Vol 8, No 6 (2020)


Mechanisms of cytokine storm development in COVID-19 and new potential targets of pharmacotherapy

Petrov V.I., Amosov A.A., Gerasimenko A.S., Shatalova O.V., Ponomareva A.V., Akinchits A.N., Kulakova I.S., Gorbatenko V.S.


The development of a “cytokine storm”, characteristic of severe COVID-19 forms, can be defined as a state of uncontrolled release of a large number of inflammatory mediators.

The attachment of SARS-CoV-2 S-glycoprotein to angiotensin-converting enzyme 2 is considered a process that triggers complex molecular interactions that lead to hyperinflammation. In its turn, it is realized through several systems: renin-angiotensin-aldosterone, kallikrein-kinin and a complement system. Knowledge of these mechanisms suggests potential therapeutic interventions that can be targeted by existing therapeutic agents to counter the cytokine storm and treat the acute respiratory distress syndrome associated with COVID-19.

The aim of the review article is to summarize the currently known data on the molecular processes underlying the uncontrolled “cytokine storm” in the patients with severe COVID-19, and possible options for their pharmacological correction.

Materials and methods. The data base was represented by such systems as Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, Elibrary, Google-Academy. A search was carried out for the following keywords and combinations: COVID-19, renin-angiotensin-aldosterone system, bradykinin, complement system, hyaluronic acid, pharmacotherapy.

Results. The development of a “cytokine storm” in COVID-19 is mediated by pathogenetic changes in the body in response to the penetration of SARS-CoV-2 into the cell. In the RAAS, suppression of ACE2 leads to a decrease in its ability to degrade ATII, which, on the one hand, leads to a decrease in the amount of AT1-7, and, on the other hand, to the effect of ATII on AT1R with the subsequent development of vasoconstriction and lung damage. The disturbances in the kallikrein-kinin system are associated, on the one hand, with the increased expression of kallikrein and an increase in the formation of bradykinin and its metabolite des-Arg 9-bradykinin. On the other hand, the disturbances are associated with the suppression of the expression of the C1-esterase inhibitor which prevents the formation of kallikrein, and impaired inactivation of des-Arg 9-bradykinin under the action of ACE 2. The nucleocapsid protein SARS-CoV-2 triggers the activation of the complement system through the lectin pathway. It leads to the production of anaphylatoxins C3a and C5a, which stimulate the synthesis of pro-inflammatory cytokines. Proinflammatory cytokines are potent inducers of the HAS 2 gene in the endothelium, which encodes the membrane enzymes of hyaluronate synthase. The sweating of the fluid into the alveoli caused by the “bradykinin storm” in combination with the overproduction of hyaluronic acid, which accumulates water 1000 times its own mass, can lead to the formation of a dense jelly-like substance that prevents gas exchange.

Conclusion. Promising areas of pharmacotherapy for “cytokine storm” are associated with its impact on the dysfunction of the listed above systems. However, the efficacy and safety of most drugs for the treatment of COVID-19, is to be studied through carefully designed clinical trials.

Pharmacy & Pharmacology. 2020;8(6):380-391
pages 380-391 views

Pharmacogenetic bases of individual sensitivity and personalized administration of antiplatelet therapy in different ethnic groups

Kantemirova B.I., Orlova E.A., Polunina O.S., Chernysheva E.N., Abdullaev M.A., Sychev D.A.


Cardiovascular diseases (CVDs) are the leading cause of disability and mortality worldwide. Increased thrombosis is the trigger point for the development of various CVDs and their complications, and therefore, therapy with P2Y12-receptor inhibitors is always pathogenetically justified and vital. However, according to the various data, 10-25% of patients treated with clopidogrel have “resistance” to antiplatelet therapy. The causes for the formation of resistance are still not clear. There is no generally accepted, standard methodology for determining resistance to antiplatelet agents. In addition, there are no methodological approaches to identify the patients with resistance to antiplatelet drugs, and standardized schemes for correcting a low sensitivity to these drugs.

