Antihypoxic action - what is it? Antihypoxants: a list of drugs. Antioxidants (drugs)

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

One of the universal pathological processes at the cell 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 nature, heart failure, coma, colaptoid reactions, fetal hypoxia during pregnancy, childbirth, anemia, surgical interventions and etc.).

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

Energy deficiency underlying any form of hypoxia leads to qualitatively similar metabolic and structural changes 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, the 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 adverse shifts, which in turn disrupt the functions of mitochondria and lead to even greater energy deficiency, which ultimately can cause irreversible damage and cell death.

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

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What are antihypoxants?

The first highly effective antihypoxants were created in the 60s. The first drug of this type was gutimine (guanylthiourea). Modification of the gutimin molecule showed the particular importance of the presence of sulfur in its composition, since replacing it with O2 or selenium completely removed the protective effect of gutimin during hypoxia. Therefore, further search went towards the creation of sulfur-containing compounds and led to the synthesis of an even more active antihypoxant amtizol (3,5-diamino-1,2,4-thiadiazole).

Appointment of amtizol in the first 15-20 minutes after massive blood loss in the experiment led to a decrease in 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 circulating blood volume.

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

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

Gutimin shows a clear nephroprotective effect in renal ischemia in the experiment and in the clinic.

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

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 crucial for saving the patient's life in critical situations.
Antihypoxants act at the cellular, not systemic level. This is expressed in the possibility of maintaining the functions and structure of various organs under conditions of regional hypoxia, affecting only individual organs.
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. In the implementation of the antihypoxic action of these drugs, a number of points are important:

Decrease in the oxygen demand of the body (organ), which, apparently, is based on the economical use of oxygen. This may be due to inhibition of non-phosphorylating oxidation species; in particular, it was found that gutimin and amtizol are able to suppress the processes of microsomal oxidation in the liver. These antihypoxants also inhibit free radical oxidation reactions in various organs and tissues. Economization of O2 can also occur as a result of a total decrease in respiratory control in all cells.
Maintaining 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.
Maintaining the structure and function of mitochondria during hypoxia.
Protection of biological membranes.

All antihypoxants to some extent affect the processes of free radical oxidation and the endogenous antioxidant system. This influence consists in direct or indirect antioxidant action. Indirect action is inherent in all antihypoxants, while direct action may be absent. An indirect, secondary antioxidant effect stems from the main action of antihypoxants - maintaining a sufficiently high energy potential of cells in 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 direct action of gutimin is much less pronounced.

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 be subjected to peroxidation.

The total antioxidant effect of these antihypoxants is manifested by a decrease in the accumulation of lipid hydroperoxides, diene conjugates, and malondialdehyde in tissues; the decrease in the content of reduced glutathione and the activities of superoxide cismutase and catalase are also inhibited.

Thus, the results of experimental and clinical studies indicate the prospects for the development of antihypoxants. Currently, a new dosage form of amtizol has been created in the form of a lyophilized drug in vials. So far, only a few drugs used in medical practice with an antihypoxic effect are known all over the world. For example, the drug trimetazidine (preductal from Servier) is described as the only antihypoxant that consistently exhibits protective properties in all forms of coronary heart disease, which is not inferior or superior in activity to the most effective known first-line antiginal drugs (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 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 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 respiratory mitochondrial chain, ubiquinone (ubinone), is also beginning to be used in medical practice.

The antihypoxant oliphen, which is a synthetic polyquinone, is now also being introduced into practice. Olifen is effective in pathological conditions with hypoxic syndrome, but a comparative study of oliven and amtizol showed greater therapeutic activity and safety of amtizol. An antihypoxant mexidol, which is a succinate of the antioxidant emoxipin, has been created.

