[Pharmacokinetics and pharmacodynamics of rebamipide. New possibilities of therapy: A review].

The MedLine database contains 570 publications, including 71 randomized clinical trials and 6 meta-analyses on the rebamipide molecule in 2022. Indications for the use of rebamipide are gastric ulcer, chronic gastritis with hyperacidityin the acute stage, erosive gastritis, prevention of damage to the gastrointestinal mucosa while taking non-steroidal anti-inflammatory drugs, eradication of Helicobacter pylori. Currently trials are studying the efficacy and safety of the drug in gouty and rheumatoid arthritis, osteoarthritis, Sjögren's syndrome, bronchial asthma, vitiligo, atherosclerosis, diseases of the kidneys and liver; using in traumatology to accelerate bone regeneration; in ophthalmology to improve the regeneration of corneal epithelium; in oncology to reduce inflammatory changes in the oral mucosa after chemoradiotherapy. The review article is about the main pharmacokinetic and pharmacodynamic characteristics of rebamipide. A detailed understanding of pharmacodynamics and pharmacokinetics allows for individual selection of therapy based on the characteristics of the patient's body - gender, age, comorbidities; choose the optimal route of administration and dosing regimen; predict adverse effects and drug interactions; be determined with new clinical indications.

[Molecular mechanisms of hypoxia and adaptation to it. Part II]. / Molekulyarnye mekhanizmy razvitiya gipoksii i adaptatsii k nei. Chast' II.

Reprogramming of the mitochondrial electron transport chain (ETC) is the most important physiological mechanism that provides short- and long-term adaptation to hypoxia. The possibilities of additional pharmacological regulation of ETC activity are of considerable practical interest in correcting hypoxia-associated disorders. This review considers the main groups of antihypoxic compounds that exhibit their effect at the interface of ETC and the cycle of tricarboxylic acids, including succinate-containing and succinate-forming antihypoxants. The role of succinate during adaptation to hypoxia, the biological activity of the succinate, and its potentially adverse effects are currently not fully understood and require further clarification.

[Molecular mechanisms for hypoxia development and adaptation to it. Part I]. / Molekulyarnye mekhanizmy razvitiya gipoksii i adaptatsii k nei. Chast' I.

Hypoxia is a typical pathological process characterized by the occurrence of oxygen deficiency in tissues and cells and accompanied by the development of immediate and delayed compensatory and adaptive reactions. Reprogramming of the mitochondrial electron transport chain (ETC) function is one the most essential regulatory mechanisms that allow for immediate adaptation to hypoxia. Succinic acid, or succinate, is involved in this process not only as one of the intermediates of the tricarboxylic acid (TAC) cycle, but also as a signaling molecule. In this connection, the purpose of this review was to systematize the available data on the molecular mechanisms for the development of hypoxia and its adaptation at the ETC/TAC coupling site, as well as on the role of succinic acid in these processes.

[Ornitine-dependent mechanisms of muscle fatigue correction and recovery from physical activity]. / Ornitinzavisimye mekhanizmy korrektsii myshechnogo utomleniya i vosstanovleniya posle fizicheskikh nagruzok.

The article analyzes the literature data characterizing modern concepts of the mechanisms of muscle fatigue and metabolic features of recovery processes after exhausting loads. The significance of transient hyperammonium in the formation of the developed complex of fatigue manifestations in the central and peripheral links of motor units, its pathogenetic links with oxygen debt, lactacidosis, violation of ATP resynthesis, deficiency of energy-supplying substrates in working skeletal muscles, damage to muscle fibre structures, and dysfunction of various parts of the CNS is shown. The necessity of correction of hyperammoniemia associated with physical activity has been confirmed to reduce the speed of formation and expression of fatigue feeling, to reduce the risks of development of fatigue and overtraining states in sportsmen and to ensure effective course of recovery processes after exhausting physical activity. It was revealed that ornithine-containing preparations can be used for correction of post-load hyperammonium and acceleration of recovery processes. The data characterizing the high efficiency of L-ornitine-L-aspartate in sports medicine practice are presented.