The aim of this review was to summarize the available results of foreign and domestic studies devoted to the investigation of the effectiveness and safety problems of antiplatelet drugs administration from the point of view of the genetic predisposition to changes in their metabolism.

Materials and methods. For the review, the following information from scientific literature represented in open and accessible sources for the period of 1996-2020, was used: pharmgkb.org, PubMed, Scopus, Web of Science Core Collection, Elibrary. Search queries – “Genetic features+antiplatelet therapy+ethnic groups”, “CYP2C19+clopidogrel+antiplatelet therapy effectiveness”; “Stent retrombosis+CYP2C19 polymorphism+ residual platelet reactivity” and “CYP2C19 polymorphism+ethnic groups+clopidogrel resistance” in both Russian and English equivalents. All these data are placed in electronic databases.

Results. Currently, the problem of the resistance formation to antiplatelet drugs is studied insufficiently. The best thought-out issue is the research of the effect of the polymorphic alleles carriage of the CYP2C19 gene on the residual platelet reactivity in the patients administrated with dual antiplatelet treatment, including clopidogrel. In general, the analysis of open literature sources indicates the presence of a statistically significant association between the carrier of slow alleles of the CYP2C19 gene and the residual platelet reactivity, clinically manifested by thrombosis and adverse cardiovascular events. The occurrence frequency of polymorphic carriage of the CYP2C19 gene varies in different ethnic groups, so it cannot be extrapolated to individual subjects, peculiar in the ethnic diversity.

Conclusion. To develop preventive and predictive measures aimed at overcoming resistance to antiplatelet agents, as well as working out methodological approaches to personalized prescribtion of this group drugs, a further investigation with the expansion of the search for causes and the study of the other genes participation of the cytochrome P450 system, is required.

Pharmacy & Pharmacology. 2020;8(6):392-404
pages 392-404 views

Phleboprotectors based on flavonoids: dosage forms, biopharmaceutical characteristics, technological features

Stepanova E.F., Remezova I.P., Shevchenko A.M., Morozov A.V., Maltseva V.K.


Micronized purified flavonoid fraction (MPFF) is the original phlebotropic drug. Its marketed form (Detralex®) consists of 90% diosmin and 10% of other flavonoids. Calculated as hesperidin, it is the most widely used drug today. Diosmin and hesperidin, which are parts of the majority of venoactive drugs, are sparingly water-soluble compounds, and this feature can effect on their clinical efficacy. One of the ways to increase the solubility of these compounds leading to an increase in bioavailability, is the micronization of the active ingredients.

The aim of the investigation is a comparative determination of the dynamics and dissolution efficiency of the drugs containing bioflavonoid fractions in the dissolution test, as well as the analysis of the micronization degree and its impact on technology and biopharmaceutical parameters.

Materials and methods. A biopharmaceutical release profile was determined using HPLC. Disintegration, characteristics of the shape and size of the tablets’ particles were determined according to the methods of the State Pharmacopoeia of the XIV edition.

Results. The objects created with the use of diosmin and hesperidin, have been considered in detail. The role of technological solutions in relation to the corresponding dosage forms is notified. Detailed biopharmaceutical characteristics have been established with a choice of HPLC-based release control methodology. All the drugs in this group have a low water solubility leading to the maximum bioavailability for Detralex® which is about 1.26%; and no more than 0.2% for other analyzed models.

Conclusion. Detralex® dominates among the analyzed objects (tablets) in terms of the release rate. With regard to the overall quantitative indicators of release, the actual numbers are quite low, which is associated with the poor water solubility of the active substances.

Pharmacy & Pharmacology. 2020;8(6):405-415
pages 405-415 views

Application of multipotent mesenchymal stem cell secretome in the treatment of adjuvant arthritis and contact-allergic dermatitis in animal models

Golubinskaya P.A., Sarycheva M.V., Dolzhikov A.A., Bondarev V.P., Stefanova M.S., Soldatov V.O., Nadezhdin S.V., Korokin M.V., Pokrovsky M.V., Burda Y.E.


