (TE) was used to investigate ethanol pharmacodynamics in C57BL/6 and CBA mice, differing in levels of alcohol predisposition. It is observed that ethanol produces a powerful anticonvulsant action antagonizing convulsant effects of bicuculline. On a long-term scale, the pharmacological action of alcohol had two phases in both strains of mice: anticonvulsant (in the interval 5 min to 4 h after ethanol administration) and subconvulsant (4-24 h after ethanol administration). C57BL/6 mice were characterized by a more rapid development of the anticonvulsant effect and its faster decay in comparison to CBA strain. A possibility of correct quantitative evaluation of data allows using the method of MED determination as an express model of an acute alcohol abstinence syndrome, as well as for screening of new antialcohol drugs.

Elimination kinetics of the novel prodrug cinazepam possessing psychotropic activity in mice

The kinetics of excretion of the novel tranquilizer cinazepam (3-hydroxy-7-bromo-5-(ortho-chlorophenyl)-1,2-dihydro-3H-1,4-benzdiazepin-2-one hemisuccinate (I)) in mice after a single administration and different schemes of multiple administration were determined. Mass balance was studied daily in excretions of mice (feces and urine) for 5-10 days. We observed that monoexponential renal excretion of (14)C-cinazepam and its metabolites predominated with all dosage regimens. Cinazepam and its metabolites were almost fully (> 90%) eliminated in urine and feces over the period of study (5-10 days), which means that no significant accumulation of the drug in the body occurred. The kinetic parameters of drug excretion were not significantly different after a single injection compared with those following multiple doses of (14)C-cinazepam administration. This finding suggests the absence of induction (repression) of enzymatic systems after multiple administration and lack of influence on the kinetic scheme of cinazepam elimination from mice. In our work, we also presented a modification of the Mansgeldorfs method for analysis of kinetic parameters during multiple administration of the tranquilizer. We demonstrated that our modified approach could be equally and efficiently applied for interpreting experimental data during a single dose administration and after chronic administration of xenobiotics. The use of this method made it possible to evaluate the relative efficiency of elimination processes and to find current values for excretion constants during sampling intervals.

Pharmacokinetics of Ethanol in Mice with Different Alcohol Motivation

We studied the pharmacokinetics of 14C-ethanol administered in various doses and via different routes to CBA, C57Bl/6, and (CBA×C57Bl/6)F1 mice. Kinetic scheme of ethanol distribution included its elimination by enzymatic (80-90% C0) and exponential (10-20% C0) mechanisms. Ethanol pharmacokinetics did not depend on the administration route and mouse strain. The kinetic scheme of ethanol distribution in mice was characterized by a dose-dependent linear increase in alcohol concentration in the plasma and brain and nonlinear (parabolic) increase in the area under its pharmacokinetic curve in the test tissue.

Modeling of the Dynamics of Paroxysmal Activity and Pharmacokinetics of GABAA Receptor Ligands

We developed mathematical models allowing us to calculate the parameters of pharmacokinetics of exogenous ligands based on the analysis of their pharmacodynamics under the direct influence of a pharmacological agent (agents), PhA, on tissues possessing the receptor–effector system for this PhA, i.e., on the biophase of action of this PhA. The dynamics of the paroxysmal activity induced by application to the rat brain cortex of convulsant drugs (modulators of the GABAA transmitter system) in different doses were studied. It has been demonstrated that the pharmacokinetic scheme of physiologically active substances, in the case of their direct application, can be interpreted using a chain-chamber model, whose parameters are determined by two irreversible processes of the first order: entry and elimination. The hypothesis supposing the irreversibility of the kinetic scheme of PhA mass transfer under conditions of direct application of these agents was experimentally verified.

Optimal infusion of reverse agonists of the GABA-receptor complex for analysis of the fast reversible effects of tranquilizers and ethanol

A method for intravenous infusion of reverse agonists of the GABA-receptor complex (bicuculline, pentylentetrazol, and others) was used to examine the pharmacodynamics and pharmacokinetics of GABA-receptor complex agonists (benzodiazepines and barbiturates) and aliphatic alcohols in mice. A correlation was observed between the recorded indicators of convulsive seizures in intact mice and those administered ethanol or phenazepam. The dose—effect relationship and concentration ratios of the labeled analogs of the studied compounds were estimated in the brain and blood plasma to assess their distribution in the body. Examples of tests for the pharmacokinetics of ethanol, phenazepam, and their14C-analogs in mice are given.