[The application of succine in sports].

The development of energy deficiency in the course of physical exercises that eventually leads to serious derangement of the energy metabolism is an important component of the deterioration of physical and intellectual working capacity. The most promising approach to the correction of impaired physical and intellectual working capacity associated with energy deficiency consists in the application of pharmaceutical preparations containing intermediate products of the tricarbonic acid cycle. Of great promise in this context is succinic acid by virtue of its oxidation in endogenous reactions that constitutes the physiological adaptive mechanism by which resistance of the organism to oxygen deficiency is promoted.

[Rat heat structural and functional characteristics and gas exchange parameters after experimental myocardial infarction].

Rat heart structural and functional changes and gas exchange parameters were investigated in six months after experimental myocardial infarction. Left ventricular end-systolic and end-diastolic dimensions in rats with chronic heart failure were 78 and 30% higher than in control respectively. Left ventricle cavity volume in systole and diastole were 5 and 2 times increased respectively. Left ventricular cavity stretching was accompanied by thinning of the interventricular septum. Left ventricular structural changes leads to its functional deterioration. Left ventricular contraction fraction was reduced by 60%, and the ejection fraction--by 52% in comparison with control. Gas exchange investigation revealed that in six month after myocardial infarction oxygen consumption of operated rats was increased by 30% and production of carbon dioxide by more than 40%. Respiratory quotient, which reflects the nature of oxidized substrates, in rats with myocardial infarction was amounted to 0.85, indicating significant increase in the contribution of carbohydrates as an energy substrate for myocardial metabolism.

[Cough: differential diagnosis and rational pharmacotherapy].

This publication deals with topical problems in the management of patients with cough. It presents its epidemiology and clinical classification, an analysis of its causes, a list of required diagnostic techniques, and areas of pharmacotherapy. Emphasis is laid on the differential diagnosis of different abnormalities and diseases, the leading clinical sign of which is cough. The authors provide the detailed characteristics of medicaments for its treatment and the principles of rational antitussive and mucoactive pharmacotherapy.

[Reaction of population of pulmonary mast cells in rat bronchial asthma under the effect of ß-adrenoreceptor antagonists].

Multifunctional granular mast cells (MCs) are among targets in bronchial asthma (BA) therapy. We studied pulmonary MC population in a rat model of BA under the effect of ß-adrenoreceptor antagonists and of the latter combined with the standard therapy (glucocorticoid budesonide + ß2-adrenergic agonist salbutamol). MCs of different degrees of maturity were identified on paraffin section of lung stained with Alcian blue and Safranin. MC density in the lung of rats with BA increased 1.9 times. Alcian blue-positive immature cells predominated in the lungs of both intact rats and rats with BA. In response to pharmacological agents, the mean MC densities were reduced in 2-2.7 times in all the variants of experiments and were close to the norm. It allows us to suppose that MCs migration from the outside was suppressed and, in consequence of the decline of MC densities, the release of the mediators involved in the progression of BA may be diminished.

[Pharmacological activity of runihol and S-adenosyl-L-methionine in rats with experimental liver damage by reserve antituberculosis drugs].

The hepatoprotective action of runihol and S-adenosyl-L-methionine (ademethionine) has been studied in a group of 47 white outbred male rats with model liver injury induced by reserve antituberculosis drugs (PAS, prothionamide, cycloserine). The ability of test drugs to correct structural and functional liver disorders is established. Both runihol and ademethionine favored decrease in the signs of structural and functional liver disorders induced by reserve antituberculosis drugs, Showing mixed type of action, the test drugs promoted recovery of the liver parenchyma and reduced manifestations of hepatocyte dystrophy to the same extent, without manifestations of necrobiotic processes and a mononuclear infiltration.

[Meglumine acridonacetate in combined antiviral treatment of HBeAg-positive chronic hepatitis B].

