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 1 (2022)

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Reviews

Toxicology of carbon nanostructures. Part I. Spherical nanoparticles (fullerenes and nanoonions)
Litasova E.V., Iljin V.V., Myznikov L.V., Piotrovskiy L.B.
Abstract

The literature review is devoted to the generalization of publications on the toxicity of carbon nanostructures, which have recently been increasingly used in biological and pharmacological research, in medicinal chemistry with the prospect of being used in medicine. Analysis of the literature data shows that, despite a huge amount of work, there are no unambiguous conclusions about the toxicological characteristics of various types of carbon nanomaterials. The use of carbon nanostructures in medicine can be questioned due to the potentially adverse health effects of their use. To clarify the harmlessness, it is necessary to develop more effective tests on animals, taking into account the characteristics of each type of nanomaterial.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):5-15
pages 5-15 views
Role of glutamate receptor complex in the organism. Ligands of NMDA receptors in neurodegenerative processes – a modern state of the problem
Dergachev V.D., Yakovleva E.E., Bychkov E.R., Piotrovskiy L.B., Shabanov P.D.
Abstract

(S)-glutamic acid (glutamate) is the main excitatory mediator in the central nervous system, responsible for regulating of many physiological functions. Dysfunction of the glutamatergic system characterizes of many pathological conditions in neurology and psychiatry, and the aberrant function of glutamate receptors plays a key role in the development of neurodegenerative processes. Glutamate is crucial for many aspects of normal brain function, including memory, learning, and motor planning. In addition, glutamate is involved in the regulation of the peripheral nervous and endocrine systems. Glutamate receptors are critically important molecules necessary for the physiological functioning of the brain: they modulate neurotransmission and regulate the strength of excitatory and inhibitory transmission in the nervous system. In this regard, the use of drugs that affect glutamatergic transmission has an impact on the most important processes of neuronal transmission. The research and development of pharmacological agents involved in the processes of glutamate transmission is a relevant task of modern neuropsychopharmacology and has a purpose to improve the effectiveness and safety of available glutamatergic molecules.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):17-28
pages 17-28 views
Ghrelin-dependent mechanisms of food reward. Part 1. Ghrelin and dopamine
Reikhardt B.A., Shabanov P.D.
Abstract

Feeding behavior includes both the satisfaction of metabolic nutrient requirements and the hedonic aspects of pleasure. The orexigenic hormone ghrelin increases motivation to food intake. In addition, by modulating the reward system, ghrelin enhances the rewarding properties of non-food stimuli. The dopaminergic mesolimbic system plays a key role in the mechanisms of reward. Ghrelin regulates the activity of this system by acting on several levels of brain organization. The hierarchy of ghrelin-sensitive neural networks, as well as afferent connections and reciprocal interactions between its components, mediating the effect of ghrelin on the process of motivation in metabolic and hedonic type of feeding are considered.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):29-54
pages 29-54 views

Original articles

Evaluation of the bioavailability of 1H-imidazole-4,5-dicarboxylic acid derivatives using the calculated and experimental lipophilicity index of the molecule logP
Iljin V.V., Litasova E.V., Kvasov M.S., Brusina M.A., Piotrovskiy L.B.
Abstract

BACKGROUND: It is important to know the ability of a substance to penetrate the cell membrane to assess the bioavailability of drugs. The distribution of matter between the organic phase and water can be used as a model of the distribution between the membrane and extracellular fluid, and can be expressed by a partion coefficient, called logP.

AIM: The aim of this work was to determine the logP of 1H-imidazole-4,5-dicarboxylic acid (IDC) derivatives in various media and compare the values with theoretical ones.

RESULTS: As a result of the work, the distribution coefficients of the IDC derivatives were determined from the optical density data for a fixed wavelength of 250 nm (without a buffer). The distribution coefficients of the IDC derivatives over the maxima of the UV spectra (in the buffer) were determined. A comparison of theoretical and experimental values of the distribution coefficients of some IDC derivatives is carried out.

CONCLUSION: Thus, it has been shown that for a more accurate assessment of the bioavailability of drugs, it is not enough to rely only on the calculated logP index, it is necessary to conduct an experimental test, or introduce some correction factors to recalculate the theoretical logP index, in each specific class of compounds.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):55-60
pages 55-60 views
Level of mRNA of orexin receptors of second type (ORXR2) in conditions of chronic alcoholation in structures of the rat brain
Sekste E.A., Airapetov M.I., Eresko S.O., Bychkov E.R., Lebedev A.A., Kosyakova G.P., Shabanov P.D.
Abstract

BACKGROUND: Orexin and its receptors are involved in the mechanisms of pathological craving for alcohol, but there is no unambiguous answer about the expression of the OX2R gene in the rat brain under conditions of alcohol addiction.

AIM: The aim of this study was to determine the level of OX2R mRNA in brain structures in rats under conditions of prolonged alcoholization and during the period of abstinence.