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

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

Antihypoxic activity, of course, contributes to the therapeutic effects of piracetam (nootropil), used as a means of metabolic therapy, 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 antihypoxants of domestic and foreign production in combination with intensive care 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 into the tissue and compensate for the negative metabolic shifts that occur during oxygen deficiency. A promising approach is based on the use of pharmacological preparations 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 an inhibitory effect on the mitochondrial phosphorylation systems. The presence of the inhibitory effect of the studied substances on LPO processes of various nature allows us to assume the influence of the compounds of this group on the common links in the chain of radical formation. It is also possible that the antioxidant effect is associated with the 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, the preservation of the antioxidant reserve in the cell prevents the disintegration of membrane structures. The 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. 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 gutimine increased the survival of animals after clinical death by 50% and 30%, respectively. The preparations provided more stable hemodynamics in the postresuscitation 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 that of benzomopine. The obtained results indicate that benzomopine and gutimine have a prophylactic protective effect when dying from blood loss and contribute to an increase in the survival of animals after an 8-minute clinical death. When studying the teratogenic and embryotoxic activity of a synthetic antihypoxant, benzomopine, a dose of 208.9 mg/kg of body weight from the 1st to the 17th day of pregnancy turned out to be partially fatal for pregnant females. The delay in embryonic development is obviously associated with the general toxic effect on the mother of a high dose of antihypoxant. Thus, when administered orally 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, benzomopine does not lead to a teratogenic effect, but has a weak potential embryotoxic effect. .

The works show the antihypoxic effect of benzodiazepine receptor agonists. Subsequent clinical use of benzodiazepines has confirmed their high efficacy as antihypoxants, although the mechanism of this effect has not been elucidated. The experiment showed the presence of receptors for exogenous benzodiazepines in the brain and in 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 - life expectancy in the main group was 32 ± 4.2; 58 ± 7, respectively). ,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 that are independent of GABAergic control, at least from GABA-type receptors.

A number of modern works convincingly show the high efficiency of antihypoxants in the treatment of hypoxic-ischemic brain lesions in a number of pregnancy complications (severe preeclampsia, fetoplacental insufficiency, etc.), as well as in neurological practice.

Regulators with a pronounced anti-hapoxic effect include substances such as:

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

Correction of hypoxic disorders should be carried out in a complex manner with the involvement of antihypoxants, which have an effect on various parts of 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 the maintenance of ATP concentration at the level of neurons under hypoxic conditions that becomes especially significant.

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

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

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

In any critical condition, 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. Maintenance of homeostasis is carried out by the higher cortical and vegetative centers, the reticular formation of the trunk, the thalamus, specific and nonspecific nuclei of the hypothalamus, and the neurohypophysis.

These neuronal structures control the activity of the main "working blocks" of the body, such as the respiratory system, blood 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 in this case is manifested by changes in neuronal activity, neurochemical processes, and metabolic shifts. The sympathetic nervous system in pathological conditions changes the functional readiness of organs and tissues.

In the nervous tissue itself, under pathological conditions, processes can take place that are to a certain extent similar to adaptive-trophic changes in the periphery. They are implemented through the monaminergic systems of the brain, 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 an adequate cerebral metabolism makes it possible to preserve the adaptive-trophic influences of the nervous system and prevent the development and progression of multiple organ failure syndrome.

Actovegin and instenon

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

The possibilities of pharmacological correction of hypoxia with the help of 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 not enough.

Actovegin-deproteinized hemoderivative from the blood serum of young calves contains a complex of low molecular weight 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 in conditions of hypoxia and ischemia by increasing the accumulation of glucose and oxygen. An increase in the transport of glucose and oxygen into the cell and an increase in intracellular utilization accelerate ATP metabolism. Under the conditions of Actovegin application, the anaerobic oxidation pathway most characteristic of hypoxia conditions, 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 makes it possible to increase the efficiency of oxidative phosphorylation by 18 times and increase the yield of ATP, ensuring its adequate content.

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

The use of large doses of actovegin (up to 4 g of dry matter per day intravenously) makes it possible to achieve an improvement in the condition of patients, a decrease in the duration of mechanical ventilation, a decrease in the incidence of multiple organ failure syndrome after critical conditions, a decrease in mortality, and a reduction in the length of stay in intensive care units.

Under conditions of hypoxia and ischemia, especially cerebral, the combined use of actovegin and instenon (a multicomponent neurometabolism activator), 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 metabolism of neurotransmitters and the restoration of synaptic transmission, the depression of which is the leading pathogenetic mechanism for disorders of consciousness and neurological deficit during hypoxia and ischemia.

With the complex use of actovegin and instenon, it is also possible to achieve activation of the consciousness of patients who have undergone acute severe hypoxia, which indicates the preservation of the integrative and regulatory-trophic mechanisms of the CNS.

