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 19, No 1 (2021)

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Proposed mechanisms of systemic cardiovascular action of gliflosins
Zverev Y.F., Rykunova A.Y.

The literature review is devoted to the study of the mechanisms of the cardioprotective action of a new class of glucose-lowering drugs glyflozins, which inhibit the joint transport of sodium and glucose in the proximal renal tubules. The large-scale clinical trials carried out in recent years have demonstrated the beneficial effect of these compounds not only on glycemic control, but also on the progression of heart failure in patients with diabetes mellitus. Analysis of literature data shows that the effect under consideration is due to both the positive systemic cardiovascular and direct cardiotropic action of the drugs. The first part of the review examines the systemic effect of drugs, including their diuretic, natriuretic and antihypertensive effects, increased hematocrit, vascular effects that influence arterial stiffness, smooth muscle tone, and endothelial dysfunction. The metabolic effects of type 2 sodium and glucose co-transport inhibitors are discussed separately, including an increase in lipolysis, the role of glucagon and activation of ketogenesis, and their contribution to the development of a probable cardioprotective effect.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):5-22
pages 5-22 views
Zinc, brain, behavior
Yakimovskii А.F.

The purpose of the review was to analyze current notions about role of essential trace element zinc in brain activity and therefore – in behavior. At the beginning of the review the basic data about zinc metabolism was described. The facts of zinc involvement into neurologic disorders and human cognition were represented. The results of the own investigation, devoted zinc peroral treatment and intrabrain microinjections influence on rats normal and pathological motor behavior were described. In particular, it is shown that zinc, depending on the dose and its mode of entry into the organism, can weaken and prevent the development of picrotoxin-induced neostriatal hyperkinesis (human Huntington horea analog), but it may aggravate hyperkinesis symptoms and even independently cause the motor stereotypy. On the basis of their own data and literary, it was suggested that neurons membranes structures are different sensitive to a certain zinc concentration and what does the specific way of behavior realization is ultimately depend.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):23-35
pages 23-35 views

Original articles

Hypolipidemic drugs inhibiting the proprotein convertase of subtilisin/kexin type 9 (PCSK9): monoclonal antibodies, antisense oligonucleotides, small interfering ribonucleic acids
Chaulin A.M.

Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic drugs. In 2003, canadian and french research groups led by N. Seidah and M. Abifadel discovered a new enzyme – proprotein convertase subtilisin/kexin type 9 (PCSK9), which later turned out to play an important role in lipid metabolism. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 significantly accelerates the degradation of LDL and leads to an increase in the concentration of atherogenic classes of lipoproteins-low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Given this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit THIS enzyme. To date, several new groups of drugs have been developed that target the stages of biosynthesis and the function of PCSK9. In this article, we will focus in detail on discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):37-46
pages 37-46 views
Conditioned place preference of kisspeptin-10
Tissen I.Y., Chepik P.A., Lebedev A.A., Magarramova L.A., Bychkov E.R., Shabanov P.D.

INTRODUCTION: Kisspeptins (KISS), a group of brain neuropeptides are involved in sexual behavior. KISS activate the hypothalamic neurons that synthesize gonadotropin releasing hormone. KISS was also detected in the limbic system. Earlier, we showed the activation of sexual motivation after the administration of kisspeptin-10 without increasing the level of testosterone in male rats, which suggests the extrahypothalamic effect of KISS.

The aim of this work was to study the possibility of aquisition of conditioned place preference of kisspeptin-10, as well as to study the emotional and investigational behavior in rats after intranasal peptide administration.

METHODS: Conditioned place preference test (CPP), “open field” test (OP) and “elevated plus maze” (EPM) were used in male Wistar rats.

RESULTS: When studying CPP, animals spent 78.6 ± 6.3% of the time in the chamber associated with the administration of KISS compared to control animals with administration of physiological saline (51.2% of the experiment time; p < 0.05). After kisspeptin-10 administration locomotor activity was 2-fold increased (p < 0.05), and the number of sniffings was 2-fold increased too (p < 0.05). The parameters did not significantly differ in animals treated with kisspeptin or saline in PCL.

CONCLUSION: Thus repeated intranasal administration of kisspeptin-10 induces the aquisition of CPP in rats. This suggests that kisspeptin-10 can cause activity in the reward system or the activation of brain regions associated with this system, which ultimately leads to the formation of an emotionally positive state.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):47-53
pages 47-53 views
Evaluation of the activity of antihypoxants with an isothiourea structure in a model of hypercapnic hypoxia with a shutdown of the cerebral hemispheres
Marysheva V.V., Mikheev V.V., Shabanov P.D.

