Reviews on Clinical Pharmacology and Drug Therapy

Reviews on Clinical Pharmacology and Drug Therapy is a scientific peer-reviewed medical journal published quarterly since 2002 under supervision of professor Petr Dmitriyevich Shabanov, MD, PhD, Head, Dept. of Pharmacology of S. M. Kirov Military Medical Academy. The journal is published with the assistance of "The St. Petersburg scientific organization of pharmacologists" and "The St. Petersburg scientific organization of physiologists, biochemists, pharmacologists of I.M. Sechenov".

The journal publishes original papers reporting fundamental, medical experimental and clinical research, literature reviews, lectures, case reports, and information on all relevant issues of clinical pharmacology, drug therapy and related subjects.

Topics focused on key issues in basic and clinical pharmacology.

The journal is aimed at researchers, physicians, educators of medical academic institutions, scientists, pharmacologists, druggists  and all specialists in related fields of medicine including residents, research fellows, and medical students.

Our mission:

  1. Integrate Russian scientific efforts and vast experience  in development and use of medicines of various groups with international science and create international space for discussion and opinion sharing scientists in the field of clinical pharmacology and drug therapy.
  2. Provide physicians with actual and qualitative scientific information on the most modern and effective medicines.

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Vol 20, No 3 (2022)

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Ghrelin mechanisms of food reward. Part 2. Interaction of ghrelin with hormones, neuropeptides and other endogenous ligands
Reikhardt B.A., Shabanov P.D.

The hunger hormone, ghrelin, is produced not only in response to food deprivation, but is also released during various types of stress. In recent years, the rise in ghrelin levels has come to be seen as an essential component of the stress response. The review is devoted to ghrelin-dependent mechanisms providing reciprocal interaction between the hypothalamus–pituitary–adrenal cortex axis and the dopaminergic reward system. Direct and feedback links between the stress-realizing system of the paraventricular nucleus, the neural networks of the lateral hypothalamus and the arcuate nucleus (which form the centers of hunger/satiation), and the mesolimbic reward system are considered. The role of peripheral satiety hormones and glucocorticoids in the regulation of motivation and reinforcement is discussed, as well as the involvement of endogenous opioid and endocannabinoid receptors in the “learning” of dopaminergic neurons in the ventral tegmental area and the hippocampus.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):229-254
pages 229-254 views
Peculiarities of carbamazepine pharmacogenetics and the most common adverse drug reactions during its use (literature review)
Skryabin V.Y., Zastrozhin M.S., Bryun E.A., Sychev D.A.

Carbamazepine is widely used for the treatment of epilepsy, trigeminal neuralgia and psychiatric disorders. However, therapy is often ineffective, and some patients experience adverse drug reactions, which negatively affect both the efficacy and safety of therapy.

This review systematized and presented up-to-date information regarding the pharmacokinetics and pharmacogenetics of carbamazepine, as well as the most common adverse drug reactions arising from its use. Knowledge of the pharmacokinetics, pharmacodynamics and pharmacogenetics of carbamazepine is necessary to assess the effect of genetically determined activity of cytochrome P450 isoenzymes on the efficacy and safety of this drug. This will make it possible to develop approaches to personalizing the selection of an effective and safe dose of therapy in patients based on individual clinical and biological parameters.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):255-267
pages 255-267 views
Immunotropic effects of hypoglycemic agents on coronavirus infection: a view from the perspective of pharmacogenetics
Gurevich K.G., Sorokina Y.A., Urakov A.L., Sinyushkina S.D., Pryazhnikova M.I., Gorinova A.V., Lovtsova L.V., Zanozina O.V.

