Antihypoxants

Antihypoxants - drugs that can prevent, reduce or eliminate the manifestations of hypoxia due to the maintenance of energy metabolism in a regime sufficient to preserve the structure and functional activity of the cell, even at the level of the permissible minimum.

One of the universal pathological processes at the cell level for all critical states is the hypoxic syndrome. In clinical conditions, "pure" hypoxia is rare, most often it complicates the course of the underlying disease (shock, massive blood loss, respiratory insufficiency of various nature, heart failure, coma, kolaptoid reactions, fetal hypoxia in pregnancy, childbirth, anemia, surgery and other).

The term "hypoxia" refers to the conditions under which the intake in the O2 cell or its use in it is not sufficient to maintain optimal energy production.

The energy deficit that underlies any form of hypoxia leads to qualitatively similar metabolic and structural shifts in various organs and tissues. Irreversible changes and cell death during hypoxia are caused by the disruption of many metabolic pathways in the cytoplasm and mitochondria, the onset of acidosis, the 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 the mitochondria under hypoxia causes the development of a variety of adverse changes, which in turn disrupt the functions of mitochondria and lead to an even greater energy deficit, which ultimately can lead to irreversible damage and cell death.

Violation of the energy homeostasis of the cell as a key link in the formation of the hypoxic syndrome puts the task of pharmacology to develop means that normalize energy metabolism.

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

What are antihypoxants?

The first highly effective antihypoxants were created in the 60's. The first drug of this type was gutimine (guanylthiourea). In the modification of the molecule of guatimine, the special importance of the presence of sulfur in its composition was shown, since its replacement with O2 or selenium completely removed the protective effect of guatimine during hypoxia. Therefore, a further search followed the path of creating sulfur-containing compounds and led to the synthesis of an even more active antihypoxant amtisol (3,5-diamino-1,2,4-thiadiazole).

The administration of amtisol in the first 15 to 20 minutes after massive blood loss resulted in an experiment to reduce the amount of oxygen debt and sufficiently effective inclusion of protective compensatory mechanisms, which contributed to better tolerability of blood loss on the background of a critical decrease in the volume of circulating blood.

The use of amtisol in clinical conditions made it possible to draw a similar conclusion about the importance of its early administration to increase the effectiveness of transfusion therapy in the event of massive blood loss and prevention of severe disorders in vital organs. In these patients, after administration of amtisol, motor activity increased early, dyspnea and tachycardia decreased, and blood flow returned to normal. It is worthy of note that none of the patients had purulent complications after surgical interventions. This is due to the ability of amtisol to limit the formation of pograumatic immunosuppression and reduce the risk of infectious complications of severe mechanical injuries.

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

Gutimin has a clear nephroprotective effect in kidney ischemia in the experiment and clinic.

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

1. Drugs like gutimine and amtizol have a real protective effect in conditions of oxygen deficiency of different genesis, which creates the basis for successful other types of therapy, whose effectiveness against the background of the use of antihypoxic drugs increases, which is often crucial for the survival of the patient in critical situations.
2. Antihypoxants act on the cellular, and 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. Clinical use of antihypoxants requires careful study of the mechanisms of their protective action with the purpose of clarifying and expanding indications for use, the development of new more active drugs and possible combinations.

The mechanism of action of guatimine and amtisol is complex and not fully understood. In the implementation of the antihypoxic effect of these drugs, a number of points matter:

1. Decrease in the oxygen demand of the body (organ), which is based, apparently, on the economical use of oxygen. This may be the result of oppression of non-phosphorylating oxidation species; in particular, it has been established that gutimine and amtisol can suppress the processes of microsomal oxidation in the liver. These antihypoxic drugs also inhibit reactions of free radical oxidation in various organs and tissues. O2 can also be economized as a result of a total reduction in respiratory control in all cells.
2. Maintenance of glycolysis under 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 the structure and function of mitochondria during hypoxia.
4. Protection of biological membranes.

