Vol 9, No 3 (2021)


Genetic predictors of severity and efficacy of COVID-19 pharmacotherapy

Shishimorov I.N., Magnitskaya O.V., Ponomareva Y.V.


The pandemic of the novel coronavirus infection 2019 (COVID-19) has changed many aspects of our lives and initiated numerous studies aimed at finding the factors that determine different courses of this infectious disease. The studies aimed at finding predictors of the severe course of this novel coronavirus infection, as well as the factors that determine the efficacy and safety of this disease pharmacotherapy, are acquiring special social significance.

The aim of this work is to find and summarize information on genetic predictors of severe COVID-19, as well as pharmacogenetic aspects that determine the variability of the therapeutic response to the drugs recommended for COVID-19 treatment.

Materials and methods. The article provides a review of scientific results on the research of gene polymorphism that determine a body’s response to the introduction of SARS-CoV-2 infection and the effects of pharmacotherapy for this disease, obtained from open and available sources within the period of 2019 – March 2021. The search was conducted in the following electronic databases: PubMed, Cochrane Library, ClinicalTrials.gov; Elibrary, Scopus. The main search inquiries were: “predictors + severe course + COVID-19”, “genetic variations + COVID-19”, “pharmacogenetics + COVID-19”, “gene polymorphism + SARS-CoV-2”, “pharmacotherapy + gene polymorphism + COVID-19” in both Russian and English.

Results and conclusion. The exploratory research detailing the mechanisms of infecting with SARS-CoV-2, the variability of the disease severity and the individual characteristics of therapeutic responses to the drugs used, are being actively carried out by scientists all over the world. However, most of their scientific projects are diverse, and the possible predictors of a severe course of COVID-19 found in them, have not been confirmed or investigated in subsequent studies. A generalization of the individual studies results of the genetic predictors concerning COVID-19 severity and effectiveness of its pharmacotherapy, can become the basis for further search and increase the reliability of the data obtained in order to develop a strategy for preventing the spread of COVID-19 infection, to identify potential targets of the treatment, and develop the protocols for optimizing this disease pharmacotherapy.

Pharmacy & Pharmacology. 2021;9(3):174-184
pages 174-184 views

Standardization problems of medicinal preparations from Rhodiola rosea L.

Kurkin V.A., Ryazanova T.K.


Rhodiola rosea L. rhizomes and roots are pharmacopoeial raw materials, which are used in official medicine for obtaining medicines with adaptogenic activity. One of the most common problems in the production of medicines from Rhodiola rosea L. rhizomes and roots is the use of poor quality medicinal plant materials, which leads to the absence of biologically significant compounds in the preparations. One of the possible reasons is the shortcomings in the existing approaches to the standardization of Rhodiola rosea L. raw materials and preparations.

The aim of the study is the improvement of approaches to the standardization of medicinal preparations from Rhodiola rosea L. rhizomes and roots.

Materials and methods. Experimental and industrial samples of liquid extract from Rhodiola rosea L. roots, as well as reference samples of rosavin and salidroside, were used as materials of the research. The HPLC analysis was carried out using a Milichrom-6 chromatograph (NPAO Nauchpribor) under the following conditions of reversed-phase chromatography in an isocratic mode: a steel column KAKH-6-80-4 (2 mm x 80 mm; Separon-C18 7 μm), a mobile phase – acetonitrile: 1% solution of acetic acid in water in the ratio of 14:86, the elution rate was 100 μL/min, the eluent volume was 2000 μL. The constituents were detected at the wavelength of 252 nm (rosavin) and 278 nm (salidroside).

Results. An assay of rosavin and salidroside in the liquid extract of Rhodiola rosea L. was developed using the HPLC method. It was determined that the content of rosavin in the samples of the liquid extracts obtained from Rhodiola rosea L. rhizomes and roots of the pharmacopoeial quality, varied from 0.21%±0.03% to 0.32%±0.04%, salidroside – from 1.13% ±0.05% to 2.71%±0.12%, respectively. The results of statistical processing indicate that the relative error of the average result for the determination of rosavin and salidroside in the preparations of Rhodiola rosea L. with a confidence level of 95% does not exceed ±6.0%.

Conclusion. Thus, methodological approaches to the analysis of medicinal preparations from Rhodiola rosea L. rhizomes and roots have been substantiated. These methodological approaches consist of the quantitative determination of the dominant and diagnostically significant biologically active compounds – rosavin and salidroside.

Pharmacy & Pharmacology. 2021;9(3):185-194
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Effect of solid dispersions on the solubility of metronidazole

Krasnyuk I.I., Naryshkin S.R., Krasnyuk I.I., Belyatskaya A.V., Stepanova O.I., Bobrov I.S., Yankova V.G., Rau J.V., Vorobiev A.N.


The aim of the work is to study the effect of solid dispersions using polyethylene glycols of various molecular weights on the solubility of metronidazole in water. Metronidazole is an antimicrobial and antiprotozoal drug. Its low solubility in water limits the use of metronidazole, causing technological difficulties and reducing its bioavailability. The solubility and release of the active substance from dosage forms can be increased using the solid dispersion methods. Solid dispersions are bi- or multicomponent systems consisting of an active substance and a carrier (a highly dispersed solid phase of the active substance or molecular-dispersed solid solutions) with a partial formation of complexes of variable compositions with the carrier material.

