Vol 17, No 1 (2019)

Reviews
Hypoxia and antihypoxants, focus on brain injury
Shabanov P.D., Zarubina I.V.
Abstract

Experiments on rats showed that the individual resistance of the body to acute hypoxia is of decisive importance in the early recovery period after mechanical craniocerebral trauma. Antihypoxant ethomersol administration (25 mg/kg, 3 days, intraperitoneally) following trauma decreased behavioral impairments in rats with different levels of resistance to acute hypoxia, restored the structure of individual behavior, and prevented metabolic disturbances in the brain. Monotherapy of consequences of craniocerebral trauma with antidepressant pyrazidol (1 mg/kg) produced an anxiolytic effect in animals highly resistant to hypoxia and activating effect on low resistant animals. Treatment with bemithyl, an antihypoxant of benzimidazole structure, in a dose of 25 mg/kg produced a cerebroprotective effect and normalized individual behavioral characteristics, parameters of energy metabolism, and state of the antioxidant system in the brain of highly and low resistant rats. The effect of bemithyl was most pronounced in highly resistant animals. During combined treatment, pyrazidol and bemithyl had an additive effect in animals of both groups. They normalized behavioral reactions and prevented the development of metabolic disturbances in the brain.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):7-16
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Enhancement of physical endurance in animals by means of compounds with thiourea group (review of literature)
Marysheva V.V., Shabanov P.D.
Abstract

At the Department of Pharmacology of the S.M. Kirov Military Medical Academy, Saint Petersburg, Russia, a number of chemical compounds with thiourea group was synthesized and studied pharmacologically for some decades. Of them gutimin and amtizol are the most known for pharmacologists. They were the first antihypoxic drugs, passed clinical investigations and were approved for reanimatology practice. Bemithyl (bemaktor, metaprot) was another known drug used in clinical urgent practice as an antihypoxic drug, it was used in earthquake in Armenia (1988), in military practice in Afghanistan etc. Antihypoxic drugs were shown to possess polyvalent pharmacological activity. This review is devoted to original compounds synthesized at the Department of Pharmacology and containing pharmacophor thiourea group in mono-, bi- and tricyclic structures. The antihypoxic activity was revealed in majority of the compounds of this row. The influence of these compounds on physical activity and endurance in different situations has been considered in the article.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):17-30
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Original articles
Antihypoxic properties of condensed benzimidazole derivatives with antioxidant activity
Spasov A.A., Kosolapov V.A., Anisimova V.A., Zhukovskaya O.N.
Abstract

Hypoxia plays an important role in the vital activity of the organism and practically accompanies any pathology. Hypoxia and tissue ischemia in the early stages are accompanied by the activation of lipid peroxidation. Derivatives of 9-dialkylaminoethyl imidazobenzimidazole with a 3,4-dioxyphenyl substitute showed high antioxidant activity. Therefore, they have been studied for antihypoxic activity in experimental models of hypobaric, histotoxic and hemic hypoxia, as well as in animals pre-typed for resistance to hypoxia, and it was shown that new condensed benzimidazole derivatives with antioxidant activity showed a wide range of antihypoxic activity. The most pronounced protective antihypoxic properties were demonstrated by compound RU-185.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):31-36
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Potentiation of the hypoxic preconditioning effect by antihypoxants
Novikov V.E., Levchenkova O.S., Klimkina E.I., Kulagin K.N.
Abstract

The development of effective methods to increase the organism resistance to hypoxia is an important task of current medicine. One of such methods is preconditioning, as a result of which, a potent mobilization of the adaptive organism abilities occurs under a preconditioning factor action.

Aim. To study the possibility of potentiating of the hypoxic preconditioning effect with help of antihypoxants.

Methods. Evaluation of the effectiveness of combined preconditioning (antihypoxants + moderate hypobaric hypoxia) was performed on experimental models of acute hypoxia with hypercapnia, acute hypobaric hypoxia in mice, and bilateral occlusion of the common carotid arteries in rats. Investigated antihypoxants are amtizol, hypoxen, cobazole, metaprot, mexidol, mildronate, substances under the codes VM-606, pQ-4 and pQ-1104.

Results. PreC with use of amtizol at dose 25 mg/kg, cobazole at dose 30 mg/kg, VM-606, pQ-4 and pQ-1104 at doses 50 mg/kg in combination with moderate hypoxia increased the lifespan of mice in acute hypoxia with hypercapniamodel and acute hypobaric hypoxia from 57 to 170%. Combined preconditioning with amtizol, cobazole and pQ-4 significantly increased the survival rate of rats in cerebral ischemia, amtizol and pQ-4 reduced neurological deficiency in the post ischemic period as well.

