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УДК 616-001.8:615.355
NEW PHARMACOLOGICAL APPROACHES TO PREVENTION OF ACUTE HYPOXIC HYPOXIA © Evseev A.V.1, Surmenev D.V.1, Evseeva M.A.1, Belenky A.E.2,Tikhonov V.G.1
1Smolensk State Medical University, 28, Krupskoj St., 214019, Smolensk, Russia
Medical and Sanitary Unit of the Ministry of Internal Affairs of Russia in the Bryansk Region, 16a, Gorkogo St., 241050, Briansk, Russia
Abstract
Objective. To confirm the antihypoxic action of the metal-complex (Zn2+) compound л02721 in experiments on rats on the model of acute hypoxia with hypercapnia (AH+Hc). The substances for comparison were 2 antihypoxants of the aminothiol origin - Amtizole and Sunazole and metal-complex compound nQ1983 with confirmed antihypoxic effect.
Methods. Experiments were performed on 182 male rats of Wistar line weighing 150-170 g. The study of antihypoxic activity of substances was carried out on the model the AH+Hc. The condition of acute hypoxia in rats was roduced by placing them in glass airtight containers with a free volume of 1.0 L. the antihypoxic effect was evaluated by the life expectancy of animals in the described conditions. Substances nQ2721, nQ1983, Amtizole and Sunazole were administered once intraperitoneally at doses of 25, 50 and 100 mg/kg. Previously each substance was dissolved in 0.9% NaCl (1.0 ml). Testing the effectiveness of the substances on AH+Hc model was carried out 1 h following the administration of the substances and in 24 h. The control groups animals were injected with 1.0 ml of 0.9% NaCl. In animals exposed to test AH+Hc 1 h following the administration, measurements of the rectal temperature before the experiment and 1 h following the administration, i.e. before AH+Hc were performed. In the animals selected for 24-hour observation, rectal temperature was measured before the experiment, and then after 1, 3, 6, 12, 18 and 24 h of observation, after which they were exposed to AH+Hc.
Results. The antihypoxic effect of a selenium-containing substance nQ2721 based on Zn2+ was confirmed in experiments on rats. In a number of substances of comparison the nQ2721 proved its increased effectiveness. It was found that 1 h following the administration at a dose of 50 mg/kg nQ2721 has an more pronounced activity in comparison to all the studied compounds, including antihypoxant with succinate Sunazole. An important advantage of the new promising antihypoxic agent was the preservation of its action for 24 hours after injection.
Conclusion. In the experiment on rats, the antihypoxic effect of nQ2721 was fully confirmed. In a number of substances of comparison substance nQ2721 proved its higher effectiveness. It was found that 1 h following the administration at a dose of 50 mg/kg nQ2721 has an more pronounced activity in comparison to all the studied compounds, including antihypoxant with succinate Sunazole. An important advantage of the new promising antihypoxic agent was the preservation of its action for 24 hours after injection.
Keywords: acute hypoxia, metal-complex compounds antihypoxants, rats
НОВЫЕ ФАРМАКОЛОГИЧЕСКИЕ ПОДХОДЫ В ПРОФИЛАКТИКЕ ОСТРОЙ ГИПОКСИЧЕСКОЙ ГИПОКСИИ
Евсеев А.В.1, Сурменев Д.В.1, Евсеева М.А.1, Беленький А.Э.2, Тихонов В.Г.1
'Смоленский государственный медицинский университет, Россия, 214019, Смоленск, ул. Крупской, 28 2ФКУЗ «Медико-санитарная часть МВД России по Брянской области», Россия, 241050, Брянск, ул. Горького, 16а
Резюме
Цель. Продемонстрировать в опытах на крысах на модели острой гипоксии с гиперкапнией антигипоксическое действие металлокомплексного ^п2+) соединения л^2721. В качестве веществ сравнения были использованы антигипоксанты аминотиолового происхождения - амтизол и суназол, а также металлокомплексное соединение л^1983 с доказанным антигипоксическим действием.