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

A certain contribution to the antioxidant effect is also contributed by the ability of gutimine and amtizol to inhibit lipolysis and thereby reduce the amount of free fatty acids that could undergo peroxide oxidation.

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

Thus, the results of experimental and clinical studies indicate that the development of antihypoxants is promising. At present, a new drug form of amtisol has been created in the form of a lyophilized drug in vials. While in the whole world only single drugs used in medical practice are known, with antihypoxic effect. For example, trimetazidine (a reductase from Servier) is described as the only antihypoxic agent that stably demonstrates protective properties in all forms of coronary heart disease that is not inferior or superior in activity to the most effective antiginal drugs of the first order (nitrates, beta blockers, and calcium antagonists) .

Another known antihypoxant is the natural carrier of electrons in the respiratory chain cytochrome c. Exogenous cytochrome c is able to interact with cytochrome-c-deficient mitochondria and stimulate their functional activity. The ability of cytochrome c to penetrate through damaged biological membranes and stimulate the processes of energy production in a 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.

In medical practice, another natural component of the respiratory mitochondrial chain, ubiquinone (ubinon), is being used.

In practice, the antihypoxant oliphene is also being introduced, which is a synthetic polyquinone. Oliphen is effective in pathological conditions with hypoxic syndrome, but a comparative study of olipen and amtizole has shown great therapeutic activity and amtisol safety. Created an antihypoxant mexidol, which is a succinate antioxidant emoxipine.

Expressed antihypoxic activity have individual representatives of a group of so-called energy-producing compounds, especially creatine phosphate, which provides anaerobic resynthesis of ATP during hypoxia. Preparations of creatine phosphate (neoton) in high doses (about 10-15 g per 1 infusion) were useful in myocardial infarction, critical heart rhythm disturbances, ischemic stroke.

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

Antihypoxic activity, of course, contributes to the therapeutic effects of pyracetam (nootropil), used as a means of metabolic therapy, practically not toxic.

The number of new antihypoxants offered for study is rapidly increasing. N. Yu. Semigolovsky (1998) conducted a comparative study of the efficacy of 12 antihypoxants of domestic and foreign production in combination with intensive therapy of 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 antihypoxic agents that stimulate the transport of oxygen into the tissue and compensate for the negative metabolic shifts that occur with oxygen deficiency. Perspective is the approach based on the use of pharmacological drugs that can change the intensity of oxidative metabolism, which opens the possibility of controlling the processes of oxygen utilization by tissues. Antihypoxants - benzopomin and azamopin do not exert oppressive effects on mitochondrial phosphorylation systems. The presence of the inhibitory effect of the test substances on LPO processes of various nature allows one to assume the effect of compounds of this group on the general links in the chain of radical formation. The possibility of the fact that the antioxidant effect is connected with the direct reaction of the test substances with free radicals is not excluded. In the concept of pharmacological protection of membranes in hypoxia and ischemia, the inhibition of LPO processes undoubtedly plays a positive role. First of all, preserving the antioxidant reserve in the cell hinders the disintegration of the membrane structures. A consequence of this is the preservation of the functional activity of the mitochondrial apparatus, which is one of the most important conditions for maintaining the viability of cells and tissues under conditions of severe, deenergizing effects. The preservation of the membrane organization will create favorable conditions for the diffusion flow of oxygen in the direction of the interstitial fluid-the cytoplasm of the cell-mitochondria, which is necessary to maintain optimal concentrations of O2 in its interaction zone with cytochrome. The use of antihypoxic agents of benzomopin and guatimine increased the survival rate of animals after clinical death by 50% and 30%, respectively. The drugs provided more stable hemodynamics in the postresuscitation period, contributed to a decrease in lactic acid in the blood. Gutimin had a positive effect on the baseline and dynamics of the studied parameters in the recovery period, but less pronounced than in benzomopin. The results obtained indicate that benzomopin and guzumine have a preventive protective effect when dying from blood loss and contribute to an increase in the survival rate of animals after an 8-minute clinical death. When studying the teratogenic and embryotoxic activity of a synthetic antihypoxant - benzomopin - a dose of 208.9 mg / kg of body weight from the 1st to the 17th day of pregnancy was partially fatal to pregnant females. The delay in embryonic development is obviously associated with a general toxic effect on the mother of a high dose of an antihypoxant. Thus, benzomopin when administered to pregnant rats at a dose of 209.0 mg / kg during 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 is shown in the works. Subsequent clinical use of benzodiazepines confirmed their high efficacy as antihypoxic agents, although the mechanism of this effect is not clear. In the experiment, the presence in the brain and in some peripheral organs of the receptors for exogenous benzodiazepines is shown. In experiments on mice, diazepam clearly delays the development of respiratory rhythm disturbances, the appearance of hypoxic convulsions, and prolongs the life span of animals (in doses 3, 5, 10 mg / kg, the life span in the main group was 32 ± 4.2, 58 ± 7 , 1 and 65 ± 8.2 min, in the control 20 ± 1.2 min). It is believed that the antihypoxic effect of benzodiazepines is associated with a system of benzodiazepine receptors independent of GABA-ergic control, at least from GABA receptors.