MATERIALS AND METHODS: Adult male Wistar rats were alcoholized with 15% ethanol as the only source of liquid for 6 months. The rats were decapitated after chronic alcoholization, as well as on the 1st and 7th days of alcohol withdrawal. Samples of brain structures (prefrontal cortex, hippocampus, ventral tegmental area) were frozen in liquid nitrogen and stored at –80°C. Determination of the level of OX2R mRNA was carried out using the method of PCR-analysis.

RESULTS: The level of ORXR2 gene expression significantly increased in the hippocampus on the 7th day of abstinence in relation to the group of intact animals and in relation to the group of chronically alcoholized rats. The level of OX2R mRNA in the prefrontal cortex and ventral tegmental area in animal groups of abstinence (1st and 7th days) did not change in relation to both alcohol and the intact animals.

CONCLUSIONS: It is concluded that the orexin brain system may represent a new potential therapeutic target for the prevention of relapse in alcohol withdrawal. Together with the previously obtained data it was concluded that orexin receptor antagonists can be used to reduce the pathological craving for alcohol.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):61-66
pages 61-66 views
A promising method for the diagnosis of preclinical hypoxic state
Lyubimov A.V., Khokhlov P.P., Bychkov E.R., Shabanov P.D.
Abstract

BACKGROUND: The state of hypoxia in natural conditions occurs in certain cases and is considered as a negative process in the overwhelming majority of cases. However, exogenous hypoxia is used as a factor of adaptation / preconditioning and training to the forthcoming hypoxic stress under some conditions, as well as increasing physical endurance and working capacity in normoxic conditions among specialists of various profiles. The mechanisms of adaptation to exogenous hypoxia have been studied in detail. Earlier in our studies, the value of artificial exogenous normobaric hypoxic hypoxia, which does not have a negative effect on the human body, was determined.

AIM: The aim of this work was to determine hypoxia inducible factor 1α (HIF-1α) as a possible marker of adaptation to normobaric hypoxic hypoxia.

MATERIALS AND METHODS: For 100 days, 6 test volunteers were continuously in a sealed residential test room based on the test bench of ASM JSC (St. Petersburg) in a state of normobaric hypoxic hypoxia (oxygen content 12–20%).

RESULTS: No clinically significant erythrocyte response to long-term exposure to normobaric hypoxic respiratory mixture was expectedly detected, although statistically significant fluctuations in the level of hemoglobin and the absolute number of erythrocytes were determined. When analyzing the HIF-1α concentration, qualitative data were obtained, characterizing a significant response (p < 0.05) in the change in HIF-1α concentration during the observation period. Additionally, a Kendall consistency factor of 0.68 was calculated, suggesting a significant difference in HIF-1α concentration dynamics.

CONCLUSIONS: The chosen mode of hypoxia can be used as a method of exogenous preconditioning.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):67-74
pages 67-74 views
Assessment of ethylthiobenzimidazole and fabomotizole activity in a model of hypercapnic hypoxia with cutting off the brain hemispheres work
Marysheva V.V., Mikheev V.V., Shabanov P.D.
Abstract

BACKGROUND: Resistance to hypoxia depends on the type of animal, its condition (fatigue, pre-exposure, pregnancy in females) and the conditions of the experiments.

AIM: study the effect of ethylthiobenzimidazole (Metaprot, Bemityl) and fabomotizole (Afobazole), which were antihypoxants with an isothiourea group, on the resistance of male outbred mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one of the cerebral hemispheres.

MATERIALS AND METHODS: Acute hypoxia with hypercapnia was simulated by the “cupping method” by placing male mice in a closed hermetic volume (200 cm3) until the death of the animal. Previously, in some mice, one of the cerebral hemispheres was temporarily switched off according to the Leao method.

RESULTS: It has been shown that ethylthiobenzimidazole and fabomotizole, administered intraperitoneally in equimolar doses (25 and 32.8 mg/kg, respectively) 30 min before a hypoxic episode, increase the life time of experimental animals when either of the hemispheres (right or left) is turned off approximately equally.

CONCLUSIONS: Data are considered in terms of the possibility of using both drugs in the prevention and treatment of ischemic strokes.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):75-82
pages 75-82 views
Effect of orexin and its antagonist on the organization of emotional and exploratory behavior of rats in a model of psychic trauma
Tissen I.Y., Lebedev A.A., Khokhlov P.P., Bychkov E.R., Tsikunov S.G., Shabanov P.D.
Abstract

BACKGROUND: A number of recent studies have revealed the role of orexins in regulating emotional behavior and emotional memory. The rationale for this role of orexin regulation is the close bi-directional interaction of orexin neurons with emotional structures of the brain, such as the bed nucleus of the stria terminalis, locus ceruleus, central and dorsomedial amygdala, hippocampus, medial prefrontal cortex. There is experimental and clinical evidence that an endogenous or induced deficiency of orexin effects accelerates the elimination of traumatic memory.

AIM: To study the effect of the OX1R Orexin Receptor Antagonist SB408124 and orexin on the emotional and exploratory behavior of animals after predator-induced stress.