Методика. Опыты выполнены на 182 крысах-самцах линии Wistar массой 150-170 г. Изучение антигипоксической активности веществ осуществляли на модели ОГ+Гк. Состояние острой гипоксии у крыс формировали, помещая их в стеклянные герметичные ёмкости со свободным
объёмом 1,0 л. Антигипоксический эффект оценивали по продолжительности жизни животных в описанных условиях. Веществал^2721, л^1983, амтизол и суназол вводили однократно внутрибрюшинно в дозах 25, 50 и 100 мг/кг. Предварительно каждое вещество растворяли в 0,9% КаС1 (1,0 мл). Тестирование эффективности веществ на модели ОГ+Гк проводили спустя 1 ч. после введения веществ и спустя 24 ч. Животным групп контроля инъецировали 1,0 мл 0,9% КаС1. У животных, подвергавшихся испытанию ОГ+Гк через 1 ч. после введения, проводили замеры ректальной температуры перед началом опыта, а также через 1 ч. после введения, т.е. перед ОГ+Гк.У животных выбранных для 24-часового наблюдения, измеряли ректальную температуру перед началом опыта, а затем через 1, 3, 6, 12, 18 и 24 ч. наблюдения, после чего подвергали воздействию ОГ+Гк.
Результаты. В опытах на крысах был подтвержден антигипоксический эффект селенсодержащего соединения на основе 2и2+ л^2721. В ряду веществ сравнения соединение л^2721проявило себя не только как равноэффективное. Установлено, что через 1 ч. после введения в дозе 50 мг/кг л^2721 превосходит все изученные соединения, включая и содержащий сукцинат антигипоксант суназол. Важным преимуществом нового перспективного антигипоксического средства явилось сохранение его действия на протяжении 24 ч.
Заключение. Экспериментально на крысах был подтвержден антигипоксический эффект л^2721. В ряду веществ сравнения соединение л^2721проявило себя не только как равноэффективное. Установлено, что через 1 ч. после введения в дозе 50 мг/кг л^2721 превосходит все изученные соединения, включая суназол. Важным преимуществом нового антигипоксического средства явилось сохранение его действия на протяжении 24 ч.
Ключевые слова: острая гипоксия, металлокомплексные соединения, антигипоксанты, крысы
Introduction
The problem of pharmacological protection of the organism from complications caused by sudden oxygen deficiency, despite significant achievements in this field, remains relevant today. The most frequently exposed to acute hypoxia are people who are related to extreme activities [17]. Acute hypoxic hypoxia may occur during the operation of aircraft, submarines, in the event of failure of systems that provide the supply or regeneration of air in closed spaces.
In many studies, it is noted that adaptation to acute hypoxia can be carried out by changing the level of the activity of various functional systems of the body, and is aimed primarily at the delivery of oxygen to brain cells [11]. It should be noted that under these conditions, the general orientation of adaptation processes does not exclude the possibility of parallel negative reactions. In this regard, as an integral criterion of adaptation of the organism to the lack of oxygen, the indicator of the life expectancy of the organism in the hypoxygenated environment is usually used [8].
Many authors assume that an effective way to increase the human survival in conditions of acute hypoxic hypoxia is to limit physical activity that reduces the consumption of oxygen and substrates for biological oxidation [13, 14, 18]. The decrease in metabolism can also be achieved through the use of pharmacological substances from the class of antihypoxants. Derivatives of aminothiols - Amtizole and its succinate modification Sunazole proved their effectiveness. Unfortunately, ready-made dosage forms of these compounds are still not available, which requires further research.
In the last 10 years high antihypoxic activity of metal-complex compounds containing various endogenous biologically active substances (vitamins, antioxidants, amino acids, etc.) as ligands [1,12] was revealed. For the first time the synthesis of such compounds was carried out in Russia by E. Parfenov in the end of the XX century, and the substances themselves, marked with the laboratory code "nQ", were initially defined by the author as physiologically compatible antioxidants (PCAO) [16]. In the course of studying PCAO of various groups besides the antihypoxic effect, other types of their biological activity were found. However, the antihypoxic effect of metal-complexes was especially noticeable and often surpassed in this respect the known antihypoxants. The main disadvantage of PCAO in their use as antihypoxic agents is their high toxicity.
