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Vol 19, No 2 (2021)

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Direct cardial effects and mechanisms of cardiovascular action of gliflosins

Zverev Y.F., Rykunova A.Y.


The literature review is devoted to the study of the mechanisms of the cardioprotective action of a new class of glucose-lowering drugs glyflozins, which inhibit the joint transport of sodium and glucose in the proximal renal tubules. Favorable changes in ion transport in cardiomyocytes with the use of these drugs are considered. The inhibition of the activity of the sodium-hydrogen exchanger (NHE) was found, followed by a decrease in the activity of Na+/ Ca2+ exchange on the mitochondrial membranes of the cardiomyocytes, which leads to a decrease in the concentration of Ca2+ in the cytoplasm with a simultaneous increase in mitochondria. This initiates a number of intracellular signaling cascades that contribute to the optimization of mitochondrial homeostasis. The use of glyflozins, apparently, provides a balance between the fusion and fission of mitochondria, which determines the bioenergetic adaptation of the cell to the state of intracellular metabolism, weakens the development of the inflammatory response, fibrosis and oxidative stress in the myocardium, which are activated under conditions of diabetes mellitus. The point of view is discussed, according to which the mechanism of anti-inflammatory action of glyflozins is associated with inhibition of the activity of the NLRP3 inflammasome, which contributes to the progression of myocardial dysfunction and subsequent chronic heart failure. The results of clinical trials and experimental data on the beneficial effect of glyflozins in the development of various phenotypes of heart failure with reduced and preserved ejection fraction are analyzed. The assumption is substantiated about the prospects for wider use of these hypoglycemic drugs in heart failure, which is not limited to diabetes mellitus. The assumptions made require further experimental and clinical studies.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):131-143
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Biological role of miRNA-146a at virus infections. Modern strategy of search of new safe pharmacological agents for treatment

Shabanov P.D., Vashchenko V.I.


Cellular microRNAs (miRNAs) were identified as a key player in the posttranscriptional regulation of cellular-genes regulatory pathways. Here, we review the current knowledge on the interaction between RNA viruses and cellular miRNAs. We also discuss how cell and tissue-specific expression of miRNAs can directly affect viral pathogenesis. They also emerged as a significant regulator of the immune response. In particular, miR-146a acts as an importance modulator of function and differentiation cells of the innate and adaptive immunity. It has been associated with disorder including cancer and viral infections. Given its significance in the regulation of key cellular processes, it is not surprising which virus infection have found ways to dysregulation of miRNAs. miR-146a has been identified in exosomes (exosomal miR-146a). After the exosomes release from donor cells, they are taken up by the recipient cell and probably the exosomal miR-146a is able to modulate the antiviral response in the recipient cell and result in making them more susceptible to virus infection. In this review, we discuss recent reports regarding miR-146a expression levels, target genes, function, and contributing role in the pathogenesis of the viral infection and provide a clue to develop the new preventive and therapeutic strategies for medical treatment viral disease, and СOVID-19.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):145-174
pages 145-174 views

Temperature, osmotic and acidic activity of infusion solutions as an integral part of their mechanism of action

Urakova N.A.


A review of the literature shows that the physical-chemical properties of infusion solutions can be an integral part of the mechanism of their local action on the routes of administration. This new scientific and practical direction in clinical pharmacology was born at the end of the 20th century in Russia. Initially, it was found that isotonic solutions of glucose, mannitol, and sodium chloride with different temperatures have different local effects on the metabolism and viability of isolated biological objects such as mitochondria and blood plasma. At the same time, it was shown that increasing the temperature of solutions from +37 to +45°C accelerates the metabolism of these biological objects, increases their reactivity and enhances their response to the action of many drugs-activators of metabolism and function. And vice versa, lowering the temperature of these solutions from +37 to +20°C and below (up to 0°C) slows down their metabolism, reduces their reactivity, weakens their response to the action of drugs-activators of metabolism and function, and also increases survival in conditions of ischemia and hypoxia. These results allowed us to recommend warm infusion solutions as universal means of activating aerobic metabolism in tissues and the response of tissues to drugs with local physical-chemical action, and cold infusion solutions as universal means of inhibiting aerobic metabolism in tissues and increasing the resistance of tissues to the action of drugs on them. Following this, it was shown that many infusion solutions do not have isoosmotic activity, since the osmotic activity of drugs is not controlled. Therefore, one part of the solutions has hypotonic activity, and the other part has hypertonic activity. Therefore, sometimes the infusion solution can increase the hypoosmotic or hyperosmotic activity of the blood plasma. Then it was shown that the absolute majority of infusion solutions do not have a pH of 7.4. At the same time, very many infusion solutions have acidic activity, so they have an acidifying effect on the blood. The chronology of the development of inventions based on the achievements of the physical-chemical pharmacology of infusion agents is shown.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):175-182
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Original articles

Participation of HIF-1 in the mechanisms of neuroadaptation to acute stressful exposure

Lyubimov A.V., Khokhlov P.P.


