Antihypoxants

Antihypoxants are drugs that can prevent, reduce or eliminate the manifestations of hypoxia by maintaining energy metabolism in a mode sufficient to preserve the structure and functional activity of the cell at least at the level of the permissible minimum.

One of the universal pathological processes at the cellular level in all critical conditions is hypoxic syndrome. In clinical conditions, "pure" hypoxia is rare, most often it complicates the course of the underlying disease (shock, massive blood loss, respiratory failure of various origins, heart failure, comatose states, colaptoid reactions, fetal hypoxia during pregnancy, childbirth, anemia, surgical interventions, etc.).

The term "hypoxia" refers to conditions in which the supply of O2 to or use of O2 in a cell is insufficient to maintain optimal energy production.

Energy deficiency, which underlies any form of hypoxia, leads to qualitatively uniform metabolic and structural shifts in various organs and tissues. Irreversible changes and cell death during hypoxia are caused by disruption of many metabolic pathways in the cytoplasm and mitochondria, occurrence of acidosis, activation of free radical oxidation, damage to biological membranes, affecting both the lipid bilayer and membrane proteins, including enzymes. At the same time, insufficient energy production in mitochondria during hypoxia causes the development of various unfavorable shifts, which in turn disrupt the functions of mitochondria and lead to even greater energy deficiency, which ultimately can cause irreversible damage and death of the cell.

Violation of cellular energy homeostasis as a key link in the formation of hypoxic syndrome poses the challenge for pharmacology to develop agents that normalize energy metabolism.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

What are antihypoxants?

The first highly effective antihypoxants were created in the 60s. The first drug of this type was gutimin (guanylthiourea). When modifying the gutimin molecule, the special importance of the presence of sulfur in its composition was shown, since replacing it with O2 or selenium completely removed the protective effect of gutimin during hypoxia. Therefore, further research went along the path of creating sulfur-containing compounds and led to the synthesis of an even more active antihypoxant amtizole (3,5-diamino-1,2,4-thiadiazole).

The administration of amtizol in the first 15-20 minutes after massive blood loss led in the experiment to a decrease in the magnitude of the oxygen debt and a fairly effective activation of protective compensatory mechanisms, which contributed to better tolerance of blood loss against the background of a critical decrease in the volume of circulating blood.

The use of amtizol in clinical conditions allowed us to draw a similar conclusion about the importance of its early administration to increase the effectiveness of transfusion therapy in massive blood loss and prevent severe disorders in vital organs. In such patients, after the use of amtizol, motor activity increased early, dyspnea and tachycardia decreased, and blood flow returned to normal. It is noteworthy that none of the patients had purulent complications after surgery. This is due to the ability of amtizol to limit the formation of post-traumatic immunodepression and reduce the risk of infectious complications of severe mechanical injuries.

Amtizol and gutimin cause pronounced protective effects of respiratory hypoxia. Amtizol reduces the oxygen supply of tissues and due to this improves the condition of operated patients, increases their motor activity in the early stages of the postoperative period.

Gutimin exhibits a clear nephroprotective effect in renal ischemia in experiments and clinical studies.

Thus, the experimental and clinical material will provide the basis for the following general conclusions.

1. Preparations such as gutimin and amtizol have a real protective effect in conditions of oxygen deficiency of various origins, which creates the basis for the successful implementation of other types of therapy, the effectiveness of which increases against the background of the use of antihypoxants, which is often of decisive importance for preserving the patient's life in critical situations.
2. Antihypoxants act at the cellular level, not at the systemic level. This is expressed in the ability to maintain the functions and structure of various organs in conditions of regional hypoxia, affecting only individual organs.
3. The clinical use of antihypoxants requires a thorough study of the mechanisms of their protective action in order to clarify and expand the indications for use, the development of new, more active drugs and possible combinations.

The mechanism of action of gutimin and amtizol is complex and not fully understood. A number of factors are important in the implementation of the antihypoxic action of these drugs:

1. A decrease in the oxygen demand of the body (organ), which is apparently based on the economical use of oxygen. This may be a consequence of the suppression of non-phosphorylating types of oxidation; in particular, it has been established that gutimin and amtizol are capable of suppressing microsomal oxidation processes in the liver. These antihypoxants also inhibit free radical oxidation reactions in various organs and tissues. O2 economization may also occur as a result of a total decrease in respiratory control in all cells.
2. Maintenance of glycolysis in conditions of its rapid self-limitation during hypoxia due to the accumulation of excess lactate, the development of acidosis and the depletion of the NAD reserve.
3. Maintenance of mitochondrial structure and function during hypoxia.
4. Protection of biological membranes.