Nevertheless, during the search of low-toxic metal-complex compounds, it was found that the compounds containing metal-complexing agent Zn2+, and part of ligand (ligands) - selenium, presented the most successful combination of activity-toxicity. For example, in experiments on mice, nQ2721 compound at a dose of 50 mg/kg increased the life expectancy of animals in acute hypoxia with hypercapnia (AH+Hc) by almost 3 times, which is 20% higher than the effect of the standard Amtizole used in the same dose [2]. It is important to note that often obtained in the experiments on mice, the results of the screening are not reproduced or reproduced to a small extent in larger animals, e.g. in rats. In this regard, the aim of the
study was to confirm in experiments on rats antihypoxic action of metal-complex (Zn2+) compound nQ2721, which turned out to be the most effective of 11 selenium-containing substances previously studied in experiments on mice. It was also necessary to compare its activity with the activity of reference compounds - Amtizole and Sunazole, to the antihypoxic effect of the substance nQ1983 studied a few years earlier.
Methods
Experiments were performed on 182 male rats of Wistar line weighing 150-170 g. As previously in experiments on mice, the study of antihypoxic activity of substances was carried out on the AH+Hc model [4]. The condition of acute hypoxia was produced in rats by placing them in glass airtight containers with a free volume of 1.0 L. In the described conditions, the life expectancy of animals was an indication of the antihypoxic effect. After the second agonal breath, the death of rats was recorded.
During the experiments, the rats were injected once intraperitoneally 4 substances, namely nQ2721, nQ1983 (tab. 1, fig. 1), Amtizole and Sunazole (fig. 2) at doses of 25, 50 and 100 mg/kg. Each substance was dissolved in 0.9% NaCl (1.0 ml) before injection. Each group included 7 rats. Testing the effectiveness of substances on the AH+Hc model was carried out after 1 h after the injection of substances (12 groups) and after 24 h (12 groups). Animals of 2 control groups were injected 1.0 ml of
0.9% NaCl.
In animals exposed to test by AH+Hc in 1 h after the injection, measurements of the rectal temperature using electrothermometry, immediately before the start of the experiment and 1 h following the injection,
1.e., before AH+Hc were carried out. In animals selected for 24-hour observation, rectal temperature was measured just before the experiment, and then after 1, 3, 6, 12, 18 and 24 hours of observation. Then they were exposed to AH+Hc.
Table 1. Genera characteristics of selenium-containing complex zinc compounds nQ2721 and nQ1983
Laboratory code Ligand 1 Ligand 2 Base Cation
nQ2721 Diselendipropionic acid Acetic acid - Na
nQ1983 3-Hydroxy-2- ethyl-6-methylpyridine - Dibenzylselenide -
Statistical processing of the received data was carried out with the help of Microsoft Excel 2010 and Statistica 7 application packages. Comparison of the significance of the differences in the results was performed using the nonparametric Wilcoxon criterion. The differences between the compared parameters were considered reliable at p<0.05.
