Pharmacokinetics of Succinate in Rats after Intravenous Administration of Mexidol.

The pharmacokinetics of succinate was studied in Wistar rats after a single intravenous administration of Mexidol in a dose 100 mg/kg body weight. The concentration of succinate in blood plasma, cytoplasmic and mitochondrial fractions of cells of the cerebral cortex, left-ventricular myocardium, and liver was measured by HPLC-MS/MS. After single intravenous administration of Mexidol, succinate was evenly distributed in organs and tissues and quickly eliminated from the body. The pharmacokinetics of succinate was described by a two-chamber model. An increase in the level of succinate in the cytoplasmic fraction of the liver, myocardium, and cerebral cortex cells and a minor increase in the mitochondrial fraction were observed. The maximum increase in the level of succinate in the cytoplasmic fraction was observed in the liver tissue, a less pronounced elevation was observed in the cerebral cortex and myocardium; no significant differences between the cerebral cortex and myocardium were observed by this parameter.

Functioning of P-Glycoprotein during Pregnancy in Rabbits.

The level P-glycoprotein (Pgp) in organs of pregnant rabbits and its content and activity in the placental barrier at different stages of pregnancy were studied. An increase in Pgp content in the jejunum on days 7, 14, 21, and 28 of pregnancy in comparison with this parameter non-pregnant females was revealed by ELISA; in the liver, Pgp content was higher on day 7 and tended to increase on day 14; in the kidney and cerebral cortex, Pgp content was higher on day 28 of pregnancy in parallel with an increase in serum progesterone concentration. We also observed a decrease in Pgp content in the placenta on days 21 and 28 of pregnancy in comparison with day 14 and a decrease in Pgp activity in the placental barrier, which was confirmed by enhanced penetration of fexofenadine (Pgp substrate) through the barrier.

Glycoalkaloids of Plants in the Family Solanaceae (Nightshade) as Potential Drugs.

Worldwide interest in medicinal plants and related drugs is growing because of the increased spectrum of new synthetic drugs. In this context, secondary plant metabolites are most significant. This review analyzes data on the structures and biosyntheses of metabolites such as glycoalkaloids; methods for their extraction from plants of the family Solanaceae, particularly potato S. tuberosum; their qualitative and quantitative analysis; biological activity; and toxicity. This information could be useful in the selection of methods for sample preparation and extraction of glycoalkaloids during the search for new plant sources with prospects of creating effective and safe pharmacological agents.

Regulation and Role of Hypoxia-Induced Factor 1α (HIF-1α) under Conditions of Endogenous Oxidative Stress In Vitro.

The effect of endogenous oxidative stress induced by γ-glutamyl cysteinesynthetase inhibitor D,L-buthionine sulfoximine (BSO) on the functioning of hypoxia-induced factor 1α (HIF-1α) was studied on Caco-2 cells. BSO was added for 24 h in concentrations of 5, 10, 50, 100, and 500 µM. It was shown that BSO in concentrations of 10, 50, and 100 µM induced endogenous oxidative stress and increased the content of HIF-1α; this effect was regulated through nuclear factor of erythroid origin 2 (Nrf2). Activation of HIF-1α had an independent protective effect, as evidenced by the decrease in cell viability after HIF-1α inhibition under these conditions. When the concentration of BSO was increased to 500 µM the content of HIF-1α did not change, and cell viability decreased.

Assessment of Malondialdehyde Belonging to Modulators and Substrates of the P-Glycoprotein Transporter Protein.

In the study on cells of the Caco-2 line, the affiliation of malondialdehyde (MDA) to modulators and substrates of P-glycoprotein (Pgp) was assessed, and the biological role of Pgp in conditions of oxidative stress (OS) was studied. MDA was used at concentrations of 10, 50, 100, and 150 µM; OS was simulated by incubation with hydrogen peroxide (H2O2) at concentrations of 0.1-100 µM for 24 h. The relative amount of Pgp was evaluated by the Western blot hybridization, and the activity was estimated by the transport of its substrate fexofenadine (HPLC with UV detection, HPLC MS/MS). In this study, it was shown that MDA at concentrations of 10 and 50 µM and exposure duration of 24 h increases the relative amount and activity of Pgp by acting through CAR and PXR, and MDA can be transported by Pgp. The induction of Pgp under the action of MDA during the development of OS can have a protective significance, ensuring the removal of the peroxidation product from cells into the extracellular space and thereby increasing the viability of cells.