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

Regulators with a pronounced antihapoxic effect include substances such as: 

• inhibitors of phospholipases (mecaprin, chloroquine, batamethasone, ATP, indomethacin);
• inhibitors of cyclooxygenases (converting arachidonic acid into intermediates) - ketoprofen;
• inhibitor of thromboxane synthesis - imidazole;
• activator of prostaglandin synthesis PC12-cinnarizine.

Correction of hypoxic disorders should be carried out in a complex manner with the use of antihypoxianges, which exert an effect on various parts of the pathological process, primarily on the initial stages of oxidative phosphorylation, which in many cases suffer from a deficiency of high-energy substrates such as ATP.

It is maintenance of ATP concentration at the level of neurons in conditions of hypoxia that becomes especially significant.

The processes in which ATP participates can be divided into three consecutive stages:

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

Thus, adequate ATP content in neuronal structures provides not only adequate flow of all stages of oxidative phosphorylation, providing energy balance of cells and adequate functioning of receptors, ultimately preserves integrative and neuro-trophic activity of the brain, which is of paramount importance in any critical states.

At any critical conditions, the effects of hypoxia, ischemia, disturbances of microcirculation and endotoxemia affect all spheres of life support of the organism. Any physiological function of the organism or a pathological process is the result of integrative processes, during which the crucial is the nervous regulation. Maintenance of homeostasis is carried out by higher cortical and vegetative centers, reticular formation of the trunk, visual hummock, specific and nonspecific nuclei of the hypothalamus, neurohypophysis.

These neuronal structures control the activity of the basic "working blocks" of the body, such as the respiratory system, blood circulation, digestion, etc., through the receptor-synaptic apparatus.

To homeostatic processes from the side of the central nervous system, the maintenance of the functioning of which is especially important in pathological conditions, are coordinated adaptive reactions.

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

In the nervous tissue itself, in pathological conditions, processes can take place that are to a certain extent analogous to adaptation-trophic changes at the periphery. They are realized by means of monominergic systems of the brain, originating from the cells of the brain stem.

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

[5], [6], [7]

Actovegin and instenon

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

The possibility of pharmacological correction of hypoxia with Actovegin has been studied for a long time, but for a number of reasons its use as a direct antihypoxant in the therapy of terminal and critical states is clearly not enough.

Actovegin-deproteinized gemoderivat from the serum of young calves-contains 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 organism, mainly in conditions of hypoxia and ischemia due to an increase in the accumulation of glucose and oxygen. Increasing the transport of glucose and oxygen into the cell and enhancing intracellular utilization speed up the metabolism of ATP. In the conditions of application of actovegin, the most anaerobic oxidation pathway, typical for hypoxia, leading to the formation of only two ATP molecules, is replaced by an aerobic route, during which 36 ATP molecules are formed. Thus, the use of actovegin allows an 18-fold increase in the efficiency of oxidative phosphorylation and an increase in the yield of ATP, ensuring its adequate content.