[ZnODhAôBî 15,5H20 A 8
Fig. 1. Structural formula of the substance nQ1983 - hexaxis(3-hydroxy-2-ethyl-6-methylpyridine)[tris(dibenzyldiselenid)]dizinc(II)pentadecasemihydrate. A and B - ligands consist of a complex molecule [7]
Fig. 2. Structural formulae: (A) Amtizole (3,5-diamino-1,2,4-thiadiazolum), (B) succinic acid (ethane-1,2-dicarboxylic acid)
Results
In one way or another in relation to rats, the protective effect of all the included in the study substances was established. The life expectancy of the animals in both control groups was 1 h and 24 h 38.33±3.47 and 35.96±4.08 min respectively, which does not contradict the literature data [9]. Thus, practically in all series of the experiments with placement of animals in conditions of AH+Hc in 1 h. (tab. 2) we observed dose-dependent action of the substances. At the highest dose (100 mg/kg), Sunazole - Amtizole modified with succinate most clearly demonstaretd its activity. It increased the life expectancy of rats in the conditions of AH+Hc by 2.37 times compared with the control (p<0.001). The closest in efficiency to Sunazole was nQ2721 metal-complex compound with the result of 1.97 times (p<0.005). At the same time, at a dose of 50 mg/kg, their protective effect was leveled, and at a dose of 25 mg/kg nQ2721 still had an effect (+17.6%; p<0.05), while Sunazole lost its activity. It should be noted, that both compounds 1 h following the injection reduced the rectal temperature to 31.5OC, i.e. 5.5OC lower than the norm.
The relatively insignificant results were demonstrated by the nQ1983 substance and antihypoxant Amtizole. At a dose of 100 mg/kg, the tested compounds increased rat life expectancy by an average of 1.7 times, and decreased the rectal temperature by 3.2 and 4.5°C., respectively. Being injected in doses of 50 and 25 mg/kg, they lost their protective effect simultaneously with the ability to cause hypothermia.
Interesting were the results of the experiments, which evaluated the possibility of preserving the effect of the compounds during the day (table 3). According to the dynamics of rectal temperature (measured 5-times for 24 h) only the nQ2721 substance after injection at a dose of 100 mg/kg provided the phenomenon of hypothermia in the final part of the experiment (-2.2°C), which affected the ability of rats to resist AH+Hc. Life expectancy of the animals in this group was 75.38±4.77 min, which is 23% more than the control parameter 35.96 ±4.08 min (p<0.05). The effect was statistically insignificant at lower doses. Other substances in 24 h after injection were ineffective as the protectors of AH+Hc.
Table 2. Effect of substance nQ2721 and substances for comparison (nQ1983, Amtizole, Sunazole) on the dynamics of rectal temperature and life expectancy of rats undergoing acute hypoxia with hypercapnia 1 h after intraperitoneal injection. There are ^ 7 animals in each group. __
Groups Dose, mg/kg Rectal temperature just before injection (M±m) Rectal temperature 1h after injection (M±m) Temperature difference Life expectancy, min (M±m)
Control (one group) - 37.0±1.9 36.8±1.6 -0.2 38.33±3.47
nQ2721 (three groups) 25 50 100 36.7±1.6 36.6±1.7 36.9±1.3 35.0±1.5 32.7±1.6** 31.3±2.0*** -1.7 -3.9 -5.6 50.86±3.42* 62.01±4.12* 75.38±4.77**
nQ1983 (three groups) 25 50 100 37.1±1.6 37.0±1.4 36.4±1.2 36.5±1.5 34.9±1.8* 33.2±1.6** -0.6 -2.1 -3.2 45.09±3.03 53.00±3.52* 64.18±4.29**
Amtizole (three groups) 25 50 100 36.8±1.9 36.4±1.5 36.6±1.5 36.7±1.5 35.3±1.4 32.1±1.5*** -0.1 -1.1 -4.5 36.65±2.98 41.27±3.43 65.81±4.26**
Sunazole (three groups) 25 50 100 37.0±1.8 37.0±1.5 36.8±1.7 35.6±1.5 33.5±1.7** 31.4±1.6*** -1.4 -3.5 -5.4 43.11±3.75 54.24 ±3 .85* 91.04±5.66***
Note: *** - p<0.001; ** - p<0.005; * - p<0.05
Discussion
It is known, that primary researches of new pharmacologically active agents are usually carried out by a screening method on small rodents - mice, Mongolian gerbils, etc. [10, 15]. However, literature data and our own results previously obtained, say that the desired effect in relatively large laboratory animals (rats, rabbits) is often much weaker. All this causes the researcher disappointment, especially in case of premature announcement of the discovery in the press.