[Evaluation of female sex hormones influence on the protein-transporter p-glycoprotein functioning in vitro]. / Otsenka vliianiia zhenskikh polovykh gormonov na funktsionirovanie belka-transportera glikoproteina-P in vitro.

The effects of female sex hormones estradiol and progesterone on P-glycoprotein (Pgp) functioning have been investigated using Caco-2 cells. Pgp activity was analyzed in a transwell system by the transport of its substrate, fexofenadine. The amount of the transporter protein was analyzed by enzyme immunoassay. Incubation of Caco-2 cells with 10 µM estradiol and incubation for 3 days increased activity and synthesis of Pgp. Moreover, this effect was suppressed by the inhibitor of the constitutive androstane receptor (CAR) CINPA 1. Incubation of these cells with 100 µM progesterone for 3 days increased Pgp synthesis, but its activity remained unchanged due to non-genomic (direct) inhibition of Pgp molecule by gestagen. The pregnan-X receptor inhibitor (PXR), ketoconazole suppressed the inducing effect of progesterone on Pgp synthesis. The combination of 10 µM estradiol and 100 µM progesterone increased Pgp synthesis, but did not increase the transporter protein activity, due to direct inhibition of the Pgp molecule by progestogen. Thus, it was found that estradiol increased activity and synthesis of Pgp by stimulating CAR, and progesterone stimulated transporter protein synthesis by activating PXR.

[An effect of mexidol on the expression of the transcription factor Nrf2 in the rat cerebral cortex in ischemia]. / Vliianie meksidola na ékspressiiu transkriptsionnogo faktora Nrf2 v kore bol'shikh polusharii golovnogo mozga pri éksperimental'noi ishemii.

AIM: To study an effect of the antioxidant and antihypoxant mexidol (ethylmethylhydroxypyridine succinate) on the transcription factor Nrf2 expression in neuronal nucleis of frontal cortex cells autor the common carotid artery unilateral occlusion. MATERIAL AND METHODS: The study was performed on 64 male Wistar rats. The Nrf2 expression was determined immunohistochemically. RESULTS: Single intraperitoneal mexidol (120 mg/kg b.w.) infusion and oral (100 mg/kg p.w. thrice a day for 14 days) administration of mexidol did not affect Nrf2 expression. Unilateral common carotid artery occlusion led to the increase in Nrf2 expression 4 h and 5 days after occlusion. Oral administration of mexidol in dose of 100 mg/kg b.w. thrice a day for 14 days before and after ischemia increased Nrf2 expression on the 4th h and on the 12th day in comparison with intact animals. Nrf2 expression was higher after 4 h and 12 days in comparison with the control occlusion group. CONCLUSION: Mexidol increases Nrf2 expression in the frontal cortex of rats not under normal conditions but in common carotid artery unilateral occlusion.

[Mexidol effect on the factor induced by hypoxia HIF-1α expression in the rat cerebral cortex in ischemia]. / Vliianie meksidola na ékspressiiu faktora, indutsiruemogo gipoksiei HIF-1α, v kore bol'shikh polusharii golovnogo mozga krys pri ishemii.

The aim of the research - to study the Mexidol (ethylmethylhydroxypyridine succinate) effect on the factor induced by hypoxia (HIF-1α) expression in the frontal cortex of the brain in its ischemia. MATERIAL AND METHODS: The work was performed on the 64 male Wistar rats. The expression of HIF-1α was determined immunohistochemically. RESULTS AND DISCUSSION: It is determined that single intraperitoneal administration of Mexidol at a dose 120 mg/kg and oral administration at a dose 100 mg/kg three times a day for 14 days is not affected the expression of HIF-1α. Unilateral occlusion of the common carotid artery increases the expression of HIF-1α at 4 hours after the occlusion. Oral administration of Mexidol at a dose 100 mg/kg three times a day for 14 days before and after ischemia increases the expression of HIF-1α after 4 and 12 hours in comparison with the norm, on the 5th day in comparison with occlusion control. Thus, it has been established that Mexidol increases the expression of HIF-1α in the frontal cortex of rat brain not under normal conditions, but in unilateral occlusion of the common carotid artery.