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

Probucol

Probucol is currently one of the few available and cheap domestic antihypoxants that cause a moderate, and in some cases a significant decrease in serum cholesterol (Cholesterol) levels. Probucol causes a decrease in the level of high density lipoproteins (HDL) due to the reverse transport of cholesterol. The change in reverse transport during probucol therapy is judged mainly by the activity of transferring cholesterol esters (PECHS) from HDL to very low and low density lipoproteins (VLDL and LPN P, respectively). There is also another factor - apoprotsin E. It has been shown that when using probucol for three months, cholesterol levels are reduced 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 violation of lipoprotein metabolism 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 further lower cholesterol levels. The pronounced antioxidant properties of probucol were revealed, while the stability of erythrocyte membranes increased (decrease in lipid peroxidation), a moderate lipid-lowering effect was also revealed, which gradually disappeared after treatment. When using probucol, some patients have a decrease in appetite, bloating.

Promising is the use of the antioxidant coenzyme Q10, which affects the oxidizability of lipoproteins in blood plasma and antiperoxide resistance of plasma in patients with coronary heart disease. In a number of modern works, it has been revealed that taking large doses of vitamin E and C leads to an improvement in clinical parameters, a decrease in the risk of developing coronary artery disease and the mortality rate from this disease.

It is important to note that the study of the dynamics of LPO and AOS indicators during the treatment of IHD with various antianginal drugs showed that the outcome of treatment is directly dependent on 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, at present, antioxidants have not yet become widely used 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 technique for determining the presence of one of the most active free OH free radicals in the studied medium, it was found that melatonin has a significantly more pronounced activity in terms of OH inactivation than such powerful intracellular AOs as glutathione and mannitol. Also under in vitro conditions, it was 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 identified a phenomenon indicating the dominant 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).

Therefore, melatonin also has protective properties against free radical damage to proteins. Of course, studies that show the role of melatonin in the interruption of LPO are of great interest. Until recently, vitamin E (a-tocopherol) was considered one of the most powerful lipid AOs. In experiments in vitro and in vivo, when comparing the effectiveness of vitamin E and melatonin, it was shown that melatonin is 2 times more active in terms of inactivation of the ROO radical than vitamin E. Such a high AO efficiency of melatonin cannot be explained only 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 AO activity of melatonin itself, it was found in in vitro experiments that its metabolite 6-hydroxymelatonin, which is formed during the metabolism of melatonin in the liver, gives a much more pronounced effect on lipid peroxidation. Therefore, in the body, defense mechanisms against free radical damage include not only the effects of melatonin, but also of at least one of its metabolites.

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

In an animal experiment, melatonin has been shown to be highly effective in protecting against oxidative stress caused by bacterial lipopolysaccharides.

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 to its oxidized form. During this reaction, the H2O2 molecule, which is active in terms of producing an extremely toxic OH radical, is converted into a water molecule, and an oxygen ion is attached to glutathione, forming oxidized glutathione. It has also been shown that melatonin can inactivate the enzyme (nitric oxide synthetase) that activates the processes of nitric oxide production.

The effects of melatonin listed above allow us to consider 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, etc. on the survival time of animals during anoxic and hypobaric hypoxia. Indomethacin was used at a dose of 1-10 mg/kg of body weight orally, and other antihypoxants at doses of 25 to 200 mg/kg. It has been established that indomethacin increases 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 it promising to search for antihypoxants among cyclooxygenase inhibitors. When studying the antihypoxic effect of indomethacin, voltaren and ibuprofen, A. I. Bersznyakova and V. M. 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 the 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 metabolic acidosis products, a decrease in the content of lactic acid, and an increase in hemoglobin synthesis. Voltaren, in addition, is able to increase the number of red blood cells.

The protective and restorative effect of antihypoxants during posthypoxic inhibition of dopamine release has also been shown. The experiment showed that antihypoxants improve memory, and the use of gutimin in the complex of resuscitation therapy facilitated and accelerated the recovery of body functions after a terminal state of moderate severity.

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Antihypoxic properties of endorphins, enkephalins and their analogues

Naloxone, a specific antagonist of opiates and opioids, has been shown to shorten the lifespan of animals under conditions of 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 an antihypoxic effect through opioid receptors. Experiments on male mice showed that leuenxfalin and endorphin are endogenous antihypoxants. The most likely way of protecting the body from acute hypoxia with opioid peptides and morphine is associated with 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 also has a certain significance. Therefore, the mobilization of endogenous opioid peptides to a strong hypoxic stimulus is biologically expedient and has a protective character. Antagonists of narcotic analgesics (naloxone, nalorphine, etc.) block opioid receptors and thereby prevent the protective effect of endogenous and exogenous opioids against acute hypoxic hypoxia.