All antihypoxants affect free radical oxidation processes and the endogenous antioxidant system to a greater or lesser extent. This effect consists of direct or indirect antioxidant action. Indirect action is inherent in all antihypoxants, while direct action may be absent. Indirect, secondary antioxidant effect follows from the main action of antihypoxants - maintaining a sufficiently high energy potential of cells with O2 deficiency, which in turn prevents negative metabolic shifts, which ultimately lead to the activation of free radical oxidation processes and inhibition of the antioxidant system. Amtizol has both indirect and direct antioxidant effects, while gutimin has a much weaker direct effect.

A certain contribution to the antioxidant effect is also made by the ability of gutimin and amtizol to inhibit lipolysis and thereby reduce the amount of free fatty acids that could undergo peroxidation.

The overall antioxidant effect of these antihypoxants is manifested by a decrease in the accumulation of lipid hydroperoxides, diene conjugates, and malonic dialdehyde in tissues; the decrease in the content of reduced glutathione and the activities of superoxide dismutase and catalase is also inhibited.

Thus, the results of experimental and clinical studies indicate the prospects of developing antihypoxants. At present, a new dosage form of amtizol has been created in the form of a lyophilized preparation in vials. So far, only a few preparations used in medical practice with antihypoxic action are known worldwide. For example, trimetazidine (preductal by Servier) is described as the only antihypoxant that consistently exhibits protective properties in all forms of ischemic heart disease, not inferior to or superior in activity to the most effective known antihypoxic agents of the first line (nitrates, ß-blockers and calcium antagonists).

Another well-known antihypoxant is a natural electron carrier in the respiratory chain, cytochrome c. Exogenous cytochrome c is capable of interacting with cytochrome-c-deficient mitochondria and stimulating their functional activity. The ability of cytochrome c to penetrate damaged biological membranes and stimulate energy production processes in the cell is a firmly established fact.

It is important to note that under normal physiological conditions, biological membranes are poorly permeable to exogenous cytochrome c.

Another natural component of the mitochondrial respiratory chain, ubiquinone (ubinone), is also beginning to be used in medical practice.

The antihypoxant olifen, a synthetic polyquinone, is also being introduced into practice. Olifen is effective in pathological conditions with hypoxic syndrome, but a comparative study of olifen and amtizol has shown greater therapeutic activity and safety of amtizol. The antihypoxant mexidol, a succinate of the antioxidant emoxypine, has been created.

Some representatives of the group of so-called energy-giving compounds have pronounced antihypoxic activity, primarily creatine phosphate, which provides anaerobic resynthesis of ATP during hypoxia. Creatine phosphate preparations (neoton) in high doses (about 10-15 g per 1 infusion) have proven useful in myocardial infarction, critical heart rhythm disturbances, and ischemic stroke.

ATP and other phosphorylated compounds (fructose-1,6-diphosphate, glucose-1-phosphate) exhibit low antihypoxic activity due to almost complete dephosphorylation in the blood and entry into cells in an energetically devalued form.

Antihypoxic activity certainly contributes to the therapeutic effects of piracetam (nootropil), used as a metabolic therapy agent with virtually no toxicity.

The number of new antihypoxants proposed for study is rapidly increasing. N. Yu. Semigolovsky (1998) conducted a comparative study of the effectiveness of 12 domestic and foreign antihypoxants in combination with intensive therapy for myocardial infarction.