[A role of P-glycoprotein in neurology]. / Rol' glikoproteina-R v nevrologii.

On the basis of the analysis of literature data, the authors show a role of P-glycoprotein in the pathogenesis, pharmacotherapy and a prophylaxis of neurologic diseases (Alzheimer's disease, Parkinson's disease, epilepsy, stroke).

[The distribution of mexidol in the rat's brain and its subcellular fractions].

OBJECTIVE: To study the penetration of mexidol through the blood-brain barrier into different brain compartments and cell mitochondria. MATERIAL AND METHODS: The study was carried out on adult male Wistar rats using the drug mexidol ("Farmasoft" Russia). The penetration of mexidol into different compartments of the brain (the cortex, cerebellum, thalamus and medulla) and distribution between mitochondrial and cytoplasmic fractions of the cerebral cortex was studied. The concentration of mexidol in blood plasma and brain tissues was measured using HPLC. RESULTS AND CONCLUSION: Mexidol penetrated through the blood-brain barrier into brain compartments of rats with the maximal accumulation in the cortex. In the brain cortex cells, mexidol was identified in the cytoplasmic and mitochondrial fractions.

[Sex differences of P-glycoprotein functional activity and expression in rabbits].

The research consists in the investigation of the sex differences of P-glycoprotein functional activity and expression in Chinchilla rabbits. P-glycoprotein functional activity was assessed by the pharmacokinetics of its probe substrate--fexofenadine after its single oral administration. P-glycoprotein expression was investigated by immunohistochemistry method. It is shown that male's maximal concentration of fexofenadine, its areas under concentration-time curves, half-life and retention time were higher and its clearance was lower than female's. The efficient differences in pharmacokinetic parameters of fexofenadine confirm more intensive excretion and less intensive absorption in gastro-intestinal tract of fexofenadine. This data indicate that P-glycoprotein activity is more active in female than in male. Immunohistochemistry analysis shows that total liver and intestine P-glycoprotein expression is more intensive in females, than in males that correlates with its more active functioning.

[P-glycoprotein: structure, physiological role and molecular mechanisms of modulation functional activity].

In the review of literature the structure, localization and a physiological role of efflux biobiotics and xenobiotics transporter - P-glycoprotein - is characterized, molecular mechanisms of induction and inhibition of its functional activity are systematized.

[A comparative study of mexidol and mexiprim pharmacokinetic parameters]. / Sravnenie farmakokineticheskikh parametrov preparata meksidol s preparatom étilmetilgidroksipiridina suktsinat.

Objective. To compare pharmacokinetic parameters of mexidol (coated tablets, "Farmasoft") and mexiprim (tablets film-coated, "STADA CIS"). Material and methods. The study included 14 adult male Chinchilla rabbits. Concentration of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the blood plasma of animals was analyzed using HPLC with UV detection. Results and conclusion. Mexidol as compared to mexiprim was more completely and rapidly absorbed from the gastrointestinal tract, it was confirmed by the higher value of maximal concentration of 2-ethyl-6-methyl-3-hydroxypyridine succinate and less maximal concentration time after mexidol administration. The drugs had similar excretion that was confirmed by the lack of significant differences in the values of total clearance, half-life, and the average retention time.

Measurements of the neutron dose and energy spectrum on the International Space Station during expeditions ISS-16 to ISS-21.