All considered mechanisms of antihypoxic action of substrates of oxidative phosphorylation, and first of all ATP, are realized in conditions of application of Actovegin, especially in large doses.

The use of large doses of Actovegin (up to 4 g of dry matter per day intravenously drip) makes it possible to achieve improvement in the condition of patients, reducing the duration of mechanical ventilation, reducing the incidence of multiple organ dysfunction syndrome after critical conditions, reducing lethality, and shortening the stay in intensive care units.

In conditions of hypoxia and ischemia, especially cerebral, the combined use of actovegin and instenon (a multicomponent neurometabolism activator) possessing the properties of a stimulant of the limbic-reticular complex due to 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 a synaptic transmission, whose depression is the leading pathogenetic mechanism of consciousness disorders and neurological deficits in hypoxia and ischemia.

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

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

Probucol

Probucol is currently one of the few affordable and cheap domestic antihypoxants, which cause a moderate, and in some cases, significant reduction in the content of cholesterol (CS) in the serum. Reducing the level of high-density lipoprotein (HDL) probucol is due to reverse transport of cholesterol. The change in reverse transport in the treatment with probucol is judged mainly by the activity of the transfer of cholesterol esters (PECC) from HDL to very low and low density lipoproteins (VLDL and L PN, respectively). There is also another factor - apoprotin E. It is shown that when probucol is used for 3 months, cholesterol level is reduced by 14.3%, and after 6 months - by 19.7%. In the opinion of MG Gribogorova et al. (1998), when probucol is used, the effectiveness of lipid-lowering action depends mainly on the features of lipoprotein metabolism in the patient, and is not determined by the concentration of probucol in the blood; an increase in the dose of probucol in most cases does not contribute to a further decrease in cholesterol. The pronounced antioxidant properties of probucol were revealed, while the stability of erythrocyte membranes (decrease in LPO) was increased, and a moderate lipid-lowering effect, which gradually disappeared after treatment, was also revealed. When probucol is used, in some patients, a decrease in appetite, bloating is noted.

Promising is the use of the antioxidant coenzyme Q10, which affects the oxidation of lipoproteins in the blood plasma and the antiperoxide resistance of plasma in patients with ischemic heart disease. A number of modern studies have shown that taking large doses of vitamin E and C leads to improved clinical performance, a reduction in the risk of developing coronary artery disease and the death rate from this disease.

It is important to note that the study of the dynamics of LPO and AOS indicators against the background of the treatment of IHD with various antianginal drugs showed that the outcome of treatment is directly related to the level of LPO: the higher the content of LPO products and the lower the activity of AOS, the less the effect of the therapy. However, antioxidants are not yet widely used in everyday therapy and the 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 technique of determining the presence of one of the most active OH free radicals in the investigated medium, it was found that melatonin has a much more pronounced activity in terms of inactivation of OH than such potent intracellular AOs as glutathione and mannitol. Also in vitro, it has been demonstrated that melatonin has a stronger antioxidant activity against 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 Starak (1996), and the a phenomenon evidencing the predominant 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 alone. Protein-protective effects of melatonin are comparable with those of glutathione (one of the most powerful endogenous antioxidants).

Consequently, melatonin has protective properties for free radical damage to proteins. Of course, studies of the role of melatonin in LPO interruption are of great interest. Until recently, one of the most powerful lipid AO was considered to be vitamin E (a-tocopherol). In experiments in vitro and in vivo, when comparing the efficacy of vitamin E and melatonin, it was shown that melatonin is 2 times more active in terms of inactivating the ROO radical than vitamin E. Such a high AO efficiency of melatonin can not be explained solely by the ability of melatonin to interrupt the process of lipid peroxidation by inactivation of ROO, but also includes the inactivation of the OH radical, which is one of the initiators of the LPO process. In addition to the high activity of melatonin itself, in vitro experiments it was found that its metabolite 6-hydroxymelatonin, formed by the metabolism of melatonin in the liver, gives a much more pronounced effect on LPO. Consequently, in the body, the 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 state that one of the factors that lead to toxic effects of bacteria on the human body is the stimulation of LPO processes by bacterial lipopolysaccharides.