It has been 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.

Antihypoxic action of catecholamines, adenosine and their analogues

It is generally accepted that adequate regulation of energy metabolism largely determines the body's resistance to extreme conditions, and a targeted pharmacological effect on key links in the natural adaptive process is promising for the development of effective protective substances. Stimulation of oxidative metabolism (calorigenic effect) observed during the stress reaction, the integral indicator of which is the intensity of oxygen consumption by the body, is mainly associated with the activation of the sympathetic-adrenal system and the mobilization of catecholamines. The important adaptive value of adenosine, which acts as a neuromodulator and "response metabolite" of cells, has been shown. As shown in the work of I. A. Olkhovsky (1989), various adrenoagonists - adenosine and its analogues cause a dose-dependent decrease in oxygen consumption by the body. The anticalorigenic effect of clonidine (clophelin) 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. The antihypoxic efficacy of the compounds is due to relatively independent mechanisms: metabolic and hypothermic action. These effects are mediated, respectively, by α2-adrenergic and α-adenosine receptors. Stimulants of these receptors differ from gutimin in lower effective doses and higher protective indices.

A 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 (clophelin) allowed the author to propose the use of this compound in surgical interventions. In patients treated with clonidine, basic hemodynamic parameters are more consistently maintained, and microcirculation parameters are significantly improved.

Thus, substances capable of stimulating (a2-adrenergic receptors 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 substances may reflect the reproduction of natural hypobiotic adaptive reactions of the organism, useful in conditions of excessive action of damaging factors.

Thus, in increasing the body's tolerance to acute hypoxia under the influence of a2-adrenergic receptors 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, which potentiates the state of reduced oxygen demand. Probably, metabolic shifts useful under hypoxic conditions are associated with receptor-mediated changes in the tissue pool of cAMP and subsequent regulatory restructuring of oxidative processes. The receptor specificity of the protective effects allows the author to use a new receptor approach to the search for protective substances based on the screening of α2-adrenergic and A-receptor agonists.

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

optimization of protective and adaptive reactions of the body (it is achieved, for example, thanks to cardiac and vasoactive agents in shock and moderate degrees of atmospheric rarefaction);
a decrease in the body's oxygen demand and energy consumption (most of the means used in these cases - general anesthetics, antipsychotics, central relaxants - increase only passive resistance, reducing the body's performance). Active resistance to hypoxia can only be if the antihypoxant drug provides economy of oxidative processes in tissues with a simultaneous increase in the conjugation of oxidative phosphorylation and energy production during glycolysis, inhibition of non-phosphorylating oxidation;
improvement of interorgan exchange of metabolites (energy). It can be achieved, for example, by activating gluconeogenesis in the liver and kidneys. Thus, the provision of these tissues with the main and most beneficial energy substrate in hypoxia, glucose, is maintained, the amount of lactate, pyruvate and other metabolic products that cause acidosis and intoxication decreases, and the autoinhibition of glycolysis decreases;
stabilization of the structure and properties of cell membranes and subcellular organelles (the ability of mitochondria to utilize oxygen and carry out oxidative phosphorylation, reduce the phenomena of dissociation and restore respiratory control is supported).

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

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

decrease in the oxygen demand of the body (organ), which, apparently, is based on the economization of the use of oxygen with the redistribution of its flow to intensively working organs;

Antihypoxants and how to use them

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

Antihypoxant	Release form	Introduction	Dose mg/kg day	Number of applications per day
	ampoules, 1.5% 5 ml	intravenously, drip
	ampoules, 7% 2 ml	intravenously, drip
Riboxin	ampoules, 2% 10 ml	intravenously, drip, jet
Cytochrome C	vial, 4 ml (10 mg)	intravenous, drip, intramuscular
middronate	ampoules, 10% 5 ml	intravenously, jet
Pirocetam	ampoules, 20% 5 ml	intravenously, drip	10-15 (up to 150)
	tab., 200 mg	orally
Sodium oxybutyrate	ampoules, 20% 2 ml	intramuscularly
	ampoules, 1 g	intravenously, jet
Solcoseryl	ampoules, 2ml	intramuscularly
Actovegin	vial, 10% 250 ml	intravenously, drip
Ubiquinone (coenzyme Q-10)		orally
	tab., 250 mg	orally
Trimetazidine	tab., 20 mg	orally

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 means of intensive care is accompanied by an improvement in the clinical course, a decrease in the frequency of complications and mortality, and the normalization of laboratory parameters.

