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Vol 19, No 4 (2021)

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Pathophysiology of miR-146a in lung cancer. Prospects of rising of efficiency of targeted therapy

Vashchenko V.I., Romashova J.E., Shabanov P.D.


Lung cancer is a well-known malignant tumor of the respiratory tract, which has caused a significant level of damage to human health. Micro-RNAs (miRNAs) are tiny, non-coding RNA stem-loop structures with a length of roughly 20–25 nucleotides that function as powerful modulators of mRNA and protein products of a gene. miRNAs may modulate many biological processes involving growth, differentiation, proliferation, and cell death and play a key role in the pathogenesis of various types of malignancies. Several accumulating pieces of evidence have proven that miRNA, especially miR-146a, are crucial modulators of innate immune response sequences. A novel and exciting cancer research field has involved miRNA for the detection and suppression of cancer. However, the actual mechanism which is adopted by these miRNA is still unclear. miRNAs have been used as a cancer-associated biomarker in several studies, suggesting their altered expression in various cancers compared to the normal cells. The amount of expression of miRNA can also be used to determine the stage of the disease, aiding in early detection. In breast, pancreatic, and hepatocellular carcinoma, and gastric cancer, cancer cell proliferation and metastasis has been suppressed by miR-146a. Changes in miR-146a expression levels have biomarker importance and possess a high potential as a therapeutic target in lung cancer. It retards epithelial-mesenchymal transition and promotes the therapeutic action of anticancer agents in lung cancer. Studies have also suggested that miR-146a affects gene expression through different signaling pathways viz: TNF-α, NF-κB and MEK-1/2, and JNK-1/2. Further research is required for understanding the molecular mechanisms of miR-146a in lung cancer. The potential role of miR-146a as a diagnostic marker of lung cancer must also be analyzed. This review summarizes the tumor-suppressing, anti-inflammatory, and antichemoresistive nature of miR-146a in lung cancer.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):359-381
pages 359-381 views

Acute respiratory syndrome-2 (SARS-CoV-2): A solution of hydrogen peroxide and sodium bicarbonate as an expectorant for recanalization of the respiratory tract and blood oxygenation in respiratory obstruction (review)

Urakov A.L., Shabanov P.D.


The immediate cause of death of patients in the final stage of a new coronavirus infection is hypoxia, which develops due to respiratory obstruction. In accordance with the standard of treatment of patients with the most severe atypical pneumonia with COVID-19, artificial lung ventilation and extrapulmonary blood oxygenation are used to preserve their lives. However, these methods do not eliminate airway obstruction, one of the causes of which is mucus hypersecretion. The review shows that a new vector for the search and development of medicines for the drug elimination of hypoxia in respiratory obstruction has been identified in Russia. The high prospects of solutions of hydrogen peroxide and sodium bicarbonate with original physicochemical properties and local mechanisms of action providing urgent recanalization of the respiratory tract and oxygenation of blood in respiratory obstruction caused by blockage of the respiratory tract with thick sputum, mucus, pus and blood are shown. Domestic inventions are indicated, the essence of which is the basis of this scientific direction. Original formulations of solutions of hydrogen peroxide and sodium bicarbonate are given, as well as new technologies for their local application, providing urgent dissolution of mucus, sputum, pus and blood with simultaneous immediate release of oxygen gas.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):383-393
pages 383-393 views

Original articles

Effects of high doses of ouabain on cardiac, respiratory, and motor activity at newborn rats

Kuznetsov S.V., Kuznetsova N.N.


BACKGROUND: In the early postnatal period, the activation of cholinergic regulation was shown to reveal that lead to development of atypical cardiac rhythm in form of alteration of normal and weak bradycardic rhythm and periods of significant bradycardia.

AIM: To study the change in the rhythmic activity of cardiac, respiratory and somatomotor systems after Na+/K+-ATPase blockade by ouabain in rats of 3 and 16 days old

MATERIALS AND METHODS: In 3- (P3) and 16-day-old (P16) rats the change in the rhythmic activity of cardiac, respiratory and somatomotor systems after Na+/K+-ATPase blockade by ouabain was studied.