In this regard, the main objective of this study was to confirm in the exp2e+riment on rats the antihypoxic effect of substance nQ2721 (metal-complex selenium compound with Zn2+ as a metal complexing agent) earlier established in experiments on mice exposed to acute hypoxia with hypercapnia [2].
Interest in substance nQ2721 was explained by the fact that the results of many years of study of antihypoxic properties of metal-complexes led the authors to believe that the effectiveness of this kind of compounds is largely due to the presence of complex II-valence zinc in the structure, and biologically
active substances containing selenium as a ligand (ligands). In the considered case, selenium was integrated in the molecule in the form of Diselendipropionic acid. It should be noted that selenium-containing metallocomplex compounds not only have more pronounced pharmacodynamics in comparison with their metal-free analogues, but also often acquire the ability to penetrate the mucous membranes of the gastrointestinal tract, i.e., to be absorbed. The latter is not typical for most known metal-complex compounds and well-known antihypoxants - Mexidol, Amtizole [6].
Table 3. Effect of substance nQ2721 and substances of comparison (nQ1983, Amtizole, Sunazole) on the dynamics of rectal temperature and life expectancy of rats undergoing acute hypoxia with hypercapnia 24
h after intraperitoneal injection. T here are 7 animals in each group
Dose, mg/kg Rectal temperature just before injection (M±m) Rectal temperature during 24 h after injection Life expectancy, min (M±m)
Groups 1 h (M±m) 3 h (М) 6 h (М) 12 h (М) 18 h (М) 24 h (M±m)
Control (one group) - 36.8±1.9 36.5±1.3 36.6 36.6 36.5 36.4 36.5±1.6 35.96±4.08
nQ2721 (three groups) 25 50 100 37.1±1.5 36.6±1.5 36.8±1.7 34.5±1.7 33.0±1.5 31.6±1.9 35.6 33.4 31.2 36.2 34.2 31.8 36.6 35.0 32.6 36.5 35.9 33.5 36.7±1.4 36.5±1.5 34.6±1.9 38.61 ±3.69 48.43±4.42 55.38±4.72*
nQ1983 (three groups) 25 50 100 37.0±1.8 37.2±1.5 37.2±1.8 36.8±1.9 34.2±1.4 32.8±1.4 36.6 34.6 32.5 36.5 35.8 33.3 36.6 36.2 34.9 36.7 36.9 35.6 36.6±1.9 36.8±1.4 36.3±1.5 35.04±3.72 38.56±3.24 44.22±3.75
Amtizole (three groups) 25 50 100 36.5±1.4 36.8±1.6 37.0±2.0 36.2±1.5 34.7±1.8 32.6±1.4 36.4 34.9 33.4 36.5 35.7 34.1 36.4 36.2 35.6 36.6 36.4 36.4 37.0±1.3 36.7±1.6 36.6±1.6 40.02±3.50 39.18±3.27 38.46±4.09
Sunazole (three groups) 25 50 100 36.7±1.7 36.7±1.8 36.9±1.4 35.1±1.6 34.2±1.8 32.0±1.9 35.7 34.6 32.9 36.2 35.8 33.7 36.3 36.5 34.6 8 36.3 36.8 35.40 36.4±1.8 36.7±1.7 36.1±1.4 37.33±3.28 36.99±3.60 40.60±4.00
Note: * - p<0.05
The experiments was carried out not only to investigate the antihypoxic properties of substance nQ2721, but also to compare its activity with the effect of the already defined as an antihypoxant substance nQ1983, which is a compound of Zn2+ and substituted 3-hydroxypyridine with diorganodihalcogenide -hexaxis(3-hydroxy-2-ethyl-6-methylpyridine)[tris(dibenzyldiselenid)]dizinc(II)pentadecasemihydrate. The substance had previously been tested on mice, rats and cats [7]. In addition, we carried out experiments with the injection of substances known as the standards for this kind of experiments Amtizole and Sunazole. All substances were injected intraperitoneally in typical for antihypoxants doses - 25, 50 and 100 mg/kg.