Amtizol, piracetam, lithium oxybutyrate and ubiquinone have the most pronounced protective properties in patients in the acute period of myocardial infarction, cytochrome C, riboxin, mildronate and oliven are somewhat less active, solcoseryl, bemitil, trimetazidine and aspisol are not active. The protective capabilities of hyperbaric oxygen therapy 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 hydroxybutyrate and emoxipin on the functional state of myocardium damaged by adrenaline 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 antihypoxants 30 minutes after damage modeling: sodium oxybutyrate at a dose of 200 mg/kg, and emoxipine at a dose of 4 mg/kg.

Sodium oxybutyrate and emoxipine have antihypoxic and antioxidant activity, which is accompanied by a cardioprotective effect, recorded by enzyme diagnostics and electrocardiography.

The problem of FRO in the human body attracted the attention of many researchers. This is due to the fact that failure in the antioxidant system and increased FRO is considered as an important link in the development of various diseases. The intensity of FRO 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 coordination of the action of all links of this complex chain. Among the factors that protect organs and tissues from excessive overoxidation, only antioxidants have the ability to directly react with peroxide radicals, and their effect on the overall FRO rate significantly exceeds the effectiveness of other factors, which determines the special role of antioxidants in the regulation of FRO processes.

One of the most important bioantioxidants with extremely high antiradical activity is vitamin E. At present, the term "vitamin E" is used to combine a fairly large group of natural and synthetic tocopherols that are soluble only in fats and organic solvents and have 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 FRO.

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

A significant role in the processes of free radical oxidation is also assigned to selenium, which is an essential oligoelement. The lack of selenium in food leads to a number of diseases, primarily cardiovascular, reduces the protective properties of the body. Antioxidant vitamins increase the absorption of selenium in the intestine and help to enhance the antioxidant defense process.

It is important to use numerous nutritional supplements. Of the latter, fish oil, evening primrose oil, blackcurrant seed oil, New Zealand mussels, ginseng, garlic, and honey proved to be the most effective. A special place is occupied by vitamins and microelements, among which, in particular, vitamins E, A and C and the trace element selenium, due to their ability to influence the processes of free radical oxidation in tissues.

, , , ,

It's important to know!

Hypoxia - oxygen deficiency, a condition that occurs when there is insufficient supply of oxygen to the tissues of the body or a violation of its utilization in the process of biological oxidation, accompanies many pathological conditions, being a component of their pathogenesis and clinically manifesting as a hypoxic syndrome, which is based on hypoxemia.

Violation of mitochondrial oxidation leads to inhibition of phosphorylation associated with it and, consequently, causes a progressive deficiency of ATP, a universal energy source in the cell. Energy deficiency is the essence of any form of hypoxia and causes qualitatively similar metabolic and structural changes in various organs and tissues. A decrease in the concentration of ATP in the cell leads to a weakening of its inhibitory effect on one of the key enzymes of glycolysis - phosphofructokinase. Glycolysis, which is activated during hypoxia, partially compensates for the lack of ATP, but quickly causes the accumulation of lactate and the development of acidosis with the resulting autoinhibition of glycolysis.

Hypoxia leads to a complex modification of the functions of biological membranes, affecting both the lipid bilayer and membrane enzymes. Damaged or modified main

membrane functions: barrier, receptor, catalytic. The main reasons for this phenomenon are energy deficiency and activation against its background of phospholipolysis and lipid peroxidation. The breakdown of phospholipids and the inhibition of their synthesis lead to an increase in the concentration of unsaturated fatty acids and an increase in their peroxidation. The latter is stimulated as a result of the suppression of the activity of antioxidant systems due to the breakdown and inhibition of the synthesis of their protein components, and first of all, superoxide dismutase (SOD), catalase (CT), glutathione peroxidase (GP), glutathione reductase (GR), etc.