647 patients with HBeAg positive chronic hepatitis B who have not previously received antiviral therapy were participated in randomized, post-marketing, double-blinded, placebo-controlled clinical trial. Interferon inducer cycloferon was presented as study drug. 323 patients with chronic hepatitis B (HBV) with "wild" HBeAg(+) strain of HBV were treated with cycloferon and Lamivudin for 48 weeks. Control group included 324 patients with similar pathology, treated with Lamivudin and placebo for 48 weeks. The study has shown the benefit of cycloferon+lamivudin treatment in comparison with lamivudin monotherapy. Improving of liver histology in 48 weeks of the therapy was observed in 71% of patients in Study group in comparison with 57% in control group (p<0.01). Combined therapy has resulted in decrease of relapse by 24 week of the follow-up period (13% vs. 86%, p<0.001). The higher efficacy of cycloferon+lamivudin in patients with HBeAg positive chronic hepatitis B has proven the role of own antiviral effect of interferon inducer cycloferon, interferon effect of cycloferon in the elimination of virus-infected hepatocytes, as well as the presence of an immunomodulatory effect of the preparation, aimed at the elimination of HBeAg and HBsAg with the following seroconversion. 48-week course of combined antiviral therapy of HBeAg-positive patients with chronic hepatitis B is recommended as first-line therapy for patients with HBeAg-positive chronic hepatitis B, who have not previously received nucleoside analogues, as well as alternative therapy of Lamivudin-refractory patients.

[Relationship between the endogenous interferon IFN-gamma level and risk of hepatotoxic liver damage in tuberculosis patients].

Results of investigation in a group of 91 patients with infiltrative and disseminative forms of tuberculosis are presented. It is established that, at an initial level of IFN-gamma below 100 pg/ml, a higher frequency of development of the drug-induced liver injury takes place as manifested by increasing activity of the basic markers of cytolysis. Administration of the interferon inductor (cycloferon) favors positive clinical and laboratory dynamics of the tubercular process, increases the level of endogenous IFN-gamma (especially for an initial level below 100 pg/ml), and restricts the expression of drug-induced hepatotoxicity reactions.

[Hepatotropic therapy in treatment of liver injury].

At present, the conception of the use, efficacy and safety of hepatotropic agents in treatment of drug-induced liver injury, in particular due to antituberculosis drugs is not yet final, which is conditioned by extremely rare clinical trials on the subject adequate to the up-to-date principles of the conclusive medicine. The review presents data on the hepatotoxic effect of antituberculosis drugs, analysis and systematization of the data on the use of hepatotropic agents in liver injury induced by antituberculosis drugs, the principles and characteristics of their clinical use. The mechanism of action of remaxol, a new original hepatotropic agent and the indications of its use are discussed. The experimental findings on the remaxol ability to decrease the antituberculosis drug-induced liver injury through lowering the carbohydrate, albuminous and fatty degeneration and activating the organ reduction are presented. The clinical trials are evident of the most efficient action of remaxol on the signs of toxemia, as well as cytolysis and cholestasis, which along with its antiasthenic and antidepressant action allows to use remaxol as an universal hepatotropic agent in the treatment of diverse drug-induced liver injuries in both the therapeutic and prophylactic schemes.

[Aproaches to immunotherapy in different immunophenotypes of cutaneous basal cell carcinoma].

The combination of two immunomodulating agents (genferon derived from exogenous IFN-alpha2b and cycloferon, endogenous IFN inductor) was added to the complex therapy of 60 patients with different cutaneous basal cell carcinoma (CBCC) immunophenotypes. All patients underwent tumor resection, 1-3 days after surgery the patients received immunotropic therapy by focal cycloferon injections (2 ml of 12.5% solution) on days 1, 2, 4, 6, 8 and 10 post-operation with simultaneous genferon therapy via suppositoria (1 000 000 ME) twice a day for 10 days. The therapy was well-tolerated. Essential parameters of immune homeostasis were evaluated before and 3 months after immunotropic therapy. During further observation (for a mean period of 1.8 years) none of the patients displayed any signs of CBCC relapse. The immunological studies results give evidence for correction of immune disturbances characteristic for CBCC patients. This data confirm the effectiveness of immunotropic therapy for relapse prevention and immune disorders correction and allow recommending it for CBCC patients with high relapse risk.