In an animal experiment, high efficacy of melatonin was demonstrated with respect to protection 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 kind 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 involved in the conversion of reduced glutathione to its oxidized form. During this reaction, the H2O2 molecule, active in terms of producing an extremely toxic OH radical, turns into a water molecule, and the oxygen ion joins glutathione to form oxidized glutathione. It is also shown that melatonin can inactivate the enzyme (nitrikoksidsintetazu), which activates the processes of nitric oxide production.

The above effects of melatonin make it one of the most powerful endogenous antioxidants.

Antihypoxic effect of non-steroidal anti-inflammatory drugs

In the work of Nikolov et al. (1983) in experiments on mice studied the effect of indomethacin, acetylsalicylic acid, ibuprofen, and others on the survival time of animals under anoxic and hypobaric hypoxia. Indomethacin was used at a dose of 1-10 mg / kg body weight inwards, and the remaining antihypoxants in doses ranging from 25 to 200 mg / kg. It has been established 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 the inhibitors of cyclooxygenase promising. When studying the antihypoxic effect of indomethacin, voltaren and ibuprofen, AI Bersznyakova and VM Kuznetsova (1988) found that these substances in doses of 5 mg / kg, respectively; 25 mg / kg and 62 mg / kg have antihypoxic properties regardless of the type of oxygen starvation. The mechanism of antihypoxic action of indomethacin and voltaren is associated with an improvement in oxygen delivery to tissues in conditions of its deficiency, there is no realization of products of metabolic acidosis, a decrease in lactic acid, an increase in hemoglobin synthesis. Voltaren, in addition, is able to increase the number of red blood cells.

The protective and restoring effect of antihypoxants in post-hypoxic inhibition of dopamine release is also shown. In the experiment, it was shown that antihypoxants contribute to memory improvement, and the use of gutimine in the complex of resuscitative therapy facilitated and accelerated the course of recovery of the body's functions after a moderate severity of the terminal state.

[8], [9], [10]

Antihypoxic properties of endorphins, enkephalins and their analogues

It has been shown that a specific opioid antagonist and opioid naloxone shortens the life span of animals under hypoxic hypoxia conditions. It was suggested that endogenous morphine-like substances (in particular, enkephalins and endorphins) may play a protective role in the eruption of hypoxia, realizing an antihypoxic effect through opioid receptors. In experiments on male mice, it was shown that leyenxphalin and endorphin are endogenous antihypoxants. The most likely way to protect the body from acute hypoxia opioid peptides and morphine is related to their ability to reduce the oxygen demand of tissues. In addition, the anti-stress component in the spectrum of pharmacological activity of endogenous and exogenous opioids has a definite value. Therefore, mobilization of endogenous opioid peptides for a strong hypoxic stimulus is biologically expedient and protective. Antagonists of narcotic analgesics (naloxone, nalorfin, etc.) block opioid receptors and thereby prevent the protective effect of endogenous and exogenous opioids in relation to acute hypoxic hypoxia.

It is shown that high doses of ascorbic acid (500 mg / kg) can reduce the effect of excessive accumulation of copper in the hypothalamus, the content of catecholamines.