Materials and methods. The substance of metronidazole used in the experiment, was manufactured by Hubei Hongyuan Pharmaceutical Technology Co., Ltd. (China). To obtain solid dispersions, polyethylene glycols of various molar masses – 1500, 2000 and 3000 g/mol – were used. The solid dispersions were prepared by “the solvent removal method”: metronidazole and the polymer were dissolved in a minimum volume of 96% ethyl alcohol (puriss. p.a./analytical grade) at 65±2°C, and then the solvent was evaporated under vacuum to the constant weight. A vacuum pump and a water bath were used at the temperature of 40±2°C. The dissolution of the samples was studied using a magnetic stirrer with heating, and a thermostatting device. The concentration of metronidazole was determined on a spectrophotometer using quartz cuvettes at the wavelength of 318±2 nm. To filter the solutions, syringe nozzles were used, the pores were 0.45 μm, the filter was nylon. Microcrystalloscopy was performed using a microscope with a digital camera. The optical properties of the solutions were investigated using a quartz cuvette and a mirror camera (the image exposure – 20 sec).

Results. Obtaining solid dispersions increases the completeness and rate of the metronidazole dissolution. The solubility of metronidazole from solid dispersions increases by 14–17% in comparison with the original substance. The complex of physical-chemical methods of the analysis, including UV spectrophotometry, microcrystalloscopy and the study of the optical properties of the obtained solutions, makes it possible to suggest the following. The increase in the solubility of metronidazole from solid dispersions is explained by the loss of crystallinity and the formation of a solid solution of the active substance and the solubilizing effect of the polymer with the formation of colloidal solutions of metronidazole at subsequent dissolution of the solid dispersion in water.

Conclusion. The preparation of solid dispersions with polyethylene glycols improves the dissolution of metronidazole in water. The results obtained are planned to be used in the development of rapidly dissolving solid dosage forms of metronidazole with an accelerated release and an increased bioavailability.

Pharmacy & Pharmacology. 2021;9(3):195-204
pages 195-204 views

Experimental study of toxic properties of VMU-2012-05 drug – original non-nucleeside inhibitor of HIV-1 reverse transcriptase

Vavilova V.A., Shekunova E.V., Jain E.A., Balabanyan V.Y., Ozerov A.A., Makarova M.N., Makarov V.G.


Antiretroviral therapy is currently the main component of treatment for HIV patients. The development of new, more effective and safer drugs is an urgent task.

The aim of the research is to study the toxic properties of the finished dosage form (FDF) VMU-2012-05, a non-nucleoside reverse transcriptase inhibitor (1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil) for the HIV-1 infection treatment in single and repeated enteral administrations.

Materials and methods. The study of toxic properties in single administrations was carried out on outbred mice; the drug was administered at the limiting dose of 2000 mg/kg (by reference to the active substance). For 90 days, in repeated daily administrations, the toxic properties were studied in rats of both sexes at the doses of 0 mg/kg (placebo), 9 mg/kg (1 HTD), 45 mg/kg (5 HTD), 90 mg/kg (10 HTD). The toxic properties were also studied in rabbits of both sexes within a 28-day administration at the doses of 0 mg/kg, 4 mg/kg (1 HTD), 20 mg/kg (5 HTD), 40 mg/kg (10 HTD); the recovery period 30 days. Clinical observations and examinations, body weight registrations, physiological and clinical laboratory studies were carried out during the experiment. At the end of the administration period (50% of animals) and at the end of the recovery period, a pathological examination was performed.

Results. The LD50 of the drug is more than 2000 mg/kg. In the repeated administrations, the no observed adverse effect level (NOAEL) has been established. For rats, it is 9 mg/kg (1 HTD), for rabbits – 4 mg/kg (1 HTD). According to the results of the experiments carried out on rabbits and rats, the main target organ of the drug toxic effect is the liver. According to the data obtained in the study on rats, a toxic effect on the organs of the male reproductive system has been manifested (hypoplasia of the spermatogenic epithelium). Under the conditions of the experiment, the test drug had no effect on the gastrointestinal tract.

Conclusion. The results have manifested a favorable safety profile of the drug, not inferior to the ones of a similar pharmacological group used in clinical practice; it can be considered a promising drug candidate for the HIV-1 infection treatment.

Pharmacy & Pharmacology. 2021;9(3):205-221
pages 205-221 views

Synthesis, antiaggregation and antitrombotic activities of new derivatives of hydroxybenzoic acids with tauric fragment

Brel A.K., Atapina N.V., Budaeva Y.N., Lisina S.V., Tsaruk S.S., Kurkin D.V., Tyurenkov I.N.