The second part of the study should be considered important, since it includes an attempt to assess the effectiveness of the studied substances 24 h following the moment of injection. Typically, researchers monitor the development of antihypoxic effect within 1 h after introduction. The data of periodic rectal thermometry were supposed to serve as an indirect confirmation of the activity presence.
As it can be seen from the obtained findings, substance nQ2721 in experiments on rats was effective enough to classify it as an antihypoxant. The substance significantly increased the resistance of animals to the effects of AH+Hc, which in varying degrees of severity was present in other substances. The advantages of the new metal-complexes should include two undeniable facts: (1) higher activity at a dose of50 mg/kg in comparison with other agents; (2) preservation of the effect after 24 hours after administration at a dose of 100 mg/kg, as opposed to substances of comparison.
Results of the study present a new approach to the theory of mechanisms of protective action of pharmacological substances in the formation of acute hypoxic hypoxia. The concept of "optimization" of the dynamics of redox processes in the electron transport chain of mitochondria in conjunction with the limitation of microsomal oxidation in the cells of the body does not stand criticism when it comes to increasing the life expectancy of animals by more than 2 times [3, 4]. Earlier, conclusions were made about the ability of metal-complex compounds based on Zn2+ to reverse the processes of oxidative phosphorylation on the mitochondrial matrix with a decrease in ATP production in brain tissue. The decrease in animal body temperature by 5°C, and sometimes more, should be considered in favor of the antimetabolic hypothesis of the formation of the antihypoxic effect, which is most likely to be provided
by the studied metal-complex compounds. The antimetabolic effect could be the basis of the protective action of antihypoxic derivatives of aminothiol (Amtizole, Sunazole). According to different authors, there are indications about the hypoenergy activity of Amtizole. However, it seem that it will be a challenge to break the stereotypes on which the concept of "positive" influence of antihypoxants of metabolic action on the energy metabolism of the organism is based [9].
Conclusion
Thus, in experiments on rats, the antihypoxic effect of a selenium-containing substance nQ2721 based on Zn2+ was confirmed. Among a number of substances of comparison, nQ2721 revealed a more pronounced effect. It was found that 1 h following the administration at a dose of 50 mg/kg nQ2721showed higher activity in comparison to all studied compounds, including antihypoxant with succinate Sunazole. An important advantage of the new promising antihypoxic agent was the preservation of its action for 24 hours after injection.
The obtained results and literature data suggest that the mechanism of substance nQ2721 action is mainly due to its ability to slow down the speed of metabolic processes that provide energy-synthetic function at the cellular level, which allows the body in conditions of rapidly increasing oxygen deficiency to significantly reduce its consumption and, thereby, successfully resist the rising hypoxic hypoxia.