The therapeutic effect of multipotent mesenchymal stem cells has been proven on various disease models. One of the mechanisms is the paracrine effect of the cells on the surrounding tissues.

The aim. To investigate the secretome effectiveness of the multipotent mesenchymal stem cells in the treatment of adjuvant arthritis and contact-allergic dermatitis in Wistar rats.

Materials and methods. Adjuvant arthritis was simulated in 26 female rats by the administration of Freund’s complete adjuvant and then treated with the administration of 100 µl of multipotent mesenchymal stem cell secretome or saline. Contact-allergic dermatitis was modeled on 30 female rats by applying 200 μl of an oil solution of dinitrofluorobenzene to the skin on days 1, 5 and 6. Then the rats were treated with fluocinolone ointment (a positive control), baby cream (a negative control), baby cream with a secretome of native multipotent mesenchymal stem cells or from the cells processed with dexamethasone.

Results. Judging by the indicators of the longitudinal and transverse dimensions of the paws in rats and a histological examination, the secretome did not have any anti-inflammatory effect on adjuvant arthritis. A cream with a secretome from multipotent mesenchymal stem cells processed with dexamethasone, was the most effective on the model of contact-allergic dermatitis: the clinical improvement occurred on the 2nd day. The secretome from native multipotent mesenchymal stem cells and fluocinolone had a therapeutic effect on the 3rd day of application, the negative control – on the 4th day. The lymphocytic infiltration coefficient was significantly lower (p<0.05) in all the cases compared to the negative control (2.8±0.1). However, the lowest infiltration was observed when the cream with secretome from native (1.75±0.1) and dexamethasone-stimulated (1.76±0.1) multipotent mesenchymal stem cells was being used.

Conclusion. The cream with the secretome of multipotent mesenchymal stem cells suppresses lymphocytic infiltration more strongly than the highly active topical glucocorticosteroid – fluocinolone – on the model of contact-allergic dermatitis, which is a classic local delayed-type hypersensitivity reaction. However, a further study of the therapeutic effect of the secretome on models of systemic inflammatory diseases is required after its preliminary purification from large-molecular proteins.

Pharmacy & Pharmacology. 2020;8(6):416-425
pages 416-425 views

Correction of psychoneurological signs of acute alcohol intoxication in rats with a new acetylcysteine-based composition

Kurkin D.V., Morkovin E.I., Osadchenko N.A., Bakulin D.A., Abrosimova E.E., Dubrovina M.A., Kovalev N.S., Gorbunova Y.V., Tyurenkov I.N.


The aim of the study is an experimental confirmation of the use of a new combination of biologically active substances with tonic and antioxidant effects. This combination contains acetylcysteine in its composition to reduce the severity of psychoneurological consequences of alcohol intoxication.

Materials and methods. The study was conducted on male Wistar rats. The post-intoxication state was simulated by a single injection of ethanol (3 g/kg, intraperitoneally). Half an hour after awakening, the rats were divided into groups, which were injected with saline, acetylcysteine (1 g/kg), taurine (20 mg/kg), caffeine (20 mg/kg), succinic acid (100 mg/kg), lipoic acid (100 mg/kg), pyridoxine (400 mg/kg), or a combination of acetylcysteine with all these substances taken in a twice lower dose (except taurine). Before the treatment and 3 hours after it, the degree of neurological disorders was fixed according to the Combs and D’Alecy scale, in the Open Field test and the Adhesion test. Then the animals were euthanized to assess the level of glutathione, triglycerides and malondialdehyde (MDA) in liver homogenates, to determine the activity of enzymatic antioxidant systems and serum aminotransferases.

Results. In the animals injected with alcohol, there were evident signs of neuropsychiatric disorders, manifested in a low motor activity and a decrease in fine motor skills. This state did not change after an oral administration of saline. After the administration of acetylcysteine, taurine, caffeine, succinic and lipoic acids, pyridoxine and, to a greater extent, their compositions, the compensation of neuropsychiatric disorders and improvement of fine motor skills were notified. In the liver of these animals, the levels of glutathione, MDA, triglycerides, and the activity of antioxidant defense enzymes corresponded to the physiological norm.