Conclusion. Antitipoxants as amtizol, cobazole, VM-606, pQ-4, pQ-1104 potentiate the hypoxic preconditioning effect on acute hypoxia with hypercapnia, acute hypobaric hypoxia and occlusion of the common carotid arteries models, the most significant effect was noted for amtizol and pQ-4. Signal role in the adaptation induction to hypoxia and ischemia by combined preconditioning with use of antihypoxants hypoxia-inducible factor HIF-1α can play.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):37-44
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The impact of the new derivative of nicotinic acid with anti-hypoxic activity on the functions of the central nervous system
Gneushev I.M., Katunina N.P., Novikov V.E., Pozhilova E.V.
Abstract

The aim of the work was to study the effect of the complex compound of nicotine acid with antihypoxic activity under the code πQ-1043 on the function of the central nervous system. The experiments were performed on male mice of the SHR line. Influence of the compound on the function of the central nervous system was evaluated in the tests “open field”, conditioned-defense reflex of avoidance and corazole seizures. It was found that the compound πQ-1043 at a dose of 25 mg/kg increases emotional reactivity and reduces the coefficient of mobility of mice in the “open field” test, increases the latent time of the conditionally defensive reflex of avoidance, inhibits the development of seizures and increases the life expectancy of animals after administration of corazole. Such changes in the studied parameters indicate that the compound πQ-1043 has a depressing effect on the central nervous system function. It is assumed that the identified effect may be one of the components in the mechanism of antihypoxic action of the compound.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):45-52
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II-Valent metals complex compounds and prospects of the acute hypoxia protection
Evseev A.V., Belenky A.E., Surmenev D.V., Evseeva M.A., Sosin D.V.
Abstract

Aim. To find antihypoxic properties in complex compounds of some divalent metals on the model of acute hypoxia with hypercapnia.

Methods. In the experiments on mice in acute hypoxia with hypercapnia (AH+Hc), the protective effect of 6 new complex compounds was studied in comparison with the effectiveness of reference antihypoxants. Substances were injected intraperitoneally 60 min before acute hypoxia with hypercapnia in doses of 25 and 50 mg/kg. Antihypoxic effect was compared with their ability to change the rectal temperature.

Results. The most active substance πQ-2116 with Nickel as a complexing metal was established. Mice resistance to acute hypoxia with hypercapnia at a dose of 25 mg/kg was increased to 89.5%, at a dose of 50 mg/kg – to 165.8%. The effect was accompanied by serious hypothermia, reaching 28.5 °C. Antihypoxic activity of the substance πQ-2116 is comparable with reference substance πQ-1983 and greater than the effect of aminothiol antihypoxants – Amtizole and Sunazole.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):53-56
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Influence of endothelial dysfunction caused by estrogen deficiency on the severity of cerebral ischemia in rats
Tyurenkov I.N., Volotova E.V., Kurkin D.V., Bakulin D.A.
Abstract

The aim of this study was to assess the effect of endothelial dysfunction caused by a decrease in the estrogen level on the severity of cerebral ischemia.

Methods. Endothelial dysfunction was caused by extirpation of the uterus with appendages and was confirmed by counting circulating endothelial cells and evaluating stimulated and basal secretion of nitric oxide. Focal cerebral ischemia was modeled by intravasal occlusion of the middle cerebral artery. The severity of ischemia was assessed according to the scales of neurological deficit (Combs & D’Alecy and McGraw), in the Rotarod test and in terms of the volume of necrosis.

Results. Estrogen deficiency resulted in an increase in the circulating endothelial cells by 88%, as well as a decrease in stimulated and basal nitric oxide secretion by 17.1% and 14.7% respectively. Focal cerebral ischemia in animals with endothelial dysfunction caused by estrogen deficiency resulted in greater cerebral damage, resulting in an increase in the level of neurological deficit on the Combs & D’Alecy and McGraw scales for 7 days, a decrease in the retention time on the rotating rod by 32%, as well as an increase in the infarct volume by 89% relative to the group of animals without sexual hormones failure.