Antihypoxic effect of drugs

Oxygen-consuming tissue processes are considered as a target for the action of antihypoxants. The author points out that modern methods of drug prevention and treatment of both primary and secondary hypoxia are based on the use of antihypoxants that stimulate oxygen transport to tissue and compensate for negative metabolic shifts that occur during oxygen deficiency. A promising approach is based on the use of pharmacological drugs that can change the intensity of oxidative metabolism, which opens up the possibility of controlling the processes of oxygen utilization by tissues. Antihypoxants - benzopamine and azamopine do not have a depressing effect on the mitochondrial phosphorylation systems. The presence of an inhibitory effect of the studied substances on the LPO processes of various nature allows us to assume the influence of compounds of this group on common links in the chain of radical formation. It is also possible that the antioxidant effect is associated with a direct reaction of the studied substances with free radicals. In the concept of pharmacological protection of membranes during hypoxia and ischemia, inhibition of LPO processes undoubtedly plays a positive role. First of all, maintaining the antioxidant reserve in the cell prevents disintegration of membrane structures. As a result, the functional activity of the mitochondrial apparatus is preserved, which is one of the most important conditions for maintaining the viability of cells and tissues under harsh, deenergizing effects. Preservation of the membrane organization will create favorable conditions for the diffusion flow of oxygen in the direction of interstitial fluid - cell cytoplasm - mitochondria, which is necessary to maintain optimal concentrations of O2 in the zone of its interaction with cygochrome. The use of antihypoxants benzomopine and gutimin increased the survival of animals after clinical death by 50% and 30%, respectively. The drugs provided more stable hemodynamics in the post-resuscitation period, contributed to a decrease in the content of lactic acid in the blood. Gutimin had a positive effect on the initial level and dynamics of the studied parameters in the recovery period, but less pronounced than benzomopine. The results indicate that benzomopine and gutimin have a preventive protective effect in dying from blood loss and contribute to an increase in the survival of animals after 8 minutes of clinical death. When studying the teratogenic and embryotoxic activity of the synthetic antihypoxant - benzomopine - a dose of 208.9 mg / kg of body weight from the 1st to the 17th day of pregnancy was partially lethal for pregnant females. The delay in embryonic development is obviously associated with the general toxic effect on the mother of a high dose of the antihypoxant. Thus, benzomopine, when administered orally to pregnant rats at a dose of 209.0 mg / kg in the period from the 1st to the 17th or from the 7th to the 15th day of pregnancy, does not lead to a teratogenic effect,but has a weak potential embryotoxic effect.

The antihypoxic effect of benzodiazepine receptor agonists has been demonstrated in the works. Subsequent clinical use of benzodiazepines has confirmed their high efficiency as antihypoxants, although the mechanism of this effect has not been elucidated. The experiment has shown the presence of receptors for exogenous benzodiazepines in the brain and some peripheral organs. In experiments on mice, diazepam clearly delays the development of respiratory rhythm disturbances, the appearance of hypoxic convulsions and increases the life expectancy of animals (at doses of 3; 5; 10 mg/kg - the life expectancy in the main group was 32 ± 4.2; 58 ± 7.1 and 65 ± 8.2 min, respectively, in the control 20 ± 1.2 min). It is believed that the antihypoxic effect of benzodiazepines is associated with the benzodiazepine receptor system, independent of GABAergic control, at least of the GABA type receptors.

A number of modern studies have convincingly demonstrated the high effectiveness of antihypoxants in the treatment of hypoxic-ischemic brain damage in a number of pregnancy complications (severe forms of gestosis, fetoplacental insufficiency, etc.), as well as in neurological practice.

Regulators that have a pronounced antihypoxic effect include substances such as:

• phospholipase inhibitors (mecaprine, chloroquine, batamethasone, ATP, indomethacin);
• cyclooxygenase inhibitors (which convert arachidonic acid into intermediate products) - ketoprofen;
• thromboxane synthesis inhibitor - imidazole;
• activator of prostaglandin synthesis PC12-cinnarizine.

Correction of hypoxic disorders should be carried out in a comprehensive manner with the use of antihypoxants, which have an effect on various links in the pathological process, primarily on the initial stages of oxidative phosphorylation, which largely suffer from a deficiency of high-energy substrates such as ATP.

It is precisely the maintenance of ATP concentration at the neuronal level under hypoxic conditions that becomes especially important.

The processes in which ATP is involved can be divided into three successive stages:

1. membrane depolarization, accompanied by inactivation of Na, K-ATPase and a local increase in ATP content;
2. secretion of mediators, in which activation of ATPase and increased ATP consumption are observed;
3. ATP expenditure, compensatory activation of its resynthesis system, which is necessary for membrane repolarization, removal of Ca from neuron terminals, and recovery processes in synapses.

Thus, adequate ATP content in neuronal structures ensures not only adequate progression of all stages of oxidative phosphorylation, ensuring energy balance of cells and adequate functioning of receptors, and ultimately allows maintaining integrative and neurotrophic activity of the brain, which is a task of primary importance in any critical conditions.