PURPOSE: To study the effect of amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) on the resistance of male outbred mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one from the hemispheres, as well as both hemispheres of the brain.

METHODS: A model of acute hypoxia with hypercapnia (“canned” hypoxia) was used in mice of the same mass, the lifespan of all animals was determined. Temporary shutdown of the cortex of one of the hemispheres or both hemispheres was achieved by epidural application of filter paper moistened with 25% potassium chloride solution, creating a spreading depression according to Leao. Amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) at equimolar doses of 25, 32.5, and 50 mg/kg, respectively were used as pharmacological analyzers, the compounds were injected intraperitoneally 30 min before the hypoxic episode.

RESULTS: It was shown that, in contrast to amtizol, 2-ABT and VM-606 increase the life time of experimental animals when any hemisphere is turned off. The use of drugs when both hemispheres were turned off revealed that amtizol has approximately equal effect on the brain and the rest of the body, in 2-ABT antihypoxic activity is 1/3 associated with the brain, in VM-606 exclusively with the brain.

CONCLUSION: The experimental model used in this work makes it possible to quite easily evaluate the effect of either one drug or compare several drugs, their role in the functioning of the cerebral hemispheres, on which part of the sample – highly resistant or low resistant to hypoxia – they have the greatest effect.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):55-63
pages 55-63 views
Effects of S-adenosyl methionine and essential phospholipids on serum biochemical parameters in simulated acute liver disease in late pregnancy
Petrosyan M.A., Zhestkova N.V., Tumasova Z.N., Polyanskikh L.S., Balashova N.N., Baziian E.V., Kuz’minykh T.U., Razygraev A.V.

AIM: Liver diseases, developing in late pregnancy, remains a very important problem in obstetrics. In present study, the aim was to evaluate the effectiveness of monotherapy by “essential phospholipids” and by S-adenosyl methionine for simulated acute liver pathology during pregnancy using the biochemical parameters of blood serum.

STUDY DESIGN AND METHODS: Acute liver injury was simulated in rats from 15th to 18th day of pregnancy using tyloxapol (300 mg / kg daily). As drugs for monotherapy, Essentiale (Sanofi-Aventis, France) and Heptral (Abbott srl, Italy) were used separately and were administered to rats daily from the 16th to the 18th day of pregnancy (50 mg / kg and 35 mg / kg, respectively). On the 19th day of pregnancy, blood serum biochemical parameters were analyzed.

RESULTS: In the model, the concentrations of triglycerides and cholesterol were sharply increased, which can be caused not only by the inhibitory effect of tyloxapol on the lipoprotein lipase of the lumen of blood vessels, but also by damage to liver cells with the accumulation of lipids in them. The activities of aminotransferases (ALT, AST), glutamate dehydrogenase and lactate dehydrogenase were statistically significantly increased. In healthy pregnant rats, the activity of alkaline phosphatase (ALP) decreased from 15th to 19th day of gestation, but under the treatment by tyloxapol in some cases the increase of ALP activity was observed. After using essential phospholipids in the model of acute liver injury, normal values of ALT and ALP activities were observed, and a significant decrease in triglycerides was revealed, which did not reach the normal values. After using S-adenosyl methionine in this model, the significant changes in blood serum parameters were not observed. By themselves, the drugs change several biochemical parameters in the serum of healthy pregnant rats. Heptral increases urea levels and Essentiale appears to increase AST activity.

CONCLUSION: The use of essential phospholipids or S-adenosyl methionine as monotherapy in a model of acute liver damage in late pregnancy has demonstrated their low efficiency. It is possible that the combined use of drugs is necessary to increase the effectiveness. The use of S-adenosyl methionine should be carried out under the control of the urea level and glutamate dehydrogenase activity in serum. While using essential phospholipids, it is advisable to control the AST activity.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):65-70
pages 65-70 views
Behavioral analysis of anxiolytic action of phenazepam in conditions of an acute psychogenic stress (predator presentation) in Danio rerio
Lebedev A.A., Devyashin A.S., Blazhenko A.A., Kazakov S.V., Lebedev V.A., Bychkov E.R., Shabanov P.D.