Diabetes mellitus is a predictor of the severe course of a new coronavirus infection and high mortality, in this regard, the selection of appropriate hypoglycemic therapy is a vital issue. In this article, we paid attention to dipeptidyl peptidase-4 (DPP-4) inhibitors, since this group of drugs has features like low risk of hyperglycemia and immuno-mediated effects. For the most effective treatment, it is necessary to take into account the individual characteristics of each patient, namely, the achievements of pharmacogenetics. The genetic variability of the response to therapy with DPP-4 inhibitors is due to a variety of polymorphisms, several main variations are considered in the review. The ambiguity of the available studies on the effectiveness of DPP-4 inhibitors in patients with type 2 diabetes with COVID-19 indicates the need to continue pharmacogenetic studies. The combination of knowledge about the subtleties of the mechanisms of pharmacological action of drugs and individual characteristics of pharmacodinamics will ensure the greatest effectiveness and safety of personalized therapy of diabetes mellitus against the background of coronavirus infection.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):269-279
pages 269-279 views

Original articles

Application of the intranasal road of administration for delivery of drugs to the central nervous system
Litvinova M.V., Bychkov E.R., Lebedev A.A., Arseniev N.A., Shabanov P.D.

BACKGROUND: The development of effective drug delivery to the central nervous system still remains an important problem in pharmacology despite the rapid development of a large number of new treatment strategies in recent years. Recently interest of the intranasal method as delivery route has greatly increased because this method of administration allows to bypass the blood-brain barrier. There is not a single fundamental study comparing intranasal, central and peripheral methods of administration in order to determine the feasibility of using the intranasal route for delivering substances to the brain by far.

AIM: Aim is to study the effect of 6-hydroxydopamine (6-OHDA), a neurotoxin that does not penetrate through the blood-brain barrier by various administrations on the behavior of mice.

MATERIALS AND METHODS: The experiments were performed on 40 outbred female mice weighing 20–25 g. The mice were divided into groups of 10 which were injected with intraventricular, intranasal, intraperitoneal, and intact 6-OHDA. After 21 days, behavioral responses were observed in the Rotarod test, Verticalization, Open Field, and Pole test.

RESULTS: 1. A significant difference was found between animals after intraventricular administration of 6-OHDA and the intact control group when studying the behavior of animals in the “open field” test. 2. The study of coordination activity in the Rotarod test (rotating rod) showed a similar decrease in the retention time on a rotating drum in animals after intranasal and intraventricular administration of 6-OHDA. 3. Only the descent time increased after intranasal administration of 6-OHDA. 4. A significant increase in the motor activity of mice was revealed after intranasal and intraventricular administration of apomorphine in the verticalization test.

CONCLUSIONS: It was concluded that a neurotoxin that does not pass through the blood-brain barrier into the central nervous system penetrates through after intranasal administration.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):281-288
pages 281-288 views
Modeling the female hypogonadism by means of ovarian ischemization and its morphofunctional justification
Magradze R.N., Lisovsky A.D., Lisovsky D.A., Popkovsky N.A., Bobkov P.S., Bayramov A.A., Droblenkov A.V.

The present study is devoted to the morphofunctional substantiation of the model of female hypogonadism, which is important for the subsequent evaluation of the effectiveness of its targeted pharmacological correction, as well as to elucidate the resistance of ovarian endocrine cells to damage as a result of experiencing a single acute ischemic effect. In three groups of adult female rats under anesthesia, the arteries of the right and left ovaries were ligated for 30, 45, and 60 min (4 rats in each group). After the operation, the wound was sutured. Sham-operated rats (4 individuals) served as controls. After 7 days, the results were analyzed. The blood levels of sex steroid hormones (17β-estradiol, progesterone) and gonadotropins (FSH and LH) were determined by enzyme-linked immunosorbent assay. In the meridional histological sections of the mature tertiary follicle and the corpus luteum of the right and left ovaries, after survey staining, the number and percentage of viable and dead endocrinocytes were counted, and the area of viable endocrine cells was determined. The significance of differences in the median, upper and lower quartiles of the compared parameters was determined using the nonparametric Mann–Whitney test. It has been established that a single acute ovarian ischemia induces massive death and degenerative changes in a significant part of the viable endocrine cells of the mature tertiary follicle and corpus luteum, most pronounced with a one-hour bilateral occlusion of the ovarian vessels. These quantitative and structural changes in interstitial endocrine cells and ovarian luteocytes cause a significant decrease in the production of sex steroids, which, in turn, causes hyperproduction of the corresponding pituitary tropins. Morphological changes in both types of ovarian endocrine cells in this model of acute single ovarian ischemia are highly sensitive; the use of a number of morphometric parameters of endocrinocytes in combination with the determination of the concentration of peripheral and regulatory homones will allow using this model to assess the effectiveness of the correction of female hypogonadism with various pharmacological preparations.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):289-295
pages 289-295 views
Preclinical study of pharmacokinetic ADME processes of phenosanic acid in vitro and in vivo
Kosman V.M., Karlina M.V., Tyutina K.V., Makarov V.G., Makarova M.N., Morozov S.V., Gushchina E.E., Zhuravskaya N.V.