RESULTS: It was found that injection of the drug at a dose of 3/4 DL50 leads to changes in heart rhythm variability and motor activity pattern, more pronounced on P16. In the motor activity pattern in 3-day-old rats, there is a tendency to a reduction in the rhythms of the near- and multiminute ranges, while in older rats, on the contrary, their enhancement. The coefficient of variation of motor excitation periods decreased by 12% in 3-day-olds and increased by 35% in 16-day-olds. The decrease in heart rate and respiration is comparable in P3 and P16 rats. Heart rhythm disturbances occur in 37% of 3-day-old and 25% of 16-day-old rats; the arrhythmia rate increases 1,7-2-fold more in animals on P16 than on P3.

CONCLUSIONS: The severity of pathological heart rhythm disturbances, including periods of normo/bradycardia, increases with age. Comparison of the character of arrhythmia arising after sodium-potassium pump blockade with pathological heart rhythm observed under conditions of excessive activation of cholinoreactive structures does not allow us to speak about the common mechanisms of their occurrence.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):395-403
pages 395-403 views

Comparative characteristics of antimicrobial activity of water dispersions of silver and gold nanoparticles stabilized with native and synthetic polymers

Shulgina T.A., Zubova K.V., Glinskaya E.V., Nechaeva O.V., Bespalova N.V.


BACKGROUND: The construction and application of antimicrobial drugs on the basis of nanoparticles of metals, silver and gold in particular, are staying casual up to now.

AIM: was to study the spectrum of antimicrobial activity of nanoparticles of silver and gold developed by means of chemical recovery and stabilized with native and synthetic compounds.

MATERIALS AND METHODS: The paper presents the results of a study of the antimicrobial activity of aqueous dispersions of silver and gold nanoparticles against standard and clinical strains of Staphylococcus aureus, which were sensitive to methicillin. Natural (carboxymethylcellulose, sodium oleate) and synthetic (polyvinyl alcohol, sodium dodecyl sulfate, polyazolidylammonium modified with iodine hydrate ions) polymeric compounds were used as stabilizers.

RESULTS: The high antistaphylococcal activity of the studied drugs was established, which depended on the stabilizer used. The highest efficiency of biocidal action was revealed for aqueous dispersions of metal nanoparticles stabilized with polyvinyl alcohol and polyazolidylammonium modified with iodine hydrate ions, which did not depend on the strain differences of microorganisms.

CONCLUSIONS: The results obtained open up prospects for the use of aqueous dispersions of silver and gold nanoparticles as active components in the development of new antiseptic preparations and photosensitizers for antimicrobial photodynamic therapy.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):405-411
pages 405-411 views

Antihypoxic effect of new synthetic derivatives of 7-alkoxycoumarin and 4-aminocoumarin in acute hypobaric hypoxia in rats

Kashirin A.O., Krylova I.B., Selina E.N., Polukeev V.A., Zarubina I.V., Bychkov E.R., Shabanov P.D.


BACKGROUND: Coumarins are naturally occurring molecules with a wide range of pharmacological activities. Their use is limited by difficulties in isolation from plant material, toxicity, and low solubility. The chemical structure of these compounds makes coumarins promising for the synthesis of a large number of derivatives that may have biological activity and be of interest as potential drugs. We had synthesized coumarin derivatives, two of which – IEM-2266 (7-alkoxycoumarin derivative) and IEM-2267 (4-aminocoumarin derivative) – have shown antihypoxic effect in mice in models of hypoxic hypoxia with hypercapnia, histotoxic and hemic hypoxia.

AIM: The aim of this work was to study the antihypoxic effect of new coumarin derivatives IEM-2266 and IEM-2267 under conditions of acute hypobaric hypoxia in rats.

METHODS: The experimental work was performed on male Wistar rats weighing 200–220 g. Acute hypobaric hypoxia was induced in rats by placing them in a flow pressure chamber. Compounds IEM-2266 and IEM-2267 were administered intraperitoneally at the dose 25 mg/kg once 50 minutes before hypoxia. Mexidol® at the dose of 100 mg/kg was used as a reference drug. The antihypoxic activity of the substances was assessed according to the following indicators: 1) lifespan at the critical height 11,000 m; 2) the value of the individual high-altitude threshold; 3) individual resistance to hypoxia calculated from high-altitude threshold, expressed in points; 4) survival at consistently presented heights; 5) determination of the structure of population resistance according to the ratio of animals with low, medium and high resistance to hypoxia.