The antihypoxic effect of catecholamines, adenosine and their analogues

It is generally recognized that adequate regulation of energy metabolism largely determines the resistance of the organism to extreme conditions, and the targeted pharmacological effect on the key links of the natural adaptive process is promising for the development of effective protective substances. The stimulation of oxidative metabolism (the caloric effect) observed during the stress reaction, the integral indicator of which is the intensity of oxygen consumption by the organism, is mainly associated with the activation of the sympathetic adrenal system and the mobilization of catecholamines. An important adaptive value of adenosine is shown, which acts as a neuromodulator and a "response metabolite" of cells. As was shown in the work of IA Ol'khovskii (1989), various adrenoagonists, adenosine and its analogs, cause a dose-dependent reduction 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 operational stress. Antihypoxic efficacy 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.) The stimulators of these receptors differ from guthimine by lower effective dose values and higher protective indexes.

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

Thus, substances capable of stimulating (a2-adrenergic receptors and A receptors in parenteral administration, increase the body's resistance to acute hypoxia of various genesis, as well as to other extreme situations involving the development of hypoxic conditions.Certainly, the decrease in oxidative metabolism under the influence of analogues of endogenous riulatory substances can reflect the reproduction of natural hypobiotic adaptive reactions of the body, useful in conditions of excessive action of damaging factors.

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

In accordance with the genesis of disturbances in bioenergetics in order to improve metabolism and, consequently, increase the body's resistance to hypoxia, it is used: 

• Optimization of protective adaptive reactions of the body (it is achieved, for example, due to cardiac and vasoactive agents in case of shock and moderate degrees of rarefaction of the atmosphere);
• reduction in the oxygen demand of the body and energy consumption (most of the drugs used in these cases - general anesthetics, neuroleptics, central relaxants, - increase only passive resistance, reducing the work capacity of the body). Active resistance to hypoxia can be only if the antihypoxant drug provides for the economization of oxidative processes in tissues with simultaneous increase in conjugation of oxidative phosphorylation and energy production during glycolysis, inhibition of non-phosphorylating oxidation;
• improvement of interorgan metabolism metabolism (energy). It can be achieved, for example, by activating glycoeogenesis in the liver and kidneys. Thus, maintenance of these tissues is supported by the main and most profitable under the hypoxia energy substrate-glucose, the amount of lactate, pyruvate and other metabolic products causing acidosis and intoxication decreases, the decrease in auto-inhibition of glycolysis;
• Stabilization of the structure and properties of cell membranes and subcellular organelles (the ability of mitochondria to utilize oxygen and maintain oxidative phosphorylation is maintained, to reduce the phenomena of disunity and to restore respiratory control).

Stabilization of membranes supports the ability of cells to utilize the energy of the macroergs - the most important factor in the conservation of active electron transport (K / Na-ATPase) membranes, and contractions of muscle proteins (ATP-as of myosin, preservation of conformational transitions of actomyosin). These mechanisms are more or less implemented in the protective action of antihypoxants.

According to research data under the influence of guatimine, oxygen consumption decreases by 25-30% and body temperature decreases by 1.5-2 ° C without disturbance of higher nervous activity and physical endurance. The drug at a dose of 100 mg / kg of body weight halved the percentage of deaths of rats after bilateral carotid arterial bandages, providing a 60% recovery of respiration in rabbits subjected to a 15-minute brain anoxia. In the posthypoxic period, animals were noted for a smaller oxygen request, a decrease in serum free fatty acids, lactic acid. The mechanism of action of guatimine and its analogues is complex both at the cellular and system levels. In the implementation of the antihypoxic effect of antihypoxants, a number of points are important:

• decrease in the oxygen demand of the body (organ), which is based, apparently, on the economization of the use of oxygen with the redistribution of its flow into intensively working organs;
• activation of aerobic and anaerobic glycolysis "below" the level of its regulation of phosphorylase and cAMP;
• significant acceleration of lactate utilization;
• inhibition of economically unfavorable lipolysis in adipose tissue under hypoxia conditions, which leads to a decrease in the content of unesterified fatty acids in the blood, reduces their share in energy metabolism and 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 the functions associated with the formation and use of macroerges.

Antihypoxants and the order of their use

Antihypoxic drugs, the order of their use in patients in the acute period of myocardial infarction.