Energy deficiency during hypoxia contributes to the accumulation of Ca 2+ in the cytoplasm of the cell, since the energy-dependent pumps that pump Ca 2+ ions out of the cell or pump it into the cisterns of the endoplasmic reticulum are blocked, and the accumulation of Ca 2+ activates Ca 2+ -dependent phospholipases. One of the protective mechanisms preventing the accumulation of Ca 2+ in the cytoplasm is the uptake of Ca 2+ by mitochondria. At the same time, the metabolic activity of mitochondria increases, aimed at maintaining the constancy of the intramitochondrial charge and pumping protons, which is accompanied by an increase in ATP consumption. A vicious circle closes: lack of oxygen disrupts energy metabolism and stimulates free radical oxidation, and activation of free radical processes, damaging the membranes of mitochondria and lysosomes, exacerbates energy deficiency, which, ultimately, can cause irreversible damage and cell death. The main links in the pathogenesis of hypoxic conditions are shown in Scheme 8.1.

In the absence of hypoxia, some cells (for example, cardiomyocytes) obtain ATP through the breakdown of acetyl-CoA in the Krebs cycle, and glucose and free fatty acids (FFA) are the main sources of energy. With an adequate blood supply, 60-90% of acetyl-CoA is formed due to the oxidation of free fatty acids, and the remaining 10-40% is due to the decarboxylation of pyruvic acid (PVA). Approximately half of the PVC inside the cell is formed due to glycolysis, and the second half - from lactate entering the cell from the blood. FFA catabolism, compared to glycolysis, requires more oxygen to synthesize an equivalent number of ATP. With a sufficient supply of oxygen to the cell, the glucose and fatty acid energy supply systems are in a state of dynamic equilibrium. Under conditions of hypoxia, the amount of incoming oxygen is insufficient for the oxidation of fatty acids.

Scheme 8.1.Some links in the pathogenesis of hypoxic conditions

As a result, underoxidized activated forms of fatty acids (acylcarnitine, acylCoA) accumulate in mitochondria, which are able to block adenine nucleotide translocase, which is accompanied by suppression of the transport of ATP produced in mitochondria into the cytosol, and damage cell membranes, and have a detergent effect.

Several approaches can be used to improve the energy status of a cell:

Increasing the efficiency of using deficient oxygen by mitochondria due to the prevention of uncoupling of oxidation and phosphorylation, stabilization of mitochondrial membranes;

Weakening of the inhibition of the reactions of the Krebs cycle, especially maintaining the activity of the succinate oxidase link;

Compensation for lost components of the respiratory chain;

Formation of artificial redox systems shunting the respiratory chain overloaded with electrons;

More economical use of oxygen and a decrease in the oxygen demand of tissues or inhibition of the ways of its consumption that are not necessary for emergency maintenance of life in critical conditions (non-phosphorylating enzymatic oxidation - thermoregulatory, microsomal, etc., non-enzymatic lipid oxidation);

Increased ATP formation during glycolysis without increasing lactate production;

Decreased consumption of ATP by the cell for processes that do not determine emergency maintenance of life in critical situations (various synthetic recovery reactions, functioning of energy-dependent transport systems, etc.);

Introduction from outside of high-energy compounds.

Classification of antihypoxants

Drugs with polyvalent action.

Fatty acid oxidation inhibitors.

Succinate-containing and succinate-forming agents.

Natural components of the respiratory chain.

Artificial redox systems.

macroergic compounds.

8.1. PREPARATIONS WITH POLYVALENT ACTION

Gutimin.

Amtizol.

The Department of Pharmacology of the Military Medical Academy became a pioneer in the development of antihypoxants not only in our country. Back in the 1960s. on it, under the guidance of Professor V. M. Vinogradov, the first antihypoxants were created: gutimine, and then amtizol, which were subsequently actively studied under the guidance of professors L. V. Pastushenkov, A. E. Alexandrova, A. V. Smirnov. These drugs have shown high efficacy in clinical trials, but, unfortunately, they are not currently produced and are not used in medical practice.

8.2. FATTY ACID OXIDATION INHIBITORS

Trimetazidine (Preductal).

Perhexilin.

Meldonium (Mildronate).

Ranolazine (Ranexa).

Etomoxir.

Carnitine (Carnitene).