[Antihypoxants in current clinical practice].

Hypoxia is a universal process accompanying and determining the development of various pathological conditions. In the most general form hypoxia can be defined as the incompatibility between energy requirements of the cell and energy production in the system of mitochondrial oxidative phosphorylation. The energetic status of the cell can be improved by such pharmacological products as antihypoxants of 5 groups: inhibitors of fatty acid oxidation, succinate-containing and succinate-producing agents, components of the natural respiratory chain, artificial redox-systems, and macroergic compounds. This paper is focused on the mechanisms of action of these products, their major effects, and results of clinical studies. Special emphasis is laid on succinate-containing products combining properties of a balanced polyionic solution and an antihypoxant (reamberin, cytoflavin, remaxol). They are known to be effective against various pathological conditions including ischemic stroke, toxic, hypoxic and dyscirculatory encephalopathies, infectious diseases, posthypoxic lesions in the central nervous system of newborns, various intoxications), etc.

[The improvement of complex treatment of odontogenous periostitis in elderly patients].

The paper presents the results of clinical examination of 114 patients aged 60-88 years with acute odontogenous periostitis receiving treatment in in-patient maxillofacial surgery unit. The dynamic of clinical symptoms is used to carry out the comparative effectiveness study of several peroral antibiotics in elderly patients.

[Drug therapy of otitis externa and otitis media].

The objective of the present work was to analyse the available pharmaceutical products used for treatment of otitis media. The rational application of these medications makes it possible to eliminate rapidly a variety of etiological factors, reduce the severity of inflammation, and improve the quality of life of the patients. One of the approaches to the achievement of these goals for the patients with otitis externa and otitis media consists of the use of combined preparations containing antibacterial, antimycotic, anti-inflammatory and analgetic components. Candibiotic is a four-components drug composed of chloramphenicol, clotrimazol, beclomethasone and lidocaine. The advantages of Candibiotic include high therapeutic efficacy due to its ethiotropic and pathogenetic activity and safety as its components do not have ototoxicity in the case of local application).

[A sharp increase in the density of pulmonary and pericardial mast cells under monocrotaline-induced pulmonary hypertension in rats].

Multifunctional granular mast cells (MCs) are involved in various pathological processes. The response of MC populations of myocardium, pericardium and lung to pulmonary hypertension (PH) has been studies 8 weeks after injection of monocrotaline. Five intact and five experimental rats were used. The density of MCs of different maturity was estimated on paraffin sections stained with Alcian blue and Safranin. Expressiveness of PH was estimated by functional parameters with the help of echocardiograms and by morphological markers. The MC density in myocardium of the intact and experimental rats was relatively low: 2 to 4 cells/mm2. MC density in the pericardium of intact rats was 14 times higher than in myocardium and increased 3 times for PH. The mature Safranin-positive cells predominated (70-80%) in myocardium and pericardium of intact and experimental rats. The MC density in the lungs of intact rats was about 30 cells/mm2; 98% of these cells were immature Alcian-positive cells. The mean density of MCs in the lungs of rats with PH increased 5.6 times. The mature Safranin-positive cells appeared in the lungs of rats with severe pathology. The greatest number of MCs in lungs was in the rats with the most pronounced disorders of myocardium function and marked histological damages (injuries) of myocardium and lungs. The finding show active response of MC population to monocrotaline-induced PH that stimulates migration of immature MCs into pericardium and lungs from the outside. Our data indicate the important role of MCs in the pathogenesis of PH.

[Pharmacological prevention of cardiovascular diseases].

At present, cardiology makes use of a wide range of drugs belonging to various pharmacological classes for both preventing and treating cardiovascular diseases. Results of recent large clinical trials show the importance of carrying out preventive actions, but data of evidence based medicine suggest that only some of the methods of pharmacological prophylaxis have unequivocally demonstrated their ability to improve the forecast of life for patients with cardiovascular pathology. We have summarized data on the efficacy of some groups of drugs used in cardiology and assessed this information from the positions of proved validity of the prophylactic effect in particular groups of patients.