In any critical conditions, the effects of hypoxia, ischemia, microcirculation disorders and endotoxemia affect all spheres of the body's life support. Any physiological function of the body or pathological process is the result of integrative processes, during which nervous regulation is of decisive importance. Homeostasis is maintained by the higher cortical and vegetative centers, the reticular formation of the brainstem, the thalamus, specific and non-specific nuclei of the hypothalamus, and the neurohypophysis.

These neuronal structures control the activity of the main “working units” of the body, such as the respiratory system, circulation, digestion, etc., through the receptor-synaptic apparatus.

Homeostatic processes on the part of the central nervous system, the maintenance of which is especially important in pathological conditions, include coordinated adaptive reactions.

The adaptive-trophic role of the nervous system is manifested by changes in neuronal activity, neurochemical processes, and metabolic shifts. The sympathetic nervous system changes the functional readiness of organs and tissues in pathological conditions.

In the nervous tissue itself, under pathological conditions, processes may take place that are to a certain extent analogous to adaptive-trophic changes in the periphery. They are realized through the brain's monaminergic systems, originating from the cells of the brain stem.

In many ways, it is the functioning of the vegetative centers that determines the course of pathological processes in critical conditions in the post-resuscitation period. Maintaining adequate cerebral metabolism allows preserving the adaptive-trophic effects of the nervous system and preventing the development and progression of multiple organ failure syndrome.

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Actovegin and Instenon

In connection with the above, in a series of antihypoxants that actively influence the content of cyclic nucleotides in the cell, and therefore cerebral metabolism, the integrative activity of the nervous system, there are multicomponent drugs "Actovegin" and "Instenon".

The possibilities of pharmacological correction of hypoxia using actovegin have been studied for a long time, but for a number of reasons its use as a direct antihypoxant in the treatment of terminal and critical conditions is clearly insufficient.

Actovegin is a deproteinized hemoderivative from the blood serum of young calves, containing a complex of low-molecular oligopeptides and amino acid derivatives.

Actovegin stimulates the energy processes of functional metabolism and anabolism at the cellular level regardless of the state of the body, mainly under hypoxia and ischemia due to increased accumulation of glucose and oxygen. Increased transport of glucose and oxygen into the cell and increased intracellular utilization accelerate ATP metabolism. Under the conditions of Actovegin use, the anaerobic oxidation pathway most typical for hypoxia, leading to the formation of only two ATP molecules, is replaced by the aerobic pathway, during which 36 ATP molecules are formed. Thus, the use of Actovegin allows for an 18-fold increase in the efficiency of oxidative phosphorylation and an increase in the yield of ATP, ensuring its adequate content.

All the considered mechanisms of antihypoxic action of oxidative phosphorylation substrates, and primarily ATP, are realized under conditions of actovegin use, especially in high doses.

The use of high doses of actovegin (up to 4 g of dry substance per day intravenously by drip) allows for improvement of the condition of patients, reduction of the duration of mechanical ventilation, reduction of the incidence of multiple organ failure syndrome after critical conditions, reduction of mortality, and reduction of the length of stay in intensive care units.

In conditions of hypoxia and ischemia, especially cerebral, the combined use of actovegin and instenon (a multicomponent activator of neurometabolism), which has the properties of a stimulator of the limbic-reticular complex due to the activation of anaerobic oxidation and pentose cycles, is extremely effective. Stimulation of anaerobic oxidation will provide an energy substrate for the synthesis and exchange of neurotransmitters and the restoration of synaptic transmission, the depression of which is the leading pathogenetic mechanism of disorders of consciousness and neurological deficit in hypoxia and ischemia.

With the combined use of actovegin and instenon, it is possible to achieve activation of consciousness in patients who have suffered acute severe hypoxia, which indicates the preservation of integrative and regulatory-trophic mechanisms of the central nervous system.

This is also evidenced by the decrease in the incidence of cerebral disorders and multiple organ failure syndrome during complex antihypoxic therapy.