RESULTS: New coumarin derivatives IEM-2266 and IEM-2267 exhibited antihypoxic activity under acute hypobaric hypoxia conditions. With the use of IEM-2266, IEM-2267, and Mexidol, the lifespan of animals at a critical altitude of 11,000 m increased by 2.4, 5.4, and 4.9 times, respectively, compared with the control, the point based assessment of individual resistance to hypoxia increased by 36, 66 and 67%, the absolute value of high-altitude threshold increased significantly (p < 0.05). Coumarin derivatives changed the structure of population resistance, increasing the proportion of highly resistant animals.

CONCLUSIONS: Thus, the effect of IEM-2267 is comparable, and even exceeds the effect of Mexidol. The 7-alkoxycoumarin derivative IEM-2266 has a moderate, and the 4-aminocoumarin derivative IEM-2267 has high antihypoxic activity in rat AHbH conditions.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):413-420
pages 413-420 views

Lateral hypothalamic self-stimulation with threshold current intensity induces emotional overeating in self-deprivation paradigm in well-fed rats: Role of orexin and dopaminergic systems of the brain

Lebedev A.A., Bessolova Y.N., Efimov N.S., Bychkov E.R., Karpova I.V., Tissen I.Y., Magarramova L.A., Kosyakova G.P., Rusanovskii V.V., Shabanov P.D.


BACKGROUND: Emotional overeating in forms of соmpulsive overeating, or bulimia nervosa, and binge eating disorder (ВED) is underlying the basis of eating disorders. In particular, binge eating disorder is included in ICD-10 as a form of nonchemical dependence.

AIM: The participation of the orexin and dopamine systems of the brain was studied in conditions of food self-deprivation caused by self-stimulation of the lateral hypothalamus.

METHODS: To reproduce the self-stimulation of the lateral hypothalamus, male Wistar rats were trained to press the pedal in Skinner box. After training, rats received a food deprivation, a feeder was placed in the Skinner box, and a conditioned reflex on food reinforcement was developed in rats for 5 days. The food self-deprivation reaction was observed in these rats with a stimulating current intensity of 10% and above the threshold for self-stimulation.

RESULTS: “Hungry” animals pressed the pedal forhypothalamic self-stimulation and did not distract to the feeding trough. Food reactions were observed only when using the threshold current. Then rats received a free access to food, but the animals, pressing the pedal for self-stimulation, continued food intakes for many times and eat up to 60 seeds in 10 minutes of the experiment. Dopamine receptor D2/D3 antagonist sulpiride at doses of 5 and 20 mg/kg ip and orexin receptor antagonists OX1RSB-408124 and OX2R TCS 29 0.5 mg/ml, 20 μl intranasally were used. Sulpiride administration in “fed” rats decreased both the eating behavior and the reinforcing properties of electrical stimulation in food self-deprivation testing. At the same time, SB-408124 administration induced a decrease in the number of seeds eaten, but the number of pedal presses increased. Administration of OX2R TCS 29 had no effect.

CONCLUSIONS: The conclusion was made about the selectivity of the orexin A OX1RSB-408124 antagonist for emotional eating forms compared with the D2/D3 receptor antagonist dopamine sulpiride.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):421-429
pages 421-429 views

Genetic correlates of creativity in military personnel under extreme conditions of the Arctic Zone of the Russian Federation: a pilot study

Spivak I.M., Zhekalov A.N., Glushakov A.I., Lemeshchenko A.V., Nyrov V.A., Trandina A.E., Shapovalov P.A., Zakharchuk A.G., Spivak D.L.


BACKGROUND: The ability of a person in the process of active activity to adapt to changing environmental conditions is largely related to his creative potential. Creativity, like other physical and mental personality traits, has its own genetic base, which has not been sufficiently studied to date. Certain genes involved in this process are regularly described. The search for an association with new candidate genes for the creative potential of practically healthy, young respondents selected for work in the extreme conditions of the North is extremely important in the selection of people for work and service in difficult conditions.

AIM: Search for the correlation of candidate gene polymorphism and the psychological state of the examined.

MATERIALS AND METHODS: The psychological block of the pilot study included determining the degree of creativity, as well as the degree of tension of key psychological defense mechanisms. All the techniques used within its framework are part of the standard psychodiagnostic tools that have been tested in domestic conditions. Genotyping was performed by real-time PCR, determining the corresponding alleles of candidate genes, and then the data were compared by the method of analysis of variance.