BACKGROUND: New laboratory and instrumental technologies for analyzing the adaptive capabilities of a biological organism to acute stressful effects including hypoxic ones have significantly facilitated the diagnosis and fixation of adaptive behavioral reactions, physiological and biochemical changes. Much attention has been paid to the phenomenon of preconditioning — a positive effect from exposure to small doses of pathogenic factors. Hypoxia-inducible factor 1 (HIF-1) is one of the most promising markers for fixing the phenomenon of hypoxic preconditioning.

AIM: To study the mechanisms of neuroadaptation to acute stressful effects.

MATERIALS AND METHODS: Using models of immobilization, hypothermic exposure, and electrocutaneous irritation of rat paws were carried out for the assessment of the mechanisms of neuroadaptation. Changes in the HIF-1 concentration were recorded in the blood and in the structures of the brain.

RESULTS: The maximum concentration of HIF-1 was found in the amygdala (±230 pg / mg), in the prefrontal cortex it was ±50.8 pg / mg in the control group. Hypothermal exposure increased the HIF-1 content in the amygdala by more than 4 times, while emotionally pain and immobilization showed a slight decrease in HIF-1 in the amygdala. All types of stressors significantly increased the concentration of HIF-1 in the prefrontal cortex of animals. The most pronounced changes were observed when using the model of emotional pain stress. The obtained experimental data allow us to draw with caution a conclusion about the universality and unity of multicomponent mechanisms of adaptation to acute stressful effects.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):183-188
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Effect of neuropeptide Y antagonist BMS193885 on overeating and emotional responses induced by social isolation in rats

Lebedev A.A., Moskalev A.R., Abrosimov M.E., Vetlugin E.A., Pshenichnaya A.G., Lebedev V.A., Evdokimova N.R., Bychkov E.R., Shabanov P.D.


BACKGROUND: Chronic stress of social isolation is associated with an increased risk of mental illness, such as atypical depression, and is usually accompanied by hyperphagia and weight gain. We have previously shown that the NPY antagonist Y1R BMS193885 reduces the conditioned place preference of ethanol. The involvement of NPY receptors in non-chemical forms of addiction is assumed.

AIM: Was to analyze the effects of NPY Y1R BMS193885 on emotional responses and elements of bindge eating in rats caused by rearing in social isolation.

MATERIALS AND METHODS: We used the tests “open field”, “elevated plus maze”, Porsolt’s forced swimming test, “resident intruder” test and method of conditioned eating test in well-fed rats.

RESULTS: The level of depression, negative emotionality and locomotor activity increased in rats reared in isolation. After intranasal administration of BMS193885 high locomotor activity was maintained, but investigating activity increased in isolated rats. Isolated animals showed an increase in body weight at the 6th week of life. By to the 9th week, the body weight of the isolated rats was significantly higher than in animals reared in the community (р ≤ 0.05). Intranasal administration of 20 μg BMS193885 for 1 week caused a decrease in feed intake in both groups of animals (р ≤ 0.05). Isolated rats began to consume the same amount of food as animals reared in the community after administration of 0.9% NaCl solution. At the same time, elements of bindge eating were observed in the study of the conditioned food test in satiated isolated rats, which did not appear after 1 week of intranasal administration of 20 μg of BMS193885.

CONCLUSIONS: The data obtained prove that rats reared in isolation can be considered as a potential model for binge eating, the basis for metabolic imbalance caused by individual housing in rodents. These considerations are of particular relevance when evaluating the effectiveness of drugs, diet, or other interventions for metabolic health and depressive disorders.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):189-202
pages 189-202 views

Reactive changes of gastric mucosa and reduction of desacyl grelin in rat brain due to psychoemotional stress

Raptanova V.A., Droblenkov A.V., Lebedev A.A., Bobkov P.S., Khokhlov P.P., Thyssen I.Y., Lisovskiy A.D., Bychkov E.R., Shabanov P.D.