[Effect of renin-angiotensin system inhibitors on the density of myocardial, pericardial and pulmonary rat mast cells under experimental heart failure].

Activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of heart failure (HF). We studied the effect of lisinopril (LP) and fosinopril (FP), the inhibitors of angiotensin-converting enzyme, and of losartan (LT), the antagonist of Angiotensin II receptors, on the behavior of multifunctional mast cells (MCs) under experimental HF. The inhibitors of RAS were daily injected during 4 weeks in 4 weeks after two (at 24-h interval) isoproterenol injections. MCs of different degrees of maturity were identified on paraffin sections stained with Alcian blue and Safranin. Expressiveness of HF was estimated by functional parameters with the help of echocardiogram and by morphological markers. The MC density in the myocardium of the intact rats as well as of the rats with HF, both treated and untreated with the preparations, was relatively low: from 3 to 4 cells/mm2. The MC density in the pericardium of the intact rats was several times higher than in the myocardium: 35 +/- 7 cells/mm2. The density ofpericardial MC under HF was 1.7 higher than that in the intact rats at the expense of the increase in the density of Alcian-positive immature cells (P < 0.05). The injections of LP increased the MC density still in 1.4 times at the expense of the density of Safranin-positive mature cells (P < 0.01). The injections of FP and LT had no influence on the MC density and the balance of cells of different degrees of maturity in the pericardium. 96-99% of MCs in lung were Alcian-positive cells. The density of such cells in the intact rats, in the rats with HF, and in the rats with HF treated with FP was 30 cells/mm2. The injections of LP and LT decreased the density of pulmonary MCs up to 7 cells/mm2 (P < 0.01) and 19 cells/mm2 (P < 0.05), respectively. Functional parameters of the hearts were consistent with the data of morphological analyses. Myocardium function improvement was noted only in the rats with HF treated with FP and LT. The reaction of MCs (as cell elements of "tissue" RAS) to injections of inhibitors of RAS was various in the myocardium, pericardium and lung of the rats with HF. The injections of LP stimulated maturation of the resident MCs in the pericardium and the replenishment of the population through immature cells migrating from the outside. It allows us to suppose an intensification of secretory activity of the cells. In contrast, the injections of LP and LT reduced the pulmonary MC population.

[Morphometry of hepatocyte mitochondrial apparatus in normal and cirrhotic rat liver].

Morphometric electron microscopy study of the hepatocyte mitochondrial apparatus and morphofunctional analysis of the degree of pathological alterations were carried out on the liver of rats with CCL4-cirrhosis (experimental group). Chronic poisoning of rats with CCL4 for 6 months led to a 4.2-fold increase in proportion of connective tissue and to a decrease in the number of hepatocytes in the liver by 21.8 %. Dry mass and ploidy of hepatocytes in the cirrhotis liver rose as compared with norm by 20.6 and 9.3%, respectively. Activities of alanine and aspartate aminotransferases in blood of rats of experimental group exceeded normal ones 2.0 and 1.4 times, respectively. Concentration of total bilirubin in blood of the cirrhotic animals increased 1.7 times, while concentration of total protein decreased by 22%. Concentration of diene conjugates in the liver of rats of experimental group increased 2.1 times as compared with normal one, while the level of malonic dialdehyde - by 34%. Activities of superoxide dismutase and catalase in the cirrhotic liver were lower than in the normal liver were lower than in the normal liver by 16 and 23 %, respectively. Morphometry of the hepatocyte mitochondrial apparatus has shown that in spite of an increase in the voluminous density of mitochondria in hepatocytes of the cirrhotic liver (by 28 %), concentration of internal mitochondrial membranes in the cells was reduced almost 1.5 times, while the total length of internal membrane in a single mitochondrion was reduced about twice as compared with norm. Thus, despite compensation of the partial loss of hepatocytes because of their polyploidization and hypertrophy, the specific synthetic activity of cells in the case of cirrhosis is decreased due to deterioration of the antioxidant system and electron transport chain of the mitochondrial apparatus.