Conclusion. It has been shown that endothelial dysfunction caused by estrogen deficiency complicates the severity of cerebral ischemia, causing a more pronounced neurological and motor deficit, and contributes to an increase in the size of infarct volume.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):57-64
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The possibility of pharmacological correction of disorders arising from cerebral ischemia and paroxysmal conditions. Derivatives of Dibenzofuran
Voronina T.A., Litvinova S.A.
Abstract

The review examines the role of brain hypoxia in the development of stroke and convulsive States and the possibility of using antihypoxants and antioxidants in various hypoxic conditions, including strokes and convulsions; provides information about the original compound from the class of dibenzofuran with antihypoxic, neuroprotective and anticonvulsant action.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):65-70
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Assessment of drugs belonging to inhibitors and inductors of p-glycoprotein in vitro
Yakusheva E.N., Shchulkin A.V., Chernykh I.V., Popova N.M., Kotlyarova A.A., Slepnev A.A.
Abstract

The article describes modern approaches for testing of drugs belonging to substrates and inhibitors of P-glycoprotein (Pgp, ABCB1-protein, MDR1-protein) according to the recommendations of Food and Drug Administration (United States) and European Medicines Agency. In vitro methods on cell lines with hyperexpression of the transporter are presented. The same analysis was done on human colon adenocarcinoma cell line (Caco-2).

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):71-78
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Infrared monitoring of the dynamics of the local temperature as a symptom of adaptation to hypoxia and efficiency of antihypoxic drugs
Urakov A.L.
Abstract

The literature review shows that the general body temperature and the local temperature of individual organs of humans and animals have a significant impact on their reaction to the lack of arterial blood, oxygen and anti-hypoxic and anti-ischemic agents. It is shown that human and animal body organs have different resistance to hypoxia. The least resistant to ischemia and hypoxia is the brain, and it is the first hypoxia damaged cerebral cortex. It is shown that with a lack of oxygen, the death of neurons in the brain can be effectively prevented by timely administration of oxygen to the brain and/or lowering its local temperature. However, to date, no technologies have been developed that provide an immediate increase in the concentration of oxygen and/or a decrease in the local temperature in the brain of people while maintaining their performance. Under these conditions, professor V.M. Vinogradov proposed to find the possibility of extending the life of brain cells in conditions of lack of oxygen using drugs that have been called antihypoxants. Technologies of infrared diagnostics of hypoxia, estimation of reserves of adaptation to it and ways of estimation of efficiency of antihypoxants are described.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):79-86
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Physical rehabilitation and pharmacotherapy of cognitive functions and asthenic disorders in stroke patients
Firileva J.E., Rodichkin P.V., Buznik G.V.
Abstract

The article deals with the state of cognitive functions (memory, attention and thought process) and asthenic disorders in stroke patients in the process of physical rehabilitation and pharmacotherapy. The study used conventional methods for determining the state of cognitive functions. To improve cognitive abilities in the process of physical rehabilitation in the experimental group of patients, traditional methods and special physical exercises in the form of training tasks for memory, attention and thought processes were used. In the control group of patients only traditional methods of restoration of cognitive functions were used. Both groups of patients took the same drugs to improve cognitive function and relieve symptoms of cerebrogenic asthenia, using classic nootropic drugs (Pyracetam, Phenotropil, Vinpotropil), peptide drugs (Cortexin, Cerebrolysin, Noopept, Semax), antidepressants and tranquilizers (benzodiazepines and non-benzodiazepine). It is determined that the most important indicator of memory quality is short-term memory. In the experimental group in the process of physical rehabilitation revealed an improvement in this memory in 50% of patients, the deterioration of this indicator in 34% of persons, and 16% memory remained at the same level. Short-term memory indices in post-stroke patients of the control group are lower and correspond to: improvement – in 35%, deterioration – in 40%, remained at the same level in 25% of patients. Since the rate of short-term memory is 7 ± 2 units of information, the study showed that in all patients after a stroke, the indicators of storing information in short-term memory have become normal. The study of attention stability revealed that in the control group of patients it is worse than in the experimental group, and that the stability of attention does not depend on the experience of the post-stroke state. Patients with 3 years of post-stroke experience show the same results as patients with 6-month stroke. The study of inductive thinking showed that in both groups of patients it is in good condition. As for the indicators of practical mathematical thinking, 83% of the participants coped with the task in the experimental group, and 17% failed. In the control group, 57% of patients coped with this task, and 43% failed. Only 50% of the patients in the experimental group and 42% of the control group coped with a more difficult task in this type of thinking. The same results were obtained in persons without stroke. This shows that the more difficult tasks of identifying this type of thinking are difficult for people after a stroke. It can be concluded that the mental processes of a person after a stroke are in optimal condition.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(1):87-92
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