BACKGROUND: The work is devoted to the analysis of the elements the reactivity of grelin system in the model of psychogenic stress. In recent years, it has been shown that the ghrelin brain system is not limited only to the regulation of energy balance and eating behavior. Along with other peptide regulatory systems, it plays an important role in the mechanisms of stress, reward and addiction. Therefore, the elements of this system should be considered primarily as molecular targets of pharmacological action in order to correct the states of addiction and post-stress disorders.

MATERIALS AND METHODS: To produce psychoemotional stress, we used an acute single traumatic situation in male Wistar rats. The animals were placed in the tiger python, one animal died as a result of its nutritional needs, the rest of the rats experienced the death of a partner. One week after exposure to python, the animals were decapitated, and the brain structures were isolated. Aliquots of the brain structures suspensions were examined for the content of desacyl ghrelin (DAG) using a highly sensitive enzyme-linked immunosorbent assay (ELISA). In another group, rats were decapitated on the 4th day after exposure to python, stomachs were removed, which were fixed in 10% formalin solution. In horizontal paraffin sections of the gastric mucosa, after staining with hematoxylin and eosin, the heights of superficial and dimple mucous cells, the height of the dimple stroma, the area of superficial, dimple mucocytes and stroma of the dimples, and the number of dead mucocytes were calculated. To clarify the differentiation of epithelial cells, they were stained with alcian blue

RESULTS: DAG was detected in all studied brain structures: amygdala, hippocampus, and hypothalamus. The highest concentration of DAG was noted in the hypothalamus (p < 0.05), which may serve as an indirect confirmation of the data on the presence of ghrelin-containing neurons in the nuclei of the hypothalamus. After exposure to stress, a sharp decrease in the level of DAG was observed in all studied brain structures (8–12 times, p < 0.01): amygdala, hippocampus, and hypothalamus. It has been established that the experience of the stress of the death of a partner is expressed by erosive inflammation of the gastric mucosa, the death of many mucous cells, and an increase in mucus production in viable epithelial cells.

CONCLUSION: Psychoemotional stress completely suppresses the content of desacyl ghrelin of the brain in rats, which may be based on both a disturbance of the central mechanisms of limbic regulation and a violation of peripheral mechanisms, in particular, reactive changes in the gastric mucosa.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):203-210
pages 203-210 views

Clinical pharmacology

Assessment of retinal photosensitivity as an objective indicator of expression psychodense effect

Ovanesov K.B., Shabanov P.D.


BACKGROUND: The retina of the eye, with its wide range of neurotransmitter systems, can be the point of application in the action of the psychotropic drugs, given their synaptotropic properties.

MATERIALS AND METHODS: In this regard, a complex of studies was carried out with the participation of volunteers to assess the effect of psychotropic substances with a depressing (melatonin, grandaxin, motherwort tincture) type of action on the functional state of the retina, registered by the campimetric method. In the course of the research, the photosensitivity of the retina and its ability to distinguish colors were evaluated. Moreover, the capabilities of the technique made it possible to assess retinal activity in the field of view from 0 to 21°. Such an approach can not only demonstrate the interest of retinal cellular elements in the action of substances, but also raise the question of the participation of the visual system in the psychopharmacological effect more broadly.

RESULTS: The work of the visual apparatus was studied both in healthy volunteers of different ages and in persons with emotional disorders, which were identified using special questionnaire tests. It was found that violations of the emotional status are often accompanied by a limitation of the photosensitivity of the retina of varying severity. These facts can be interpreted in different ways. On the one hand, violations of visual functions can lead to psychoemotional disorders and be a pathogenetic link in their development, and on the other hand, primary disorders of retinal light and color sensitivity can provoke the development of psychopathology. However, regardless of the pharmacological characteristics of the studied drugs with psychodeprimating activity, the connection between their anti-anxiety effect and changes in visual function seems to be obvious, which allows us to raise the question of the advisability of taking into account the photosensitivity of the retina for a comprehensive assessment of both the mental state of emotionally labile subjects and the pharmacodynamics of psychodemitting drugs.

CONCLUSIONS: Thus, it is legitimate to conclude that taking into account the light and color sensitivity of the retina can be one of the quantitative criteria for the severity and effectiveness of psychopharmacotherapy.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):211-220
pages 211-220 views

Long-term effectiveness and safety of antiepileptic drugs in children and adults

Shaimardanova R.M., Gamirova R.G.


AIM: To conduct a retrospective comparative analysis of the efficacy and safety of epilepsy therapy with antiepileptic drugs.

