Vol 8, No 6 (2020)

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.

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.

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.

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

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.