Probucol

Probucol is currently one of the few affordable and inexpensive domestic antihypoxants that cause a moderate, and in some cases significant, decrease in serum cholesterol (SC). Probucol causes a decrease in high-density lipoprotein (HDL) levels due to reverse CS transport. Changes in reverse transport during probucol therapy are judged mainly by the activity of cholesterol ester transfer (CHET) from HDL to very-low-density and low-density lipoproteins (VLDL and LDL, respectively). There is also another factor - apoptosisin E. It has been shown that when using probucol for three months, the cholesterol level decreases by 14.3%, and after 6 months - by 19.7%. According to M. G. Tvorogova et al. (1998), when using probucol, the effectiveness of the lipid-lowering effect depends mainly on the characteristics of the lipoprotein metabolism disorder in the patient, and is not determined by the concentration of probucol in the blood; Increasing the dose of probucol in most cases does not contribute to further reduction of cholesterol levels. Probucol has been shown to have pronounced antioxidant properties, increasing the stability of erythrocyte membranes (decreasing LPO), and also has a moderate lipid-lowering effect, which gradually disappears after treatment. When using probucol, some patients experience decreased appetite and bloating.

The use of the antioxidant coenzyme Q10, which affects the oxidizability of lipoproteins in blood plasma and the antiperoxide resistance of plasma in patients with coronary heart disease, is promising. A number of modern studies have shown that taking large doses of vitamin E and C leads to improved clinical indicators, a decrease in the risk of developing coronary heart disease and the mortality rate from this disease.

It is important to note that the study of the dynamics of LPO and AOS indices against the background of treatment of coronary heart disease with various antianginal drugs showed that the outcome of treatment is directly dependent on the LPO level: the higher the content of LPO products and the lower the AOS activity, the less the effect of the therapy. However, antioxidants have not yet become widespread in everyday therapy and prevention of a number of diseases.

Melatonin

It is important to note that the antioxidant properties of melatonin are not mediated through its receptors. In experimental studies using the method of determining the presence of one of the most active free radicals OH in the studied medium, it was found that melatonin has a significantly more pronounced activity in terms of OH inactivation than such powerful intracellular AO as glutathione and mannitol. Also, in vitro it was demonstrated that melatonin has a stronger antioxidant activity with respect to the peroxyl radical ROO than the well-known antioxidant - vitamin E. In addition, the priority role of melatonin as a DNA protector was shown in the work of Starak (1996), and a phenomenon was revealed indicating the leading role of melatonin (endogenous) in the mechanisms of AO protection.

The role of melatonin in protecting macromolecules from oxidative stress is not limited to nuclear DNA. The protein-protective effects of melatonin are comparable to those of glutathione (one of the most powerful endogenous antioxidants).

Consequently, melatonin has protective properties against free radical damage to proteins. Of course, studies showing the role of melatonin in interrupting LPO are of great interest. Until recently, vitamin E (a-tocopherol) was considered one of the most powerful lipid antioxidants. In vitro and in vivo experiments comparing the effectiveness of vitamin E and melatonin showed that melatonin is 2 times more active in terms of inactivation of the ROO radical than vitamin E. Such high antioxidant effectiveness of melatonin cannot be explained only by the ability of melatonin to interrupt the process of lipid peroxidation by inactivating ROO, but also includes inactivation of the OH radical, which is one of the initiators of the LPO process. In addition to the high antioxidant activity of melatonin itself, in vitro experiments revealed that its metabolite 6-hydroxymelatonin, formed during melatonin metabolism in the liver, has a significantly more pronounced effect on LPO. Therefore, the body's mechanisms of protection against free radical damage include not only the effects of melatonin, but also at least one of its metabolites.

For obstetric practice, it is also important to note that one of the factors leading to the toxic effects of bacteria on the human body is the stimulation of lipid peroxidation processes by bacterial lipopolysaccharides.

In animal experiments, melatonin was shown to be highly effective in protecting against oxidative stress caused by bacterial lipopolysaccharides.

The authors of the study emphasize that the AO effect of melatonin is not limited to any one type of cell or tissue, but is of an organismic nature.

In addition to the fact that melatonin itself has AO properties, it is able to stimulate glutathione peroxidase, which is involved in the conversion of reduced glutathione into its oxidized form. During this reaction, the H2O2 molecule, which is active in terms of producing the extremely toxic OH radical, is converted into a water molecule, and the oxygen ion is attached to glutathione, forming oxidized glutathione. It has also been shown that melatonin can inactivate the enzyme (nitric oxide synthetase), which activates the processes of nitric oxide production.

The above-mentioned effects of melatonin allow us to consider it one of the most powerful endogenous antioxidants.