References
1. Евсеев А.В., Ковалёва В.Л., Крылов И.А., Парфёнов Э.А.Комплексные соединения ^ацетил^-цистеина с биометаллами как факторы самозащиты биологических систем // Бюллетень экспериментальной и биологической медицины. - 2006. - Т.142, №7. - С. 26-30. [Evseev A.V., Kovaljova V.L., Krylov I. A., Parfjonov Je.A. Bjulleten' jeksperimental'noj biologii i mediciny. Bulletin of Experimental Biology and Medicine. - 2006. - V.142, N7. - P. 26-30. (in Russian)]
2. Евсеев А.В., Сурменёв Д.В., Парфёнов Э.А. и др. Тестирование на модели острой гипоксии с гиперкапнией новых металлокомплексных селенсодержащих соединений // Обзоры по клинической фармакологии и лекарственной терапии. - 2017. - Т.15, №4. - С. 46-52.[Evseev A.V., Surmenjov D.V., Parfjonov Je.A. i dr. Obzory po klinicheskoj farmakologii i lekarstvennoj terapii. Reviews of clinical pharmacology and drug therapy. - 2017. - V.15, N4. - P. 46-52. (in Russian)]
3. Зарубина И.В., Шабанов П.Д. Молекулярная фармакология антигипоксантов. - СПб: ООО «Изд. Н-Л», 2004. - 368 с. [Zarubinal.V., ShabanovP.DMolekuljarnaja farmakologij antigipoksantov.Molecular pharmacology of antihypoxants - SPb: OOO «Izd. N-L», 2004. - 368 p. (in Russian)]
4. Лукьянова Л.Д. Биоэнергетическая гипоксия: понятие, механизмы и способы коррекции // Бюллетень экспериментальной биологии и медицины. - 1997. - Т.24, №9. - С. 244-254.[Luk'janova L.D. Bjulleten' jeksperimental'noj biologii i mediciny. Bulletin of Experimental Biology and Medicine.- 1997. - V.24, N9. -P. 244-254. (in Russian)]
5. Методические рекомендации по экспериментальному изучению препаратов, предлагаемых для клинического изучения в качестве антигипоксических средств / Под ред. Л. Д. Лукьяновой. - М., 1990. -19 с. [Metodicheskie rekomendacii po jeksperimental'nomu izucheniju preparatov, predlagaemyh dlja klinicheskogo izuchenija v kachestve antigipoksicheskih sredstv. Methodical recommendations for a pilot study of drugs proposed for clinical studies as antihypoxic substances / Ed. L.D. Luk'janova. - Moscow, 1990. - 19 p. (in Russian)]
6. Сосин Д.В., Евсеев А.В., Парфёнов Э.А. и др. Изучение антигипоксической активности металло-комплексных селенсодержащих веществ после их парентерального и энтерального введения // Обзоры по клинической фармакологии и лекарственной терапии. - 2012. - Т.10, №3. - С. 28-34. [Sosin D.V., Evseev A.V., Parfjonov Je.A. i dr. Obzory po klinicheskoj farmakologii i lekarstvennoj terapii. Reviews of clinical pharmacology and drug therapy. - 2012. - V.10, N3. - P. 28-34. (in Russian)]
7. Сосин Д.В., Парфенов Э.А., Евсеев А.В. и др. Антигипоксическое средство // Патент РФ на изобретение №2472503. Опубликован 20.01.2013. Бюллетень №2. [SosinD.V., Parfenov Je.A., Evseev A.V. i dr. Antigipoksichesko esredstvo. Antihypoxic agent / Patent of Russia Federation N2472503, 20.01.2013. Bjulleten' N2. (in Russian)]
8. Хачатурьян М.Л., Панченко Л.А. Влияние сезона года на устойчивость крыс к гипоксии // Бюллетень экспериментальной биологии и медицины. - 2002. - Т.133, №3. - С. 300-303 [Hachatur'jan M.L., Panchenko L.A. Bjulleten' jeksperimental'noj biologii i mediciny. Bulletin of Experimental Biology and Medicine. - 2002. - V.133, N3. - P. 300-303. (in Russian)]
9. Шабанов П.Д., Зарубина И.В., Новиков В.Е., Цыган В.Н.. Метаболические корректоры гипоксии / Под ред. А.Б. Белевитина // СПб: Информ-Новигатор, 2010. - 912 с. [Shabanov P.D., Zarubina I.V., Novikov
V.E., Cygan V.N. Metabolicheskie korrektory gipoksii.Metabolic correctors of hypoxia / Ed. A.B. Belevitin. -Saint-Petersburg: Inform-Novigator, 2010. - 912 p. (in Russian)]
10. Яснецов В.В., Иванов Ю.В., Карсанова С.К. и др. Исследование противогипоксического действия производных 3-гидроксипиридина у животных с некоторыми видами экспериментальной патологии // Авиакосмическая и экологическая медицина. - 2010. - Т.44, №3. - С. 57-60. [Jasnecov V.V., IvanovJu.V., Karsanova S.K. i dr. Aviakosmicheskaja i jekologicheskaja medicina. Aerospace and environmental medicine.-2010. - V.44, N3. - P. 57-60. (in Russian)]
11. Bok S., Kim Y.E., Woo Y. et al. Hypoxia-inducible factor-1a regulates microglial functions affecting neuronal survival in the acutephase of ischemic stroke in mice // Oncotarget. - 2017. - V.8, N67. - P. 111508-111521.