MATERIALS AND METHODS: The analysis of the treatment of 428 patients with epilepsy at the Children’s City Hospital No. 8 in Kazan, receiving antiepileptic drugs.

RESULTS: It was found that valproic acid is more effective in the treatment of idiopathic generalized epilepsies compared to focal epilepsies (p = 0.0006). Valproate and carbamazepine were the most effective in the treatment of focal epilepsy with short- and long-term follow-up. Valproic acid is more effective than topiramate (p = 0.02), oxcarbazepine (p = 0.003), and levetiracetam (p = 0.003) in the treatment of focal epilepsy in short- and long-term follow-up. Carbamazepine is more effective than topiramate (p = 0.01), oxcarbazepine (p = 0.02), and levetiracetam (p = 0.001) in the treatment of focal epilepsy in long-term follow-up. It was revealed that more often they complained about side effects when using carbamazepine (63.2%). Levetiracetam was found to be better tolerated compared to valproate (p = 0.0006) and carbamazepine (p = 0.0006). Topiramate is better tolerated than carbamazepine (p = 0.02) and valproate (p = 0.03). Oxcarbazepine is better tolerated than carbamazepine in women (p = 0.04).

CONCLUSIONS: When choosing an antiepileptic drug, it is necessary to be guided by the principle: first the basic, and then the drugs of the next generations, in the future, rely on information about the tolerability of the drug. It is necessary to evaluate the therapeutic effect of antiepileptic drugs with long-term observation, and use the criterion of “complete absence of seizures” as an indicator of the effectiveness of drugs.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):221-228
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Pharmacoeconomical aspects of chemotherapy in children at high risk of tuberculosis

Novikov V.E., Usacheva N.E., Ponamareva N.S., Myakisheva T.V.


AIM: of the study is to analyze the results of pharmacoeconomical studies of preventive chemotherapy in children from high-risk groups of tuberculosis to optimize measures for the prevention of tuberculosis infection in children.

MATERIALS AND METHODS: Collection, systematization and analysis of data from the scientific literature and the results of their own research on the relevant problem.

RESULTS: On the problem of chemoprophylaxis of tuberculosis infection in children from high-risk groups, there is insufficient information on the pharmacoeconomical aspects of this problem. Most studies include a pharmacoeconomical assessment of the management of adult patients with tuberculosis infection. There are isolated scientific papers devoted to the pharmacoeconomical analysis of the preventive treatment of latent tuberculosis infection (LTI) in children. Different clinical and economic efficiency of the applied methods of immunodiagnostics and regimens of chemoprophylaxis of tuberculosis in children is shown. To improve the epidemic situation of tuberculosis among children, it is important to improve preventive chemotherapy regimens. Their effectiveness is largely determined by the sensitivity of Mycobacterium tuberculosis (MBT) to anti-tuberculosis drugs (PTP) and the rational choice of a chemotherapy regimen. The current chemoprophylaxis regimens for children with LTI do not take into account the sensitivity of MBT to PTP at a possible source of infection.

CONCLUSION: The analysis shows the high relevance of pharmacoeconomical studies and the practical significance of the results of such studies for optimizing preventive chemotherapy in children from high-risk groups for tuberculosis. Scientific research on the assessment of the clinical and economic effectiveness of various regimens of chemoprophylaxis of tuberculosis in children allows us to identify the most effective and least expensive ways to prevent tuberculosis through the rational use of medicines and methods of immunodiagnostics.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):229-235
pages 229-235 views


Effect of the extract of dry Serratula centauroides on the behavior of white rats in tests with positive reinforcement

Razuvaeva Y.G., Markova K.V., Toropova A.A., Olennikov D.N.


The effect was studied of dry leaf extract of Serratula centauroides L. on the behavior of white rats (Wistar) in tests with positive reinforcement. It was revealed that the extract of S. centauroides at doses of 50–200 mg/kg promotes in animals a decrease in the level of anxiety, adaptation to unfamiliar conditions, and as a consequence, to an increase in the volume of food intake. And also a more rapid formation of a conditioned reflex with positive reinforcement. In animals treated with S. centauroides extract, the volume of food taken in “hypophagia” test was 1.4–2.7 times higher than the control value. In the T-shaped maze, 50–80% of the animals in the experimental groups developed a conditioned reflex to positive reinforcement, while none of the animals in the control group reached the learning criterion. The S. centauroides extract showed the most pronounced effect on the behavior of animals in tests with positive reinforcement at a dose of 100 mg/kg.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):237-242
pages 237-242 views

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