We studied the effect of benzodiazepine anxiolytic phenazepam after the predator presentation to Danio rerio. The test of novelty was used: the fish was placed first in a beaker with a dissolved pharmacological substance (or H2O) and then into a novel tank for 6 min, where the trajectory, the path length, the number of movements to the upper part of the novel tank, the number and time of the pattern of “freezing” were measured. It is shown that, in response to the novelty of tank, the fish are reacted by submerging to the bottom, increasing the frizing, and reducing the number of movements to the upper half of the novel tank. After phenazepam administration, the fish were not only in the lower, but also in the upper part of the novel tank. The average path length did not change significantly in the range of doses used. The number and time of the frizing, as well as the time spent in the lower part of the novel tank, decreased more than 2 times compared to the control group of animals and showed a dose-dependent effect. The number of movements to the upper part of the novel tank for the experiment increased significantly from 1 in the control to 57 after phenazepam in a dose of 1 mg/l. At the same time, the number of movements of fish to the upper part of the novel tank significantly increased more than 2 times from 3th min of the experiment with the use of phenazepam in a dose of 1 mg/l. Predator presentation (Hypsophrys nicaraguensis) caused an increase in the number of freezing (temporary immobilization) and a decrease in the length of the trajectory of movement in the novel tank as compared with the Danio rerio control group. Phenazapam at a dose of 1 mg/l removed the effects of a predator, while exhibiting a typical effect: the number of movements to the upper part of the tank during the experiment significantly increased to 30; the time at the bottom of the tank was halved. It was concluded that the novelty stress test and the test with a predator are highly sensitive for studying anxiety-phobic reactions in Danio rerio.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):71-78
pages 71-78 views

Clinical pharmacology

Safety of anesthesia in acute blood loss moderate hypovolemia
Klimov A.G., Stepanov Y.A., Erdniyev L.P., Mokshanov I.V., Mikshta A.Y., Ivashev I.P., Stepanova N.V., Andreev V.A.

Acute blood loss is the most common cause of death in armed conflicts. During the great Patriotic war, 37.2% of the wounded died on the battlefield from acute blood loss and its consequences. According to statistics of military surgeons in local wars, the percentage of deaths from bleeding on the battlefield has remained quite high in recent decades: in Afghanistan, 43% due to untimely first aid for gunshot and mine-explosive wounds, of which 27% died from acute blood loss. During counter-terrorism operations in the North Caucasus, acute blood loss was the cause of death in 26.6% of cases. Analysis of recent armed conflicts shows that the main causes of death on the battlefield are the consequences of penetrating wounds, in particular blood loss with combined traumatic brain injuries of various origins. The issue of analgesia for a lack of circulating blood volume, as well as for continuing bleeding, is complex due to the need to prevent the development of shock conditions against the background of possible side effects of anesthesia. The paper presents pharmacometric and toxicometric characteristics of a model agonist of opioid receptors in acute blood loss of moderate hypovolemia in an experiment. It was shown that the sensitivity of white rats and rabbits to intravenous anesthesia according to the criteria of deep anesthesia increased by 7.3 and 7.5 times, respectively; there were no changes in the mortality criterion for acute blood loss of moderate hypovolemia. A decrease in the speed of action and an increase in the duration of the effect of deep anesthesia in hypovolemia after intravenous administration of a model opioid receptor agonist at doses of 1 ED50 was revealed. An assessment of the breadth of therapeutic action of the model agonist of opioid receptors was made, according to the results of which an increase in this indicator was revealed. It is shown that it is necessary to clarify the anaesthetic manual for more severe variations of polytrauma with blood loss.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):79-86
pages 79-86 views


Thermal pharmacology: history and definition
Urakov A.L.

The literature review shows that temperature pharmacology is a new scientific and practical direction of pharmacology, in which the local effect of drugs on individual tissues, organs or parts of the body is realized at a certain local temperature. This trend was formed in Russia at the end of the 20th century due to the fact that such great surgeons as V.A. Negovsky, E.N. Meshalkin and V.I. Shumakov proved in clinical conditions that hypothermia prolongs the safety of the brain, heart and kidneys in the absence of arterial blood and/or oxygen. Then, under the influence of the successful use of local hypothermia for therapeutic purposes in such areas as resuscitation, transplantology and surgical treatment of heart and major vascular diseases, the study of the mechanism of action of local hypothermia as a medicine began. Intensive research in this area began in 1981 at the Department of Pharmacology of the Izhevsk Medical Institute. In the following years, the features of the local action of local hypothermia, drugs and their combinations on mitochondria, blood, blood vessels, myocardium, intestines and limbs of experimental animals and patients in normal conditions, as well as in hypoxia and ischemia were studied. Very soon, the results of research allowed to reveal the main mechanisms of action of local hypothermia and the laws of temperature dependence of the local action of drugs. This allowed to invent several original methods of pharmaco-cold and pharmaco-warm effects that increase the effectiveness of treatment of arterial obstruction of the extremities, inflammatory processes and parenchymal bleeding. It is indicated, that the main provisions of temperature pharmacology were formulated by 1988. The chronology of resolving the contradictions that arose at that time between the widespread public opinion and new ideas about the role of local temperature in the mechanism of local action of drugs in hypoxia, ischemia, inflammation of organs and tissues, and bleeding is shown. Achievements and prospects of development of temperature pharmacology in medicine, biology, pharmacology and pharmacy are shown.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):87-96
pages 87-96 views

Short communications

Antistress action of Fornicium uniflorum extract in chronic stress
Gulyaev S.M., Shantanova L.N.