A high prevalence of thrombotic disorders, insufficient effectiveness or safety of antithrombotic therapy is an urgent problem of modern healthcare. The main means of preventing thrombosis is acetylsalicylic acid. Despite its long history, aspirin attracts researchers in the fields of medicinal chemistry, biology, and medicine. The development of new antiplatelet agents, including chemical modification of the acetylsalicylic acid molecule, remains relevant. Modification of the acetylsalicylic acid molecule using amino acids and obtaining their salt forms makes it possible to maintain antiplatelet or antithrombotic properties, as well as to impart additional pharmacodynamic effects. In modern science, a lot of attention is paid to the sulfur-containing amino acid taurine. An analysis of modern scientific literature revealed the protective effect of taurine in diabetes mellitus and cardiovascular diseases, liver dysfunction, gastrointestinal tract, and kidney diseases.

The aim of the article is to study synthesis of new compounds, determination of their physical characteristics and assessment of their antiplatelet and antithrombotic activities in vitro and in vivo.

Materials and methods. To confirm the structure of the synthesized new derivatives of hydroxybenzoic acids with a taurine fragment by the acelation method, thin layer chromatography and NMR spectra were used. In vitro studies were carried out on the model of ADP-induced platelet aggregation according to the Born G. methods modified by V.A. Gabbasov. In vivo, the studies were carried out on the model of arterial thrombosis induced by the application of iron chloride in the following groups of animals: intact, with experimental diabetes mellitus and three-year-olds; the rate of bleeding from the tail vein was also evaluated.

Results. New compounds – derivatives of ortho-, meta- and para-hydroxybenzoic acids with a taurine residue – were synthesized. A procedure for the preparation of N-hydroxybenzoyl taurine compounds and their salt forms have been described; their spectral characteristics and melting points have been determined. The synthesized compounds are superior to acetylsalicylic acid in solubility and are not inferior to it in antiplatelet and antithrombotic activities. The results of the in vitro antiplatelet activity assessment in a wide concentration range from 10-4M to 10-8M, are presented. It has been revealed that the dipotassium salt of N-(2-hydroxybenzoyl)taurine exhibits a less antiplatelet activity than the dipotassium salt of N-(3-hydroxybenzoyl)taurine. The most pronounced antiplatelet activity is exhibited by the compound N-(4-hydroxybenzoyl)taurine. In in vivo experiments on the model of arterial thrombosis in 3-year-olds or animals with experimental diabetes mellitus, carotid artery thrombosis occurred faster than in young or intact animals. A single preliminary oral administration of the test compounds prolonged the time of the thrombus formation, which makes it possible to conclude that they have an antithrombotic effect. In this study, the dipotassium salt of N-(3-hydroxybenzoyl)taurine exhibits a more pronounced activity than that of acetylsalicylic acid.

Conclusion. Against the background of the modeled pathologies, the studied drugs showed the expected antithrombotic activity, in terms of the severity not inferior to that found in acetylsalicylic acid.

Pharmacy & Pharmacology. 2021;9(3):222-234
pages 222-234 views

Economic aspects of application of the russian biosimilar omalizumab in patients with atopic bronchial asthma of moderate to severe clinical courses

Krysanova V.S., Ermolaeva A.D., Ermolaeva T.N., Davydovskaya M.V., Kokushkin K.A.


A certain success in the treatment of bronchial asthma is associated with the introduction of monoclonal antibodies into the treatment process. They made it possible to improve the control of the disease. A number of original genetically engineered biological drugs, such as benralizumab, reslizumab, dupilumab, mepolizumab and omalizumab, are currently registered in Russia. In 2020, this list was supplemented by the first Russian biosimilar drug omalizumab – Genolar® (JSC Generium, Russia). High rates of the development of modern medicine are closely related to the use of biosimilars. The prescription of biosimilars today often makes it possible to provide a larger number of patients with modern drugs at lower costs.

The aim of the study was a comprehensive pharmacoeconomic assessment of the application of the domestic biosimilar drug omalizumab in the treatment of patients suffering from moderate and severe atopic bronchial asthma.

Materials and methods. At the first stage, an information search in the available databases (Cochrane Library, MedLine, Embase, eLIBRARY) was carried out. According to the results obtained, a meta-analysis (Agache I. et al.) was found out; within its framework, the efficacy and safety of the use of several monoclonal antibodies was assessed. Dupilumab was chosen as the reference drug. Pharmacoeconomic analyses were carried out using a “Cost-Minimization Analysis” (CMA) and a “Budget Impact Analysis” (BIA). Taking into account various options of bronchial asthma, the developed algorithm for providing medical care to adult patients with atopic asthma made it possible to assess the costs, including direct medical and indirect costs.

Results. The cost analysis demonstrated the advantage of using the Russian biosimilar omalizumab in patients with atopic asthma compared to dupilumab due to financial savings of up to 40%. The Budget Impact Analysis showed that the use of the domestic biosimilar omalizumab, even taking into account the annual increase in the number of patients (8%), will save up to 109,641,409.64 rubles (or 3%) compared to the current practice.

Conclusion. The use of the domestic biosimilar omalizumab in patients with moderate to severe atopic bronchial asthma is a clinically effective and economically justified approach to organizing medical care for adult patients in Russia.

Pharmacy & Pharmacology. 2021;9(3):235-248
pages 235-248 views

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