Conclusion. The introduction of a combination of acetylcysteine with taurine, caffeine, pyridoxine, lipoic and succinic acids after an acute alcohol intoxication, to a greater extent than each of the substances separately, contributes to the function retention of the antioxidant system of hepatocytes. Besides, it reduces the level of their dystrophic changes and leads to a decrease in the severity of psychoneurological disturbances in the experimental animals.

Pharmacy & Pharmacology. 2020;8(6):426-435
pages 426-435 views

Pharmacoeconomic evaluation of anti-pneumococcal vaccination in risk groups for the prevention of community-acquired pneumonia among adults in the Astrakhan region

Orlova E.A., Dorfman I.P., Orlov M.A., Abdullaev M.A.


The aim. To evaluate the economic efficiency and the choice of the vaccination strategy in the respiratory pneumococcal infection risk groups among the adult population of the Astrakhan region.

Materials and methods. The data for the period of 2015–2018 were analyzed on the number of registered diseases in the patients living in the service area of the medical organizations (Form No.12, Federal State Statistics Service Orders No. 591, dated 27 November, 2015; No. 679, dated 22 November, 2019). The following working directives were studied: the base medical examination documentation submitted by medical institutions (Form No. 030/y “Dispensary Monitoring Checklist”; lists of the persons subjected to medical observation in the reporting year; Orders of the Ministry of Health of the Russian Federation: No. 1344, dated 12 December, 2012; No. 173n, dated 29 March, 2019). Statistical materials of the territorial fund for compulsory medical insurance of the Astrakhan region on the payment of medical care to 12,970 patients who had pneumonia in 2015–2018, were analyzed. The financial support of vaccination based on the results of tenders for the procurement of pneumococcal vaccines organized by the regional Ministry of Health, was considered. The calculations were carried out in accordance with the guidelines of “Cost-effectiveness of vaccine prophylaxis” (Methodological guidelines 3.3.1878-04, dated 04.03.2004).

Results. The prospective calculation of the vaccination cost showed that the benefits of vaccination with pneumococcal conjugate vaccine Prevenar13 (PCV13) and pneumococcal polyvalent vaccine Pneumovax 23 (PPV23) with a 95% vaccination coverage, are recorded after 2 years. The economic benefit of vaccination by reducing the possible number of pneumonias at the end of 2028 will be 968.2 million rubles.

Conclusion. The economic feasibility of vaccine prophylaxis of the adult contingent with an increased risk of developing pneumococcal infection has been established. The sequential strategy of PCV13 and PPV23 application provides the most effective localization of pneumococcal infection. The research results should be widely introduced into the long-term plans for vaccination and healthcare practice in the Astrakhan region.

Pharmacy & Pharmacology. 2020;8(6):436-445
pages 436-445 views

Use of quantum-chemical parameters for forecasting antiradical (HO·) activity of related structures containing a cinnamic mold fragment. III. Chalcones, flavanones and flavones with phloroglucinic type of ring “A”

Oganesyan E.T., Shatokhin S.S.


42 derivatives of chalcone, flavanone and flavone having a phloroglucinic type of ring “A” and containing the same electron-donating substituents on ring “B”, have been studied. Flavonoids with the phloroglucinic type of ring “A” are the most common in nature, which is due to the peculiarities of biogenetic formation with the participation of malonyl and acetyl fragments.

The aim. To determine the effect of the hydroxy group in position 6’ of chalcones and in position 5 of flavanones and flavones on bond numbers (Nµ), free valence indices (Fµ), Mulliken charges (a.e), electron density, unsaturation indices (IUA) of the carbon atoms C-1 → C-6 → C-7 → C-8.

Materials and methods. The calculations of the listed above parameters with the use of the semi-empirical method PM7 (WinMopac 2016 program) have been carried out on a workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.

