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"Emergency medicine" 1 (56) 2014

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Pharmacokinetic analysis of the protective action of a new antihypoxant vitagerm-3 under acute hypoxia with progressive hypercapnia on the distribution stage

Authors: V.D. Lukjanchuk, G.I. Posternak, D.S. Kravets, Е.А. Shebaldova

Categories: Medicine of emergency

Sections: Clinical researches

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Keywords

hypoxia, pharmacokinetic, antihypoxant, VITAGERM-3.

Introduction. Hypoxic hypoxia with hypercapnia is a very common form of an acute hypoxic syndrome, which is formed in a closed containment and therefore also named hypoxia of an enclosed space.

Currently, range of drugs that can effectively resist to a hypoxia of an enclosed space is extremely small, and existing remedies do not meet modern requirements due to their low efficacy and/or adverse reactions.

Earlier in screening studies on the model of hypoxic hypoxia with progressive hypercapnia was revealed a pronounced antihypoxic activity of coordination compound of germanium with diethylene triamine pentaacetic acid and potassium (VITAGERM-3).

Taking into consideration, that one of the key preclinical objectives is determination of the pharmacokinetic profile of a potential drug, the goal of research was to investigate in a comparative perspective pharmacokinetics of VITAGERM-3 on its distribution stage in the body of healthy animals and under hypoxic condition in an enclosed space.

Materials and techniques. The studies were performed on 96 adult white outbread rats of both sexes on an experimental model of an acute pathological process that develops in animals in a closed space. Modeling of hypoxia with progressive hypercapnia was performed by placing the rats in the isolated glass containments (10 dm3).

Concentration of VITAGERM-3 in biological substrates was detected by the classical method in dynamics – in 1, 3, 6, 12 and 24 hours after its administration. The pharmacokinetic parameters (tmax, Cmax, Kij, Kji, AUC) were calculated within the one-compartment model with absorption.

Results. Found that tmax of VITAGERM-3 in the brain of animals in reoxygenation period on 29.82 % lower compared to the normal range (P < 0,05). It can be explained by the fact that the neurons of the brain are the most sensitive among other cells to oxygen deficiency. Trigger mechanism of destruction of neurocytes` membranes, from our point of view, is the "hypoxic" activation of free radical reactions with subsequent accumulation of lipid peroxides, leading to disruption of lipid-protein interaction in membranes, and this ultimately reduces the value of tmax and increases Cmax of VITAGERM-3 in the brain.

Thus, a comparative analysis of the following pharmacokinetic parameters strongly suggests that evidence that VITAGERM-3 has a tropism to a brain, which, perhaps, preconditions it antihypoxic properties.

The results concerning distribution of the VITAGERM-3 in the heart under investigated experimental conditions show that in all parameters (tmax, Cmax, Kij, Kji, AUC) registered in "healthy" animals and those exposed to hypoxic conditions in an enclosed space is no significant difference (P > 0,05). Based on these data we can suggest that membranes of cardiomyocytes are relatively more resistant to hypoxia compared to neurocytes` membranes. The reason for that might be the presence of a powerful antioxidant system in cardiac muscle rather than in brain tissue. In addition, the critical part in cardiac muscle plays an energy supply system, which is more powerful compared to the one in the brain, because in the heart, along with the adenine nucleotides system creatine phosphate also takes an active part in energy production.

The results of pharmacokinetic studies of distribution of VITAGERM-3 in the lungs have shown that, it distribution in the lungs is similar to one in the heart in the group of "healthy" and hypoxic rats. Almost all parameters (tmax, Cmax , Kij, Kji, AUC) have no significant difference (P > 0,05) in both groups, that have been compared except reverse mass transfer rate, the value of which, in hypoxic animals was significantly (P < 0.05 ) higher compared to the "norm" .

Comparative analysis of pharmacokinetic parameters describing the distribution process of VITAGERM-3 in the liver suggests that hypoxia does not change the nature of distribution of VITAGERM-3 in this organ, which is very inert with respect to pharmacokinetic changes of VITAGERM-3 under hypoxic condition in an enclosed space.

Special attention was paid to study of the distribution of VITAGERM-3 in kidneys. Found that only in Kji index is no difference between the "normal" and hypoxic rats. Kji in rats with hypoxia of an enclosed space significantly (P < 0,05) higher (on 38.24 %) than in "healthy" animals. From our point of view, under hypoxic conditions kidney increases the secretion of hydrogen protons and water-soluble molecules of VITAGERM-3 with water, that eventually reduce concentration of this substance in renal tissue.

Conclusions. Thus, VITAGERM-3 on values of rate of direct and reverse mass transfer constants and pharmacokinetic area under the curves in the largest amount recorded in the brain and heart that conforms to the modern antihypoxants. The peculiarities of pharmacokinetic of  VITAGERM-3 is an unconditional basis for realization of a number of pharmacodynamic effects of VITAGERM-3 as an antihypoxant.


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