Psychopharmacology & biological narcology

This study revealed the pathogenetic patterns of the development of hypoxic and ischemic disorders in various pathological conditions and substantiated approaches to the use of drugs with antihypoxic activity. The role of the receptor interaction of succinic acid in the composition of succinate-containing antihypoxants with succinate receptor SUCNR1 has been demonstrated. The pharmacodynamic properties of the combined preparation of succinic acid that also contains vitamin precursors of the cofactors of Krebs cycle dehydrogenases nicotinamide (precursor of NAD) and riboflavin mononucleotide (precursor of FAD) and precursor of purine nucleotides (inosine) (cytoflavin) for intravenous drip and oral administration were analyzed. Literature data were also analyzed to evaluate the effectiveness of the use of the metabolic corrector of energy-dependent and hypoxic conditions (cytoflavin) in various central nervous system and cardiovascular diseases. In the case of ischemic disorders of cerebral and coronary blood flow, the effects of the drug are concentrated on the penumbra zone (ischemic penumbra), which is associated with the intravenous administration of the drug to its metabolic activity by influencing endothelial cells, restoring microcirculation, and enhancing the oxygen transport function of the blood. Among the new areas of drug use, the use of cytoflavin in the complex therapy of traumatic brain injuries, traumatic shock, acute respiratory distress syndrome, toxic lesions of the central nervous system, multiple organ failure syndrome, and post-COVID syndrome is promising.

This study analyzed the potential for the widespread use of erythropoietin, the main antihypoxic cytokine produced by renal parenchyma cells, and possible complications associated with its use. Erythropoietin is a glycoprotein heterodimer whose main function is the regulation of the formation and differentiation of erythroid germ cells and formation of the primary physiological response to hypoxia. The main effects of this cytokine are summarized, and the main points of application of the hormone, mechanisms of content regulation, and its use in medicine as a natural pharmacological agent in pharmacological preconditioning are highlighted. Attention is also drawn to the increasing role of hypoxia — one of the most dangerous typical pathological processes in the formation of life-threatening conditions, which has found its use in medicine, particularly as a physiological agent in combating vascular diseases, which are gaining enormous importance in our time.

BACKGROUND: To increase resistance to hypoxia, various methods of hypoxic training, mental effects, and use of pharmacological antihypoxants are employed.

AIM: To test new metal-complex compounds containing the antihypoxant almid in mice under conditions of acute hypoxia to determine their protective properties.

MATERIALS AND METHODS: In the first stage of the study, four new metal-complex compounds of magnesium, calcium, titanium, and vanadium containing the antihypoxant almid were screened in experiments on mice (n = 550) under acute hypoxic conditions with hypercapnia. The antihypoxants almid and amtizole were used as comparison substances. Acute hypoxia was induced by placing the animals in pharmacy glasses with a volume of 0.25 L with closed lapped stoppers. The substances were administered intraperitoneally at doses of 25, 50, and 100 mg/kg previously dissolved in 0.3 mL of NaCl solution. The incubation period was 60 min. The antihypoxic effect was considered confirmed if the lifespan increased by ≥20%. “Lifespan” refers to the time interval from the moment the mice were placed in a pharmacy glass to the development of the first agonal inhalation, after which the animals were quickly removed to preserve life. The rectal temperature of the animals was measured before the introduction of substances, immediately before being exposed to acute hypoxic conditions with hypercapnia, and after removal. Twenty-four hours after the first stage of the experiment, mice of the control group and mice that proved their ability to resist acute hypoxia with hypercapnia were repeatedly exposed to acute hypoxic conditions with hypercapnia after the use of substances.

RESULTS: A distinct antihypoxic effect exceeding the effectiveness of the comparison substances was obtained only in one substance—πQ2460 with titanium as a metal-complexing agent—and a ligand in the form of fumaric acid. After the administration of πQ2460, a dose-dependent decrease in rectal temperature was observed in mice. The lifespan of animals increased with an increase in the dosage of πQ2460, i.e., by 43.9%, 103.1%, and 152.8% for doses of 25, 50, and 100 mg/kg, respectively. The results of the second stage of the experiment confirmed the stable protective effect of πQ2460 but with an equalization of the effect of the studied doses, which increased the lifespan under acute hypoxic conditions with hypercapnia to an average of 60–70 min (control group, 40.5 min).