Results. The quantum-chemical characteristics of the considered derivatives having a phloroglucinic type of the “A” ring, indicate that the OH group in position 6’ of chalcones (in the corresponding flavanones and flavones in position 5) has different effects: a slight increase occurs in chalcones negative charge (a.e.) and electron density, the bond numbers take different values, which depends on the position and number of substituents on the ring “B”. In flavanones, Nµ practically remains at the same level of 3.822–3.829. For flavones, the binding numbers Nµ for C-8 are in the range of 3.700–3.706, and the Mulliken charges are in the range from –0.4120 to –0.4356. For position-substituted C-3 (6anone and 7anone), the charges are –0.4436 and –0.4479, respectively. The charge on C-7 of chalcones is negative for compounds 4x, 5x, 10x and 13x from –0.0204 to –0.0470. The remaining derivatives of the chalcone, as well as the corresponding flavanones and flavones, are characterized by a positive value of a.e. on C-7. Based on the bond numbers (Nµ), free valency indices (Fµ) have been found for the carbon atoms of the cinnamoyl fragment C-1 → C-6 → C-7 → C-8. When comparing the obtained data, it was found out that for chalcones on C-1 → C-8 atoms, the values of the free valence indices are in the range of 0.900–0.980 for compounds 12x, 13x, where Fµ>1. For flavanones on C-1, C-3, and C-5 atoms (compounds 12anone and 13anone), the free valence indices are in the range of 0.984-1.024, and for the remaining atoms the value of Fµ is approximately the same as that of chalcones. On the C-8 atoms of all the derivatives, as well as on C-1, C-3 and C-5 (compounds 12one, 13one), Fµ≥1.0. It can be assumed that at values of Fµ=0.850–0.955 for all the analyzed compounds, coupling reactions on the double bond are possible, and if Fµ≥1, the coupling will take place according to the free radical mechanism. The data obtained indicate that the OH group in position 6’ for the chalcone and 5 for the flavanones, does not significantly effect the Mulliken charge (a.e) and the electron density on C-8 atoms.

Conclusion. It has been established that the OH group in position 6’ of the “A” ring of chalcones (in position 5 of the “A” ring in flavones and flavanones) has a conflicting effect on the bond numbers: when passing from chalcone to flavanone, Nµ increases, and then, in flavone, sharply decreases. For C-8 of all flavone derivatives, Fµ≥1. The following conclusion has been confirmed: at the initial stage of the reaction the electrophilic hydroxyl radical is attached at the C-8 position of the cinnamoyl fragment

Pharmacy & Pharmacology. 2020;8(6):446-455
pages 446-455 views

Study of pharmaceutical specialists’ information awareness on the matters of drug abuse

Porseva N.Y., Soloninina A.V., Dvorskaya O.N.


Prevention of non-medical use of drugs is the most important task of the state anti-drug policy of the Russian Federation, the effectiveness of which can largely be due to the professional awareness of pharmaceutical specialists, their compliance with the established regulations for the dispensing of drugs, and proper pharmaceutical advice.

The aim. The research of pharmaceutical specialists’ information awareness on the matters of drug abuse.

Material and methods. The study was based on the analysis of the regulatory legal acts of the Russian Federation governing the procedure for prescribing and dispensing drugs, instructions for the medical use of the drugs used for the purpose of abuse. In the course of the study, a systematic approach has been applied. It includes methods of structural-logical, cluster and content analyses, methods of generalization and grouping. The study of pharmaceutical specialists’ information awareness on the matters of drug abuse was carried out using a random sample survey using a specially developed questionnaire: 396 employees of pharmacy organizations of various forms of property from the Perm Territory, the Chelyabinsk and Kirov regions, the Udmurt and Chuvash Republics, the Komi Republic, were questioned in the period from 2017 to 2019. The questionnaire included 35 questions, structured in 4 blocks. The first block included questions on education, position, work experience of the respondents, the second – questions on identifying knowledge on the range of drugs used for abuse, and categories of consumers of such drugs. The third block contained questions on the regulation and compliance with the procedure for dispensing drugs. The fourth block of the questionnaire was intended to establish the methods and sources of obtaining information on the abuse of the drugs sold by specialists of pharmacy organizations.