12. de Souza I.C., Faro L.V., Pinheiro C.B. et al. Investigation of cobalt(III)-triazole systems as prototypes for hypoxia-activated drug delivery // Dalton Transactions. - 2016. - V.45, N35. - P. 13671-13674.
13. Luhker O., Pohlmann A., Hochreiter M., Berger M.M. // European Journal of Applied Physiology. - 2018. -V.118, N4. - P. 865-866.
14. Moore C.M., Swain D.P., Ringleb S.I., Morrison S. The effects of acute hypoxia and exercise on marksmanship // Medicine & Science in Sports & Exercise. - 2014. - V.4, N4. - P. 795-801.
15. O'Neill M.J., Clemens J.A. Rodent models of global cerebral ischemia // Current protocols in neuroscience. -2001. - V.9, N5. - P. 1-25.
16. Parfenov E.A. Zaikov G.E. Biotic Type Antioxidants: The Perspective Search Area of Novel Chemical Drugs" // Utrecht-Boston-Tokyo: PSV, 2000. - 559 p.
17. Whayne T.F. Jr. Cardiovascular medicine at high altitude // Angiology. - 2014. - V.65, N6. - P. 459-472.
18. Zebrowska A., Hall B., Kochanska-Dziurowicz A., Janikowska G. The effect of high intensity physical exercise and hypoxia on glycemia, angiogenic biomarkers and cardiorespiratory function in patients with type 1 diabetes // Advances in Clinical and Experimental Medicine. - 2018. - V.27, N2. - P. 207-216.
Information about the authors
Evseev Andrey V. - Doctor of Medicine, professor, Chief of Normal Physiology Department, Director of Science-Research Center, Smolensk State Medical University. E-mail: hypoxia@yandex.ru
Surmenev Dmitry V. - research worker of Science-Research Center, Smolensk State Medical University. E-mail: surmenevd@rambler.ru
Evseeva Marina A. - Candidate of Medicine, associate professor, Department of Pathophysiology, Smolensk State Medical University. E-mail: hypoxia@yandex.ru
Belenky Albert E. - chief of Medical and sanitary unit of the Ministry of internal Affairs of Russia in the Bryansk region, the Lieutenant Colonel of internal service. E-mail: belenky1967@yandex.ru
Tikhonov Viktor G. - Candidate of Medicine, associate professor, Department of Otorhinolaryngology, Smolensk State Medical University. E-mail: lor_tikhonov@mai.ru
Информация об авторах
Евсеев Андрей Викторович - доктор медицинских наук, профессор, заведующий кафедрой нормальной физиологии, заведующий научно-исследовательским центром ФГБОУ ВО «Смоленский государственный медицинский университет» Минздрава России. E-mail: hypoxia@yandex.ru
Сурменёв Дмитрий Викторович - научный сотрудник научно-исследовательского центра ФГБОУ ВО «Смоленский государственный медицинский университет» Минздрава России. E-mail: surmenevd@rambler.ru
Евсеева Марина Анатольевна - кандидат медицинских наук, доцент кафедры патологической физиологии ФГБОУ ВО «Смоленский государственный медицинский университет» Минздрава России. E-mail: hypoxia@yandex.ru
Беленький Альберт Эдуардович - начальник ФКУЗ «Медико-санитарная часть МВД России по Брянской области», подполковник внутренней службы. E-mail: belenky1967@yandex.ru
Тихонов Виктор Георгиевич - кандидат медицинских наук, доцент кафедры оториноларингологии ФГБОУ ВО «Смоленский государственный медицинский университет» Минздрава России. E-mail: lor_tikhonov@mai.ru