Means similar in pharmacological effects (but not in structure) to gutimine and amtizol are drugs - inhibitors of fatty acid oxidation, currently used mainly in the complex therapy of coronary heart disease. Among them are direct inhibitors of carnitine palmitoyl transferase-I (perhexelin, etomoxir), partial inhibitors of fatty acid oxidation (ranolazine, trimetazidine, meldonium) and indirect inhibitors of fatty acid oxidation (carnitine). The points of application of some drugs are shown in Scheme 8.2.

Perhexelin and etomoxir are able to inhibit the activity of carnitine palmitoyl transferase-I, thus disrupting the transfer of long-chain acyl groups to carnitine, which leads to blockade of the formation of acylcarnitine. As a result, the intramitochondrial level of acyl-CoA decreases and the NAD-H 2 /NAD ratio decreases, which is accompanied by an increase in the activity of pyruvate dehydrogenase and phosphofructokinase, and therefore stimulation of glucose oxidation, which is more energetically beneficial compared to fatty acid oxidation.

Scheme 8.2.Fatty acid β-oxidation and some drug sites (adapted from Wolff A. A., 2002)

Perhexelin is administered orally in doses of 200-400 mg/day for up to 3 months. The drug can be combined with β-blockers, calcium channel blockers and nitrates. However, its clinical use is limited by unfavorable

obvious effects - the development of neuropathy and hepatotoxicity. Etomoxir is used at a dose of 80 mg / day for up to 3 months. However, for the final judgment on the effectiveness and safety of the drug, additional studies are needed. At the same time, special attention is paid to the toxicity of etomoxir, given the fact that it is an irreversible inhibitor of carnitine palmitoyltransferase-I.

Trimetazidine, ranolazine and meldonium are classified as partial inhibitors of fatty acid oxidation. Trimetazidine (Preductal) blocks 3-ketoacylthiolase, one of the key enzymes in fatty acid oxidation. As a result, the oxidation of all fatty acids in the mitochondria is inhibited - both long-chain (the number of carbon atoms is more than 8) and short-chain (the number of carbon atoms is less than 8), but the accumulation of activated fatty acids in mitochondria does not change in any way. Under the influence of trimetazidine, pyruvate oxidation and glycolytic production of ATP increase, the concentration of AMP and ADP decreases, the accumulation of lactate and the development of acidosis are inhibited, and free radical oxidation is suppressed.

Trimetazidine reduces the rate of penetration of neutrophilic granulocytes into the myocardium after reperfusion, as a result of which the secondary damage to cell membranes by lipid peroxidation products decreases. In addition, it has an antiplatelet effect and is effective in preventing intracoronary platelet aggregation, while, unlike aspirin, it does not affect coagulation and bleeding time. According to experimental data, trimetazidine has such an effect not only in the myocardium, but also in other organs, i.e., in fact, it is a typical antihypoxant, promising for further study and use in various critical conditions.

In the European multicenter study of trimetazidine (TEMS) in patients with stable angina, the use of the drug contributed to a decrease in the frequency and duration of episodes of myocardial ischemia by 25%, which was accompanied by an increase in patients' exercise tolerance. The appointment of trimetazidine in combination with β-blockers, nitrates and calcium channel blockers contributes to some increase in the effectiveness of antianginal therapy.

Currently, the drug is used for coronary heart disease, as well as other diseases based on ischemia (for example, with vestibulocochlear and chorioretinal pathology) (Table 8.1). Evidence of the effectiveness of pre-

paratha in refractory angina pectoris. In the complex treatment of coronary artery disease, the drug is prescribed in the form of a sustained release dosage form in a single dose of 35 mg 2 times a day, the duration of the course can be up to 3 months.

Early inclusion of trimetazidine in the complex therapy of the acute period of myocardial infarction helps to limit the size of myocardial necrosis, prevents the development of early postinfarction left ventricular dilatation, increases the electrical stability of the heart without affecting ECG parameters and heart rate variability. At the same time, within the framework of the multicenter international double-blind randomized study EMIP-FR (The European Myocardial Infarction Project - Free Radicals), which ended in 2000, the expected positive effect of a short course of intravenous administration of the drug (40 mg intravenously as a bolus before, simultaneously or within 15 minutes of initiation of thrombolytic therapy followed by an infusion of 60 mg/day for 48 hours) on long-term, in-hospital mortality and the combined endpoint in patients with myocardial infarction (MI). However, trimetazidine significantly reduced the frequency of prolonged anginal attacks and recurrent MI in patients undergoing thrombolysis.