Results. On the basis of the analysis carried out, an insufficient level of knowledge by specialists of the regulatory legal acts governing the trade of drugs, the range of drugs used for the purpose of abuse, and the categories of their consumers have been established. The violation of the rules for dispensing drugs has been revealed, as well as the lack of systematic sources of information on drug abuse.

Conclusion. The need to develop a training program for pharmaceutical specialists on the prophylaxis and prevention of drug abuse has been established. In order to work out additional competencies in the prevention of non-medical use of drugs and improve the quality of pharmaceutical consulting, it is necessary to conduct appropriate educational activities.

Pharmacy & Pharmacology. 2020;8(6):456-464
pages 456-464 views

Life quality assessment of patients with stable coronary artery disease after myocardial revascularization

Narkevich I.A., Nemyatykh O.D., Kovaleva K.A., Ratova L.G., Trushnikova I.O., Parizhskaya E.N., Konradi A.O.


The aim of this study is to assess the life quality of patients with stable coronary artery disease after angioplasty and stenting of coronary arteries at the post-hospital stage.

Materials and methods. Methods of the sociological analysis (questionnaire surveys) and methods of mathematical statistics (descriptive statistics, time series method, factor and variance analyses) were used at different stages of the prospective observational study. The research materials were as follows:1458 electronic patient records with a stable coronary heart disease (SCHD) after angioplasty and stenting of coronary arteries (ASCA); 620 questionnaires filled in by patients before the surgery, 1, 6, 12 months after discharge. The statistical analysis was performed using the IBM SPSS Statistics software.

Results. The results of a comprehensive survey make it possible for us to assert that during the studied period, stable good healths of cardiac surgery patients with ASCA were maintained. Within the framework of the EQ-5D-5L questionnaire, it was revealed that more than 50% of patients have no physiological problems. The results of the SAQ analysis demonstrate that 58% of the patients feel better, and more than 34% of the patients do not have shortness of breath 1 year after the surgery. A statistically significant improvement in their healths was established according to a visual analogue scale relatively to the annual observation mark (62.82 ±20.95), which corresponds to the high results assessment of the medical technology use. At the same time, 53% of the patients notify that the treatment results meet their own expectations.

Conclusion. The proposed calculation of the integrated index of patients’ treatment efficiency demonstrated by the patients with stable coronary heart disease after angioplasty and stenting of the coronary arteries is based on the results of the factor analysis. This calculation can be used to assess the efficiency of pharmacotherapy in the framework of a value-oriented approach to the treatment of a number of other pathologies.

Pharmacy & Pharmacology. 2020;8(6):465-475
pages 465-475 views

Number of runs variations on Autodock 4 do not have a significant effect on RMSD from docking results

Pratama M.F., Siswandono S.


The aim. The number of runs in the docking process with AutoDock 4 is known to play an important role in the validity of the results obtained. The greater the number of runs it is often associated with the more valid docking results. However, it is not known exactly how the most ideal runs in the docking process with AutoDock 4. This study aims to determine the effect of the number of runs docking processes with AutoDock 4 on the validity of the docking results.

Materials and methods. The method used is the redocking process with AutoDock 4.2.6. The receptor used is an estrogen receptor with ligand reference estradiol (PDB ID 1GWR). Variations were made on the number of runs from 10 to 100 in multiples of 10. The parameters observed were RMSD, free energy of binding, inhibition constants, amino acid residues, and the number of hydrogen bonds.

Results. All experiments produce identical bond free energy, where the maximum difference in inhibition constant is only 0.06 nM. The lowest RMSD is indicated by the number of runs of 60, with a RMSD value of 0.942. There is no linear relationship between the number of runs and RMSD, with R in the linear equation of 0.4607.

Conclusion. Overall, the number of runs does not show a significant contribution to the validity of the results of docking with AutoDock 4. However, these results have only been proven with the receptors used.

Pharmacy & Pharmacology. 2020;8(6):476-480
pages 476-480 views

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