BACKGROUND: Phenosanic acid is a synthetic antioxidant, the active ingredient of the original domestic drug recommended for the treatment of epilepsy. To improve the effectiveness and safety of the use of phenosanoic acid, additional study of its pharmacokinetic properties is necessary.

AIM: To study the pharmacokinetic parameters of the active ingredient of the drug Dibufelon, capsule 200 mg (LLC “Piq-Pharma”, Russia) in vitro and in vivo systems in rats after single administration in one dose.

MATERIALS AND METHODS: Phenosanic acid binding to blood plasma proteins, microsomal stability and permeability through the monolayer of Caco-2 cells were evaluated in in vitro tests. The pharmacokinetics parameters were studied after a single intragastric administration in Wistar rats in dose of 80 mg/kg. The samples were analyzed by HPLC-UV.

RESULTS: A high variability in the degree of binding of phenosanic acid to blood plasma proteins by 20–65% depending on the concentration was revealed, relatively high microsomal stability (half-life — 1106 ± 789 min, internal clearance — 2.05 ± 0.86 μl/min/mg protein of liver microsome; residual content after 60 min incubation — 87.9 ± 7.8%) and the ability to penetrate through the monolayer of cells Caco-2. The rapid absorbtion of the substance into the systemic bloodstream was established — its maximum concentration in blood plasma was observed already 3.6 ± 1.2 hours after administration, and its slow removal from the systemic bloodstream — the half-life was about 19 h, the average retention time was about 29 h. Phenosanic acid with different degrees of intensity was distributed to all the examined organs and tissues: kidneys > liver > brain > omentum > muscle, and invariably excreted in a small amount with urine and feces, about 0.04% and 5.5%, respectively.

CONCLUSIONS: As a result of the study, it was found that phenosanic acid is characterized by rapid absorbtion into the systemic bloodstream and a long stay in it invariably, which may be due to the peculiarities of its binding to blood plasma proteins and relatively high metabolic stability, revealed during the corresponding in vitro tests. The study of the permeability and transport of phenosanic acid showed that it can presumably be attributed to compounds with medium permeability and is not a substrate for the transport protein P-glycoprotein (P-gp). The study of tissue availability of phenosanic acid confirmed its entry into peripheral tissues, including the brain, which is the area of implementation of the anticonvulsant effect.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):297-308
pages 297-308 views
The effect of neuropeptide ACTH4-10 on the adaptation of patients to dental prostheses according to the data of monitoring the emotional state using a polygraph
Pozhilova E.V., Novikov V.E., Evseev A.V., Abolmasov N.N.

BACKGROUND: Monitoring and pharmacological correction of adaptation of patients to full removable dental prostheses is actual and practically important problem in stomatology.

AIM: To study the effect of neuropeptide ACTH4-10 on the process of adaptation of patients to complete removable prostheses by monitoring the emotional state using a polygraph.

MATERIALS AND METHODS: Examination and primary prosthetics with full removable dentures of patients (60–75 years old) were performed of both sexes with total adentia. All patients were divided into three groups: the main group (correction of the adaptation process with ACTH4-10 neuropeptide — Semax 0.1% nasal drops), the comparison group (0.9% NaCl solution was administered intranasally) and the control group (without pharmacological correction). Monitoring of the process of adaptation to prostheses was carried out by registering the emotional reaction of patients to the movements of the lower jaw with the help of a polygraph “Barrier-14” of the company “Antey” (Russia).