The anti-stress effect of the Fornicium uniflorum extract was studied in Wistar rats in model of chronic unpredictable stress. Stress disorders in rats were determined using methods open field, plus elevated maze, forced swimming test, tail suspension model, sucrose test, as well as changes in the weight indicators of stress target organs. The course administration of F. uniflorum extract to rats under conditions of chronic stress prevented the development of behavioral disorders: the indicators of horizontal, vertical motor activities and mink reflex in the open field were, respectively, 1.5, 4 and 2.5 times higher than those of control rats (without treatment) (p < 0.05); the time spent in the open arms of the plus elevated maze and the number of entries into them were respectively 3 and 8.5 times greater than the indices of control rats (p < 0.05); the time of immobility of rats in the forced swimming test and the model of hanging by the tail were 2 and 3 times less than in the control; the volume of consumption of sucrose solution in the sucrose test by rats was 1.4 times higher than that of control rats (p < 0.05), which indicated the antidepressant activity. In the rats treated with F. uniflorum, no changes in the relative mass of stress target organs were noted, in contrast to the control (p < 0.05). Therefore, the course administration of F. uniflorum has an anti-stress and antidepressant effect in chronic unpredictable stress.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):97-102
pages 97-102 views
A wide range of pharmacological properties of melatonin
Arushanian E.B., Naumov S.S.

The pineal gland hormone melatonin has various pharmacological activity. In experimental work, he revealed anti-anxiety, antidepressant, neuroprotective, anti-pain and anti-inflammatory properties.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):103-106
pages 103-106 views
Comparative evaluation of the antistress effect of phenazepam, melatonin and their combination
Arushanian E.B., Vladimirovna O., Beyer E.V.

Phenazepam and melatonin reduce anxiety in stressed rats, and their anxiolytic effect is enhanced in combination. Melatonin also limits stress-induced increases in sympathetic activity and eliminates the dysregulatory effect of phenazepam on the main indicators of heart rate variability.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):107-110
pages 107-110 views
Evaluation of the anti-inflammatory activity of melatonin in a model of experimental arthritis
Naumov S.S.

The epiphyseal hormone melatonin (1 and 5 mg/kg) significantly limited locomotor and psychoemotional disorders, indicators of inflammation and immunological reactivity in rats with experimental adjuvant arthritis.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):111-114
pages 111-114 views
Antistress properties of 2-substituted derivatives of quinazoline-4(3Н)-on
Manvelyan M.M., Manvelyan E.A., Baturin V.A., Chagarova S.A.

2-Substituted hydroxy- and methoxyphenyl derivatives of quinazoline-4(3Н)-on at doses of 0.1 and 0.2 of molecular weight in mg/kg reduce the emotional reactivity of rats, having an anti-stressant effect when tested in a “raised cruciform labyrinth”, “open field”, in a multivariable assessment of behavior.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):115-118
pages 115-118 views
Differences in consumption of psychotropis drugs in depression disorders: ethnic aspects
Stepanyan S.A., Manvelyan E.A., Manvelyan M.M., Yarovitskii V.B., Chagarova S.A.

In the pharmacotherapy of depressive disorders, drug consumption was maximal in the group of Slavs, less in the groups of Karachays, Turkmens, Nogais, and minimal in the group of Armenians.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):119-122
pages 119-122 views
Personification of the selection of pharmacological treatment of stress and post-stress disorders based on biometric data
Tataritntseva R.Y., Ivanova L.G., Migachev D.V.

Scientific researches have proven the pathogenetic relationship between stress and the development of a wide range of diseases. The impact of stress to the development of somatic diseases is well known, but greatly underestimated, since the treatment of stress and the correction of its consequences is an important aspect in the prevention and treatment of any, even infectious diseases, which was proved during the COVID-19 pandemic in 2020. The introduction of individual mobile medicine devices (M-Health) into a wide medical practice makes it possible to provide not only remote monitoring of the patient’s condition, but also to conduct remote treatment, with the selection and correction of drug therapy based on objective biometric data.

Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):123-126
pages 123-126 views

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