Antihypoxic effect of nonsteroidal anti-inflammatory drugs

In the work of Nikolov et al. (1983) in experiments on mice the effect of indomethacin, acetylsalicylic acid, ibuprofen and others on the survival time of animals in anoxic and hypobaric hypoxia was studied. Indomethacin was used in a dose of 1-10 mg/kg of body weight orally, and the remaining antihypoxants in doses from 25 to 200 mg/kg. It was found that indomethacin increases the survival time from 9 to 120%, acetylsalicylic acid from 3 to 98% and ibuprofen from 3 to 163%. The studied substances were most effective in hypobaric hypoxia. The authors consider the search for antihypoxants among cyclooxygenase inhibitors to be promising. When studying the antihypoxic action of indomethacin, voltaren and ibuprofen, A. I. Bersznyakova and V. M. Kuznetsova (1988) found that these substances in doses of 5 mg/kg; 25 mg/kg and 62 mg/kg, respectively, have antihypoxic properties regardless of the type of oxygen starvation. The mechanism of the antihypoxic action of indomethacin and voltaren is associated with improved oxygen delivery to tissues under conditions of its deficiency, no realization of metabolic acidosis products, a decrease in lactic acid content, and increased hemoglobin synthesis. Voltaren is also capable of increasing the number of erythrocytes.

The protective and restorative effect of antihypoxants in posthypoxic inhibition of dopamine release has also been demonstrated. The experiment showed that antihypoxants contribute to memory improvement, and the use of gutimin in the complex of resuscitation therapy facilitated and accelerated the course of restoration of body functions after a moderately severe terminal condition.

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Antihypoxic properties of endorphins, enkephalins and their analogues

It has been shown that the specific opiate and opioid antagonist naloxone shortens the lifespan of animals exposed to hypoxic hypoxia. It has been suggested that endogenous morphine-like substances (in particular, enkephalins and endorphins) may play a protective role in acute hypoxia, realizing the antihypoxic effect through opioid receptors. Experiments on male mice have shown that leuenxphalin and endorphin are endogenous antihypoxants. The most probable way of protecting the body from acute hypoxia by opioid peptides and morphine is associated with their ability to reduce tissue oxygen demand. In addition, the antistress component in the spectrum of pharmacological activity of endogenous and exogenous opioids is of certain importance. Therefore, the mobilization of endogenous opioid peptides to a strong hypoxic stimulus is biologically appropriate and has a protective nature. Antagonists of narcotic analgesics (naloxone, nalorphine, etc.) block opioid receptors and thereby prevent the protective effect of endogenous and exogenous opioids in relation to acute hypoxic hypoxia.

It has been shown that high doses of ascorbic acid (500 mg/kg) can reduce the effect of excess copper accumulation in the hypothalamus and the content of catecholamines.

Antihypoxic action of catecholamines, adenosine and their analogues

It is generally recognized that adequate regulation of energy metabolism largely determines the body's resistance to extreme conditions, and targeted pharmacological action on the key links of the natural adaptive process is promising for the development of effective protective substances. Stimulation of oxidative metabolism (calorigenic effect) observed during stress reaction, the integral indicator of which is the intensity of oxygen consumption by the body, is mainly associated with activation of the sympathoadrenal system and mobilization of catecholamines. Adenosine, which acts as a neuromodulator and "response metabolite" of cells, has been shown to have an important adaptive significance. As shown in the work of I. A. Olkhovsky (1989), various adrenergic agonists - adenosine and its analogues cause a dose-dependent decrease in oxygen consumption by the body. The anticalorigenic effect of clonidine (clonidine) and adenosine increases the body's resistance to hypobaric, hemic, hypercapnic and cytotoxic forms of acute hypoxia; The drug clonidine increases the resistance of patients to surgical stress. The antihypoxic effectiveness of the compounds is due to relatively independent mechanisms: metabolic and hypothermic action. These effects are mediated by (a2-adrenergic and A-adenosine receptors, respectively. Stimulators of these receptors differ from gutimin by lower values of effective doses and higher protective indices.

A decrease in oxygen demand and the development of hypothermia suggest a possible increase in the animals' resistance to acute hypoxia. The antihypoxic effect of clonidide (clonidine) allowed the author to propose the use of this compound in surgical interventions. In patients receiving clonidine, the main hemodynamic parameters are more stably maintained, and microcirculation parameters are significantly improved.