RESULTS: As candidate genes, we selected the angiotensin-converting enzyme gene, the serotonin 2A receptor gene, the neurotrophic factor BDNF, and alpha-actinin-3. According to the literature, all these genes are associated with the ability to adapt and / or psychotic states, which suggests their possible connection with creativity. The most interesting results are associated with the polymorphism of the BDNF gene: respondents with the BDNF Val/Val genotype are characterized by the maximum level of creativity and the minimum level of intensity of basic psychological defenses and coping strategies by types of distancing, as well as seeking social support. On the contrary, their maximum level is associated with the Met/Met genotype. Thus, it has been reliably shown that optimal adaptation to extreme external conditions is most likely to be ensured genetically by the presence of the Val / Val genotype, and psychologically by enhanced use of creative ability. The respondents with the ACTN3 RX genotype (with increased cold resistance) are characterized by a minimum level of creativity, and those with the RR genotype – its maximum level. It is also shown that respondents with the ACE DD genotype are characterized by a minimum level of creativity. There were no associations with creativity with the serotonin 2A receptor gene polymorphism.

CONCLUSIONS: The totality of the results obtained as a result of this pilot study allows us to consider a systematic study of creative ability and its molecular biological correlates to be correct and constructive for the development of a fundamental problem of the interaction of molecular biological and psychological mechanisms that provide active adaptation, as well as very expedient for solving the complex. scientific and applied tasks for the selection and correction of the state of persons directed to work in special and / or extreme conditions.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):431-442
pages 431-442 views

Phytopharmacology and Phytotherapy

Comparative study of the effect of Thymus marschallianus Willd. extracts on the cognitive functions of mice in the radial maze

Sheremetyeva A.S., Karetnikova A.Y., Durnova N.A., Derdyuk A.S., Skiba V.I.


BACKGROUND: Cognitive impairment is a problem of modern medicine that affects many areas of society. The search for drugs that can correct these disorders is quite relevant. Of particular interest are substances with minimal side effects, some of which are herbal products.

AIM: Study of the working and long-term spatial memory of mice in the «eight-arm radial maze» test under the influence of repeated administration of Thymus marschallianus Willd. extracts.

MATERIALS AND METHODS: The study was carried out on 36 non-linear male mice, divided into 4 groups – control and 3 experimental. For 7 days, the animals were injected daily intragastrically with caffeine at a dose of 40 mg/kg (1st group), alcoholic extract of Thymus marschallianus Willd. at a dose of 100 mg/kg (2nd group), aqueous extract of Thymus marschallianus Willd. at a dose of 100 mg/kg (3rd group). To assess cognitive function, a radial maze test was used to calculate memory scores.

RESULTS: According to the results of the study, it was found that animals receiving caffeine (40 mg/kg) showed a higher memory score compared to other study groups. The introduction of an aqueous extract of Thymus marschallianus Willd. at a dose of 100 mg/kg (group 3) led to an increase in memory points by the 4th day of testing. In the second experimental group, there were no changes in memory points depending on the administration of an alcoholic extract of Thymus marschallianus Willd. (100 mg/kg).

CONCLUSIONS: The use of caffeine (40 mg/kg) caused the activation of both short-term and long-term memory in mice. Administration of an aqueous extract of Thymus marschallianus Willd. (100 mg/kg) affected working memory and did not induce the formation of long-term spatial memory in animals. An alcoholic extract of Thymus marschallianus Willd. (100 mg/kg) showed minimal effect on the formation of working and long-term spatial memory in mice.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):443-449
pages 443-449 views

Examples of positive phytotherapy of patients with bronchial asthma

Barnaulov O.D., Timosheva Y.A.


The increasing of morbidity with bronchial asthma, allergic respiratory diseases demand active search not only medicamental treatment. The review of foreign articles states successful using plant drugs and methods of traditional medicines. Proper clinical practice confirms the foreign authors results: the phytotherapy of patients with bronchial asthma is high effective and safe method. It is necessary wide scale, state supported measures for introduction phytotherapy to practice.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):451-462
pages 451-462 views


To 90th Anniversary of academician Alexander D. Nozdrachev

Shabanov P.D.


Description of the professional activities and merits of the Russian physiologist celebrating his anniversary.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(4):463-471
pages 463-471 views

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