Antihypoxicant	Form of issue	Introduction	The dose of mg / kg day.	Number of applications per day.
Amtizol	Ampoules, 1.5% 5 ml	Intravenously, drip	2-4 (up to 15)	1-2
Olifen	Ampoules, 7% 2 ml	Intravenously, drip	2-4	1-2
Riboxin	Ampoules, 2% 10 ml	Intravenously, drip, spray	3-6	1-2
Cytochrome C	Fl, 4 ml (10 mg)	Intravenously, drip, intramuscularly	0.15-0.6	1-2
Middronate	Ampoules, 10% 5 ml	Intravenous bolus	5-10	1
Pyrocetam	Ampoules, 20% 5 ml	Intravenously, drip	10-15 (up to 150)	1-2
	TABLE, 200 mg	Orally	5-10	3
Sodium oxybutyrate	Ampoules, 20% 2 ml	Intramuscularly	10-15	2-3
Aspisol	Ampoule, 1 g	Intravenous bolus	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
Bemitil	Tab., 250 mg	Orally	5-7	2
Trimetazidine	Tab., 20 mg	Orally	0.8-1.2	3

According to N.Yu. Semigolovsky (1998), antihypoxants are effective means of metabolic correction in patients with acute myocardial infarction. Their use in addition to traditional intensive care is accompanied by an improvement in the clinical course, a reduction in the incidence of complications and lethality, and the normalization of laboratory indicators.

The most pronounced protective properties in patients in the acute period of myocardial infarction are amtizole, pyracetam, lithium oxybutyrate and ubiquinone, somewhat less active - cytochrome C, riboxin, mildronate and olifene, solcoseryl, bemethyl, trimetazidine and aspisol are not active. The protective capabilities of hyperbaric oxygenation, applied according to a standard procedure, are extremely insignificant.

These clinical data were confirmed in the experimental work of NA Sysolyatin and VV Artamonov (1998) in the study of the effect of sodium oxybutyrate and emoxipin on the functional state of an adrenaline-damaged myocardium in the experiment. The introduction of both sodium oxybutyrate and emoxipin favorably influenced the course of the catecholamine-induced pathological process in the myocardium. The most effective was the introduction of antihypoxic drugs 30 minutes after the damage simulation: sodium oxybutyrate at a dose of 200 mg / kg, and emoxipin - at a dose of 4 mg / kg.

Sodium oxybutarate and emoxipin have antihypoxic and antioxidant activity, which is accompanied by a cardioprotective effect, registered by methods of enzymodiagnostics and electrocardiography.

The problem of SRO in the human body attracted the attention of many researchers. This is due to the fact that the failure in the antioxidant system and the strengthening of the SRO are seen as an important link in the development of various diseases. The intensity of SRO processes is determined by the activity of systems that generate free radicals, on the one hand, and non-enzymatic protection, on the other. The adequacy of protection is ensured by the consistency of the action of all links of 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 speed of SRO significantly exceeds the effectiveness of other factors, which determines the special role of antioxidants in regulating SRO processes.

One of the most important bioantioxidants with extremely high antiradical activity is vitamin E. Currently, the term "vitamin E" combines 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 SRO.

It should be noted that at present the necessity of introducing the so-called antioxidant complex of vitamins (E, A, C) is justified in order to enhance the antioxidant protection of normal cells in a number of pathological processes.

An important role in the processes of free radical oxidation is also given to selenium, which is an essential oligoelement. Lack of selenium in food leads to a number of diseases, especially cardiovascular, reduces the protective properties of the body. Vitamins-antioxidants increase the absorption of selenium in the intestine and contribute to the enhancement of the antioxidant defense process.

It is important to use numerous nutritional supplements. Of the latter, the most effective were fish oil, evening primrose oil, black currant seeds, New Zealand mussels, ginseng, garlic, honey. A special place is occupied by vitamins and microelements, among them vitamins E, A and C and microelement of selenium, which is caused by their ability to influence the processes of free radical oxidation in tissues.

[11], [12], [13], [14]