Thus, substances capable of stimulating (a2-adrenoreceptors and A-receptors when administered parenterally increase the body's resistance to acute hypoxia of various genesis, as well as to other extreme situations, including the development of hypoxic conditions. Probably, a decrease in oxidative metabolism under the influence of analogues of endogenous riulatory substances may reflect the reproduction of natural hypobiotic adaptive reactions of the body, useful in conditions of excessive action of damaging factors.

Thus, in increasing the body's tolerance to acute hypoxia under the influence of a2-adrenoreceptors and A-receptors, the primary link is metabolic shifts that cause economization of oxygen consumption and a decrease in heat production. This is accompanied by the development of hypothermia, potentiating the state of reduced oxygen demand. Probably, the metabolic shifts that are useful under hypoxic conditions are associated with receptor-mediated changes in the tissue cAMP pool and subsequent regulatory reorganization of oxidative processes. The receptor specificity of protective effects allows the author to use a new receptor approach to searching for protective substances based on screening of a2-adrenoreceptor and A-receptor agonists.

In accordance with the genesis of bioenergetic disorders, in order to improve metabolism and, consequently, increase the body's resistance to hypoxia, the following is used:

• optimization of the body's protective and adaptive reactions (this is achieved, for example, thanks to cardiac and vasoactive agents during shock and moderate degrees of atmospheric rarefaction);
• reduction of the body's oxygen demand and energy expenditure (most of the drugs used in these cases - general anesthetics, neuroleptics, central relaxants - increase only passive resistance, reducing the body's performance). Active resistance to hypoxia can only be if the antihypoxant drug ensures the economization of oxidative processes in tissues with a simultaneous increase in the coupling of oxidative phosphorylation and energy production during glycolysis, inhibition of non-phosphorylating oxidation;
• improvement of interorgan exchange of metabolites (energy). This can be achieved, for example, by activating gluconeogenesis in the liver and kidneys. In this way, the provision of these tissues with the main and most beneficial energy substrate during hypoxia - glucose - is maintained, the amount of lactate, pyruvate and other metabolic products causing acidosis and intoxication is reduced, and autoinhibition of glycolysis is reduced;
• stabilization of the structure and properties of cell membranes and subcellular organelles (the ability of mitochondria to utilize oxygen and carry out oxidative phosphorylation is maintained, phenomena of disunity are reduced, and respiratory control is restored).

Membrane stabilization maintains the ability of cells to utilize macroerg energy - the most important factor in maintaining active electron transport (K/Na-ATPase) of membranes, and contractions of muscle proteins (ATPase of myosin, maintaining conformational transitions of actomyosin). The named mechanisms are realized to some extent in the protective action of antihypoxants.

According to research data, under the influence of gutimin, oxygen consumption decreases by 25-30% and body temperature decreases by 1.5-2 °C without affecting higher nervous activity and physical endurance. The drug at a dose of 100 mg/kg of body weight halved the percentage of deaths in rats after bilateral ligation of the carotid arteries, and ensured in 60% of cases the restoration of breathing in rabbits subjected to 15-minute cerebral anoxia. In the post-hypoxic period, animals showed a lower oxygen demand, a decrease in the content of free fatty acids in the blood serum, and lactacidemia. The mechanism of action of gutimin and its analogues is complex both at the cellular and systemic levels. A number of points are important in the implementation of the antihypoxic effect of antihypoxants:

• a reduction in the oxygen demand of the body (organ), which is apparently based on the economization of oxygen use with the redistribution of its flow to intensively working organs;
• activation of aerobic and anaerobic glycolysis “below” the level of its regulation by phosphorylase and cAMP;
• significant acceleration of lactate utilization;
• inhibition of lipolysis in adipose tissue, which is economically unprofitable under hypoxic conditions, which leads to a decrease in the content of non-esterified fatty acids in the blood, reduces their share in energy metabolism and the damaging effect on membrane structures;
• direct stabilizing and antioxidant effect on cell membranes, mitochondria and lysosomes, which is accompanied by the preservation of their barrier role, as well as functions associated with the formation and use of macroergs.

Antihypoxants and the procedure for their use

Antihypoxic agents, the procedure for their use in patients in the acute period of myocardial infarction.