Pharmacokinetics of bromonordiazepam and its14C-analog in single and prolonged patterns of administration

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Elimination kinetics of synthetic interferon inducer tilorone in experimental animals

Objective. A comparative investigation was carried out on the kinetics of [3H]-tilorone ([3H]-I) excretion in rats and mice. Materials and method. Kinetics of urinary and biliary excretion of [3H]-I in rats and mice was studied following a single oral and intravenous administration. The excretion mass balance was monitored in the faeces and urine of rats and mice for 5 and 10 days, respectively. Radioactivity was determined in the samples of excreta using a liquid scintillation counter. Results. In rats, [3H]-I were nearly fully (~80%) eliminated with excreta in 5 days, indicating a lack of any significant accumulation of the drug in the body. Faecal excretion of tilorone predominated (69.0% ± 2.8%), while the elimination in urine was less significant (9.8%8 ± 1.2%). A different pattern of elimination kinetics was observed in mice as excretion proceeded with equal efficiency in urine (27.85–28.9%) and faeces (26.45– 24.4 %), regardless of the route of administration of the substance and at a substantially slower rate compared to rats: only 57.35–52.68% of total radioactivity was eliminated over 10 days following oral and intravenous administration of tilorone, respectively. MRT of tilorone in rats was 36 h and in mice 120–150 h. Conclusion. Parameters for the excretion of tilorone showed significant differences between the 2 groups of animals. Using the example of tilorone excretion kinetics validates the presented novel modified approach to determine the mean residence time (MRT) and amount of drug eliminated from the body during an infinitely long experimental period. This approach can be generally applied for interpretation of nonlinear elimination kinetics of xenobiotics.

Functional Dependence Between Expectancy of People’S Life and Mankind Population During the Time of Demographic Transition / Funkcjonalna Zależność Trwałości Życia Ludzi Od Liczebności Ludzkości Świata W Okresie Przejścia Demograficznego

Abstract In this work is an attempt to mathematically prove the existence of the demographic transition taking into account one of its features, such as extension of human life dependent on the growth of the human population. Determined the functional form of this dependence, and the relationship between the probability of death, life expectancy, and social involving in the states of T (the influence of “traditional” values of concepts) and R (in the range of rules and possibilities of modern civilization). Abstrakt Na podstawie zaproponowanych metod matematycznych została zanalizowana i opisana funkcjonalna zależność między wzrostem liczebności populacji ludzkiej a długością życia ludności świata. Analiza matematyczna pozwoliła na modelowanie dynamiki przejścia demograficznego populacji ludzkiej w zakresie jej liczebności od 3 do 7 mld i określenie wpływu racjonalnego (współczesnego) i tradycyjnego trybu życia na wzrostu długości życia ludzi.

Modeling of mechanisms and dynamics of pharmacological effects of psychotropic drugs in view of temporal organization of neuronal processes

Non-equilibrium kinetic models of ligand-receptor interaction are considered to describe the types and quantitative peculiarities of pharmacological effects of exogenous modulators, agonists, and antagonists of central neurotransmitter systems. Using the proposed model, we analyze synaptic ligand-receptor non-equilibrium (impulse) interactions against the background of steady-state interaction of a given ligand with postsynaptic receptors. The type of pharmacological effects of exogenous ligands is shown to be determined by temporal organization of specific synaptic processes (namely, the relation between the rates of receptor conformational transitions and elimination of the transmitter).

Estimation Fast-Reversible of Effects of Ethanol and Pharmacokinetic Forecast

The alternative and graduated methods for estimation of fast-reversible effects of ethanol are compared. Estimation of the myorelaxing and anticonvulsive effects of ethanol by the alternative method can be used with some limitations for the effector analysis of ethanol pharmacokinetics. It is shown that the effector expectation of pharmacokinetic profile for ethanol based on the minimal effective doses of bicuculline inducing clonic convulsions and tonic extension is comparable to experimentally determined brain contents of14C-ethanol.