MATERIALS AND METHODS: The experiments were made with 36 male Wistar rats, divided into 4 groups of 8 animals. Animals of 3 groups were exposed to single simulation of post-traumatic stress disorder by exposition with the indian python and subsequent death of one rat as a result of predator activity. The rats of 2 experimental groups received SB408124 OX1R antagonist in a dose of 20 µl of 0.1% solution and Orexin A in the same dose intranasally. The other animals received physiological solution in a dose of 20 µl intranasally. Behavior tests was made 7 days after the modeling of psychotrauma. A panel of behavioral tests was used: an elevated X-maze, an “open field” test, and an “resident–intruder” test. The obtained data were statistically processed using the Student t-test and ANOVA dispersion analysis. The differences were considered statistically significant at p < 0.01.

RESULTS: Orexin antagonist SB408124 showed anxiolytic effects. SB408124 showed anxiolytic properties in stressed rats. It restored the time spent in the light arm of the elevated X-maze to the intact level. In the open field test SB408124 increased (p < 0.01) the orientation behavior and reduced the frequency of freezing in stressed animals. Orexin A suppressed (p < 0,01) locomotor activity of animals in the open field. In the “resident–intruder” test in stressed animals SB408124 restored suppressed communication activity (p < 0,01). Orexin A reduced communicative behavior and increased aggression of animals.

CONCLUSIONS: The work shows a moderate anxiolytic action of SB408124 in the post-traumatic stress model in rats.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):83-88
pages 83-88 views

Clinical pharmacology

Does succinate as a structural component of a drug enhance efficacy of treatment of asthenic disorders in patients with somatic injuries?
Buznik G.V.
Abstract

AIM: The aim was to assess the efficacy of treatment of asthenic syndrome in patients with combined injuries by means of succinate containing metabolic drugs (Mexidol, Cytoflavine, Metaprot plus) in comparison with non-succinate containing drugs of analogic structure or composition (Emoxipine, Riboxine, Metaprot) to clear up the significance of succinate as a functional structural element of the molecule.

MATERIALS AND METHODS: In 134 surgical patients and sufferers with combined injuries, an asthenic syndrome (high anxiety, depression, high psychic and physical tiredness, weakness, absent-mindedness, attention disorders, reduced physical and psychical ability, need in durative rest, high psychic exhaustion, social disadaptation) was revealed by clinical, psychological and instrumental methods.

RESULTS: Metabolic drugs containing succinate (Mexidol, Cytoflavine, Metaprot plus) in more degree than non-containing succinate in their structure (Emoxipine, Riboxine, Metaprot) were clinically effective in abolition or reduction of the asthenic syndrome in such patients. Antiasthenic action was represented by proper antiasthenic, antidepressant, anxiolytic, nootropic (cognitive) and positive general somatic effects of the drugs.

CONCLUSION: The data confirm that succinate in the structure (composition) of the metabolic drugs significantly enhances protective action against asthenic syndrome in surgical patients with combined injuries.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):89-98
pages 89-98 views

Phytopharmacology and Phytotherapy

Adaptogens as potential drugs for prevention of infectious diseases
Vershinina S.F., Yaremenko K.V.
Abstract

The work is devoted to the analysis of scientific research on the prevention of infectious diseases by adaptogens, proposed by a prominent domestic toxicologist and pharmacologist Professor Nikolai Vasilyevich Lazarev and the school of scientists he created. The role of adaptogens (dibazol, Eleutherococcus, Rhodiola rosea, Scutellaria Baicalensis) in creating a state of non-specifically increased body resistance (NSIBR according to N.V. Lazarev) for the prevention of viral diseases, including coronavirus infection, was evaluated. Analysis of the pharmacological properties of the synthetic adaptogen bendazol (dibazol) opened by N.V. Lazarev, showed that the drug has a number of positive properties: antiviral – stimulates immunity to the attack of infectious agents, being an inducer of endogenous interferon; antiproliferative – inhibits the replication of viruses inside the host cell; immunomodulatory – corrects violations of the protective functions of the body. Dibazol also has a mild effect after vaccination, stimulating the production of immunoglobulins. These properties of dibazol make it possible to recommend it and herbal adaptogens (tinctures of Eleutherococcus, Rhodiola rosea, Scutellaria Baicalensis) for the prevention of coronavirus infection.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):99-104
pages 99-104 views
Some pharmacological propertyes of Chamerion angustifolium infusions
Barnaulov O.D.
Abstract

BACKGROUND: Chamerion angustifolium has been popular among the people for many centuries as a substitute for tea and a mild sedative. Leaf infusions are used for neurosis, cephalgia, epilepsy and other neurological diseases.

AIM: Was to experimentally confirm the cerebroprotective properties of Chamerion leaf infusions.

METHODS: We used the methods of maximum electric shock, conditioned passive avoidance, and immobilization stress in rats and mice.

RESULTS: Infusions of leaves experimentally revealed no anticonvulsant properties. Cerebroprotective properties were manifested in the preservation of the passive avoidance conditioned reflex after maximum shock and faster recovery of exploratory behavior. Distinct stress-limiting properties were revealed during immobilization stress in mice. Fermented leaves have been shown to be less effective than non-fermented ones.

CONCLUSION: The data obtained confirm the presence of cerebroprotective properties of the infusion of Chamerion angustifolium.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(1):105-112
pages 105-112 views

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