CONCLUSION: Among the compounds containing the antihypoxant almid in the complex molecule, πQ2460 (metal, titanium; ligand, fumaric acid) was found to have a stable protective dose-dependent effect on the development of acute hypoxia with hypercapnia in mice exceeding that for almid and the reference antihypoxant amtizole. The antihypoxic effect of πQ2460 persisted 24 h after its administration but leveled off for the studied doses—25, 50, and 100 mg/kg. Considering the data obtained during the comparison of the indicators of resistance to acute hypoxia in the control group, a hypothesis was proposed regarding the possibility of forming a preconditioning effect in animals from the primary effects of acute hypoxia.

BACKGROUND: Analysis of literature on the structural changes in the heart in patients with vibration disease using echocardiographic research methods revealed a concentric type of remodeling of the left ventricular chambers, which is associated with a high risk of cardiovascular complications, including sudden cardiac death, in people of working age.

AIM: To determine the role of bioenergetic hypoxia in the development of morphological transformation of the myocardium to substantiate the efficacy of pharmacotherapy for vibration disease.

MATERIALS AND METHODS: The energy production activity of cellular systems of heart tissue in vitro was analyzed by the polarographic method using a closed galvanic-type oxygen sensor (Clark electrode). The stressful effects of vibration were confirmed by the dynamics of the morphohistological picture of changes in the myocardial tissue of the left ventricle in the apical region after standard alcohol–paraffin wiring and staining of histological preparations with hematoxylin and eosin.

RESULTS: Evaluation of the morphometric and bioenergetic parameters of cardiomyocytes under various experimental vibration modes (7, 21, and 56 sessions with a frequency of 8 and 44 Hz) confirmed the relationship between the provision of tissue with energy potential and morphological signs of pathological structural changes in the myocardial tissue, such as hypertrophy of cardiomyocytes, development of fibrosis, restructuring of the vascular bed, and necrosis.

CONCLUSION: Analysis of the relationship between energy metabolism and morphohistological transformation of heart tissue allows us to resolve the role of universal and specific mechanisms in cardiac remodeling in the presence of vibration and pathogenetically substantiate the choice of drugs that not only have a vibration-protective effect but also inhibit pathological structural changes in the myocardial tissue.

Vasiliy M. Vinogradov (1924–2003) and his scientific school are famous for their creation and study of two fundamental new classes of pharmacological drugs, promising for military medicine, medicine for disasters and extreme conditions, and for civilian healthcare. This refers to the development of antihypoxants, which are drugs that protect the body when there is a lack of oxygen in the cells or disturbances in its utilization, and actoprotectors (from the Latin “actus” — movement), which are drugs of a nondepleting type of action that increase and maintain the physical performance of the body in unfavorable conditions. At the Department of Pharmacology of the Military Medical Academy in the 1960^s, F.Yu. Rachinsky synthesized the first highly effective antihypoxants structurally related to aliphatic and cyclic aminothiols — gutimin, amtizole, bemitil, almid, and etomerzole. Hypoxia is the most common, everyday factor in resuscitation practice; however, it is not the only factor causing energy deficiency with severe, often dramatic consequences for cells, organs, and the body as a whole. Therefore, when we talk about antihypoxants, we are referring to drugs that can smooth out this deficiency using various mechanisms, protect cells at the reversible stage of their damage, and activate the formation of structure and functions. These drugs were subjected to a detailed pharmacological study, and a key link in their mechanism of action was identified — normalization of energy metabolism when there is a lack of oxygen in cells or disturbances in their use. All aliphatic and cyclic aminothiols (gutimin, amtizole, bemitil, almid, etomerzol, and many of their analogs) have three main types of activity, which are expressed differently in each of the drugs, which makes it possible to profile their use in different clinical situations and in healthy people. These include (1) antihypoxic effects, (2) antioxidant effects, and (3) ability to accelerate the repair and adaptive synthesis of RNA, enzymes, and functional and structural proteins under various types of damage, such as hypoxic, infectious, toxic, and stress, and in adaptation to complicated conditions. All these directions were not only evaluated experimentally but also confirmed in practice. This article examines various aspects of antihypoxic drugs synthesized and studied at the Department of Pharmacology of the S.M. Kirov Military Medical Academy for the last 60 years.