Antihypoxant	Release form	Introduction	Dose mg/kg per day.	Number of uses per day.
Amtizol	Ampoules, 1.5% 5 ml	Intravenously, drip	2-4 (up to 15)	1-2
Oliphen	Ampoules, 7% 2 ml	Intravenously, drip	2-4	1-2
Riboxin	Ampoules, 2% 10 ml	Intravenously, drip, jet	3-6	1-2
Cytochrome C	Fl., 4 ml (10 mg)	Intravenous, drip, intramuscular	0.15-0.6	1-2
Midronate	Ampoules, 10% 5 ml	Intravenously, jet	5-10	1
Pirocetam	Ampoules, 20% 5 ml	Intravenously, drip	10-15 (up to 150)	1-2
	Tab., 200 mg	Orally	5-10	3
Sodium oxybutyrate	Ampoules, 20% 2 ml	Intramuscularly	10-15	2-3
Aspisol	Ampoules, 1 g	Intravenously, jet	10-15	1
Solcoseryl	Ampoules, 2ml	Intramuscularly	50-300	3
Actovegin	Fl., 10% 250 ml	Intravenously, drip	0.30	1
Ubiquinone (Coenzyme Q-10)	Tab, 10 mg	Orally	0.8-1.2	2-4
Bemithyl	Tab., 250 mg	Orally	5-7	2
Trimetazidine	Tab., 20 mg	Orally	0.8-1.2	3

According to N. Yu. Semigolovskiy (1998), antihypoxants are effective means of metabolic correction in patients with acute myocardial infarction. Their use in addition to traditional means of intensive therapy is accompanied by an improvement in the clinical course, a decrease in the frequency of complications and mortality, and normalization of laboratory parameters.

The most pronounced protective properties in patients in the acute period of myocardial infarction are possessed by amtizol, piracetam, lithium oxybutyrate and ubiquinone, somewhat less active - cytochrome C, riboxin, mildronate and olifen, inactive solcoseryl, bemitil, trimetazidine and aspisol. The protective capabilities of hyperbaric oxygenation, applied according to the standard method, are extremely insignificant.

These clinical data were confirmed in the experimental work of N. A. Sysolyatin, V. V. Artamonov (1998) when studying the effect of sodium oxybutyrate and emoxypine on the functional state of the myocardium damaged by adrenaline in an experiment. The introduction of both sodium oxybutyrate and emoxypine had a favorable effect on the nature of the course of the catecholamine-induced pathological process in the myocardium. The most effective was the introduction of antihypoxants 30 minutes after the injury modeling: sodium oxybutyrate at a dose of 200 mg/kg, and emoxypine at a dose of 4 mg/kg.

Sodium oxybutarate and emoxypine have antihypoxant and antioxidant activity, which is accompanied by a cardioprotective effect recorded by enzyme diagnostics and electrocardiography methods.

The problem of free radical oxidation in the human body has attracted the attention of many researchers. This is due to the fact that a failure in the antioxidant system and an increase in free radical oxidation are considered an important link in the development of various diseases. The intensity of free radical oxidation processes is determined by the activity of systems generating free radicals, on the one hand, and non-enzymatic protection, on the other. The adequacy of protection is ensured by the coordination of the action of all links in this complex chain. Among the factors that protect organs and tissues from excessive peroxidation, only antioxidants have the ability to directly react with peroxide radicals, and their effect on the overall rate of free radical oxidation significantly exceeds the effectiveness of other factors, which determines the special role of antioxidants in regulating free radical oxidation processes.

One of the most important bioantioxidants with extremely high antiradical activity is vitamin E. Currently, the term "vitamin E" unites a fairly large group of natural and synthetic tocopherols, soluble only in fats and organic solvents and possessing varying degrees of biological activity. Vitamin E takes part in the vital activity of most organs, systems and tissues of the body, which is largely due to its role as the most important regulator of free radical oxidation.

It should be noted that at present the need for the introduction of the so-called antioxidant complex of vitamins (E, A, C) has been substantiated in order to enhance the antioxidant protection of normal cells in a number of pathological processes.

Selenium, an essential oligoelement, also plays a significant role in free radical oxidation processes. Deficiency of selenium in food leads to a number of diseases, primarily cardiovascular, and reduces the body's protective properties. Antioxidant vitamins increase the absorption of selenium in the intestines and help strengthen the antioxidant protection process.

It is important to use numerous food supplements. Of the latest, the most effective were fish oil, evening primrose oil, blackcurrant seeds, New Zealand mussels, ginseng, garlic, honey. Vitamins and microelements occupy a special place, among which in particular vitamins E, A and C and the microelement selenium, which is due to their ability to influence the processes of free radical oxidation in tissues.

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