RESULTS: The emotional state of patients in the main observation group who received pharmacological correction with ACTH4-10 neuropeptide reaches the values of adapted patients for most of the studied indicators within 7–14 days after the application of prostheses, and a month after the application of prostheses - for all studied indicators of the curves of the trajectories of the lower jaw (p > 0.05), which cannot be noted in patients of the comparison group (NaCl) and the control group. The results obtained indicate a positive effect of the neuropeptide ACTH4-10 on the process of getting used to patients with complete removable prostheses.

CONCLUSIONS: Neuropeptide ACTH4-10 accelerates the process of adaptation of primary prosthetic patients to complete removable dental prostheses according to the monitoring of the emotional background of patients. The method of registering the emotional state of patients using a polygraph allows us to make an objective conclusion about the effect of occlusion and articulation on the psycho-emotional background and judge the patient's adaptation to a dental prosthesis.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):309-316
pages 309-316 views

Phytopharmacology and Phytotherapy

Effect of Serratula marginata dry extract on the mice thymus and spleen structure in cyclophosphamide immunosuppression
Razuvaeva Y.G., Khobrakova V.B., Budatsyrenova A.T., Olennikov D.N.

BACKGROUND: The search of effective and safe drugs to prevent and treating the immune deficient states is an actual problem of modern medicine.

AIM: The purpose of the study is to evaluate the effect of Serratula marginata dry extract on structure of mice thymus and spleen at cyclophosphamide immunosuppression.

MATERIALS AND METHODS: The experiments were carried out on F1 (CBAxC57Bl/6) mice. Immune deficiency was simulated by a single intraperitoneal introduction of cyclophosphamide in the dose 250 mg/kg. S. marginata dry extract in the dose 100 mg/kg was administered to animals for 14 days intragastrically against cyclophosphamide. Morphological studies of the thymus and spleen were performed on day 16 after the extracts administration. Areas white and red pulp of the spleen; the area of the thymic lobule, the cortex and the medulla; the density of cells in the subcapsular zone and the deep layers of the cortex were measured using the Zen 2012 image analysis program.

RESULTS: The S. marginata extract limited the development of involutive changes in the thymus caused by cyclophosphamide: the thymus area was by 28% (p ≤ 0.05) higher and the cortical-medullary index was (ratio of the cortex area to the medulla area) by 26% higher. The number of mitotically dividing cells, blasts and large lymphocytes increased, the number of cells with structural disorders and macrophages decreased in the thymus cortex. In animals of the experimental groups, the white pulp area was 47% (p ≤ 0.05) higher than that in the control.

CONCLUSIONS: The S. marginata dry extract limited the development of involutive processes in the thymus and spleen caused by the introduction of cytostatic cyclophosphamide.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):317-324
pages 317-324 views
Antihypoxic activity and anti-ischemic effect of complex herbal remedy
Gulyaev S.M., Zhalsanov Y.V., Turtueva T.A., Nikolaeva G.G.

The present study was carried out to determine the antihypoxic and anti-ischemic effects of a polyherbal extract from Astragalus membranaceus, Scutellaria baicalensis and Phlojodicarpus sibiricus. The Wistar rats of both sexes were used in the study. The antihypoxic activity of the extract was studied using hemic and hypobaric models of hypoxia. The anti-ischemic effect of the extract was evaluated by the severity of neurological deficit and survival within 24 hours in model of bilateral occlusion of the common carotid arteries.

The course administration of the extract (100, 200 mg/kg) had an antihypoxic effect in the model of hemic hypoxia: the reserve time of life increased by 26 and 28%, respectively, compared with the control. The course introduction of the extract at doses of 50, 100 and 200 mg/kg increased the reserve time of life in hypobaric hypoxia by 12.3, 15.5 and 16.7%, respectively, compared with the control

The administration of the extract (100 and 200 mg/kg) in the model of cerebral ischemia had a cerebroprotective effect: the indicators of neurological deficit were, respectively, less than the control by 34 and 46%, and their survival was 62 and 64%, respectively, against 20% of the survival of rats in the control group. The results of the conducted studies suggest the prospects for further study of the plant extract as a cerebroprojector agent.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):325-330
pages 325-330 views

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