As part of the international Matroshka-R and Radi-N experiments, bubble detectors have been used on board the ISS in order to characterise the neutron dose and the energy spectrum of neutrons. Experiments using bubble dosemeters inside a tissue-equivalent phantom were performed during the ISS-16, ISS-18 and ISS-19 expeditions. During the ISS-20 and ISS-21 missions, the bubble dosemeters were supplemented by a bubble-detector spectrometer, a set of six detectors that was used to determine the neutron energy spectrum at various locations inside the ISS. The temperature-compensated spectrometer set used is the first to be developed specifically for space applications and its development is described in this paper. Results of the dose measurements indicate that the dose received at two different depths inside the phantom is not significantly different, suggesting that bubble detectors worn by a person provide an accurate reading of the dose received inside the body. The energy spectra measured using the spectrometer are in good agreement with previous measurements and do not show a strong dependence on the precise location inside the station. To aid the understanding of the bubble-detector response to charged particles in the space environment, calculations have been performed using a Monte-Carlo code, together with data collected on the ISS. These calculations indicate that charged particles contribute <2% to the bubble count on the ISS, and can therefore be considered as negligible for bubble-detector measurements in space.

[Results of measuring neutron dose inside the Russian segment of the International Space Station using bubble detectors in experiment Matreshka-R].

Distribution of neutron equivalent dose both inside and outside the spherical phantom (experiment Matryeshka-R) was determined with the help of dedicated research equipment "Bubble-dosimeter". Equipment is built up from an automatic bubbles counter and 8 bubble detectors of neutrons with energy ranging from approximately 200 keV to 15 MeV. Measurements inside the ISS were made in several 7-day sessions in the period from April 2006 till October 2007 (ISS increments 13-15). According to the bubble detectors on the outside of the phantom, ambient neutron dose H*(10) was equal to 0.1 mSv/d or approximately 20% of the dose from charged particles inside the ISS. In the tissue-equivalent phantom, neutron dose was 1.2 +/- 0.2 times less as compared with the phantom surface which characterized the degree of dose attenuation in cosmonaut's body.

[Dynamics of radiation environment of space station "Mir" by the "DOZA-A1" readings]. / Dinamika radiatsionnykh uslovii na orbital'nom komplekse "Mir" po dannym pribora "DOZA-A1".

One of the serious disadvantages of the U.S. (AP-8 and AE-8) and Russian trapped radiation models is the lack of data concerning the dynamics of trapped particles fluences within a time interval shorter than the solar cycle. The available models are capable to predict the energy spectra of trapped particles only for periods in the vicinity of the solar minimum or maximum. The current models are also lacking data about the angular distribution of trapped particles. Meanwhile, these facts are important in conjunction with the problems of radiation safety of space crews. DOZA-A1 incorporating 7 semiconductor detector with a dose sensitivity of 2.4. 10(-4) muGy/pulse and a temporal resolution of 15 seconds, and a reading and charging unit were delivered to MIR in September, 1995; the experiment began in January, 1996. Measurements were made in three locations of the basal module. The articles deals with the analysis and comparison of experimental data with results of other dosimetric determinations and predictions of the trapped radiation models.

[Refinement of technique for cosmonaut's body radiation loading estimation using of orbital station dosimetric monitoring system]. / Sovershenstvovanie metodiki otsenki radiatsionnoi nagruzki na organizm kosmonavta s ispol'zovaniem sistemy dozimetricheskogo kontrolia orbital'noi stantsii.

Proposed is a technique for estimation of radiation loading of cosmonauts' body from the data of the space station radiation monitoring system by bringing the objective to a linear mathematical model. Resulted matrix ratios allow to work out the challenge; test calculations illustrating efficiency of the proposed technique are included.

[Radiation control on Saliut stations using directly indicating dosimeters]. / Radiatsionnyi kontrol' na stantsiiakh "Saliut" s pomoshch'iu priamopokazyvaiushchikh dozimetrov.

Using PPD-2 dosimeters, daily radiation doses were measured in the same site of the Salyut-3. Salyut-4 and Salyut-5 stations (1974-1977). The doses were estimated to be about 13-16 mrad/day. During the flight of the Salyut-6 station (1977-1979) daily doses were measured in different sites and were found to vary significantly. By 1980, due to an increase in solar activity and lack of solar flares, the difference in the daily doses inside the station (except for the transfer module) reached the level of the error of measurements, i. t. +/- 20%.