In a small randomized controlled trial, the first data on the effectiveness of trimetazidine in patients with CHF were obtained. It has been shown that long-term use of the drug (in the study at 20 mg 3 times a day for about 13 months) improves the functional class and contractile function of the left ventricle in patients with heart failure.

Side effects when taking the drug (discomfort in the stomach, nausea, headache, dizziness, insomnia) rarely develop (Table 8.2).

Ranolazine (Ranexa) is also an inhibitor of fatty acid oxidation, although its biochemical target has not yet been established. It has an anti-ischemic effect by limiting the use of free fatty acids as an energy substrate and increasing the use of glucose. This results in the production of more ATP for every mole of oxygen consumed.

In addition, ranolazine has been shown to cause selective inhibition of late sodium flux and reduce ischemia-induced sodium and calcium overload of the cell, thereby improving myocardial perfusion and functionality. As a rule, a single dose of the drug is 500 mg 1 time per day, since it is approved

Table 8.1. The main indications for use and regimens for prescribing trimetazidine

Table 8.2. Side effects and contraindications to the use of some antihypoxants

Continuation of the table. 8.2

Continuation of table 8.2

The end of the table. 8.2

The clinically available form of ranolazine is a long-acting drug (ranolazine SR, 500 mg). However, the dose may be increased to 1000 mg/day.

Ranolazine is commonly used in combination therapy in patients with coronary artery disease along with long-acting nitrates, β-blockers, and dihydropyridine calcium channel blockers (eg, amlodipine). Thus, in a randomized placebo-controlled study ERICA showed antianginal efficacy of ranolazine in patients with stable angina who had attacks, despite taking the maximum recommended dose of amlodipine. The addition of 1000 mg of ranolazine twice a day for 6 weeks led to a significant decrease in the frequency of angina attacks and doses of nitroglycerin. In women, the effect of ranolazine on the severity of angina symptoms and exercise tolerance is lower than in men.

Results of the MERLIN-TIMI 36 study, which was conducted to clarify the effect of ranolazine (intravenously, then orally 1000 mg / day) on the incidence of cardiovascular events in patients with acute coronary syndrome (unstable angina or myocardial infarction without segment elevation ST), evaluation of the efficacy and safety of the drug in the treatment of coronary heart disease showed that ranolazine reduces the severity of clinical symptoms, but does not affect the long-term risk of death and myocardial infarction in patients with coronary artery disease. The mean follow-up time was 348 days.

The frequency of registration of the main endpoint (cardiovascular death, MI, recurrent myocardial ischemia) in this study was almost the same in the ranolazine and placebo groups: 21.8 and 23.5%. However, the risk of recurrent ischemia was significantly lower with ranolazine: 13.9% versus 16.1%. The risk of cardiovascular death or MI did not differ significantly between groups.

Analysis of additional endpoints confirmed the antianginal efficacy of ranolazine. So, against the background of taking the drug, there was a 23% lower risk of worsening angina symptoms and a 19% lower probability of prescribing an additional antianginal agent. The safety of ranolazine and placebo was comparable.

In the same study, the antiarrhythmic activity of ranolazine was found in patients with ACS without segment elevation. ST during the first week after their hospitalization (decrease in the number of episodes of ventricular tachycardia (more than 8 complexes) (5.3% vs. 8.3% in control; p< 0,001), суправентрикулярной тахикардии (44,7% против 55,0% в контроле; р < 0,001) и тенденция к снижению парок-

sisms of atrial fibrillation (1.7% vs. 2.4%; p = 0.08). Moreover, in the ranolazine group, pauses >3 s were less common than in controls (3.1% vs. 4.3%; p = 0.01). The researchers did not note intergroup differences in the incidence of polymorphic ventricular tachycardia, as well as in the frequency of sudden death.

It is assumed that the antiarrhythmic activity of ranolazine is associated with its ability to inhibit the late phase of sodium flow into the cell during repolarization (late current I), which causes a decrease in intracellular sodium concentration and calcium overload of cardiomyocytes, preventing the development of both mechanical myocardial dysfunction accompanying ischemia and its electrical instability.

Ranolazine usually does not cause pronounced side effects and does not have a significant effect on heart rate and blood pressure, however, when using relatively high doses and when combined with β-blockers or calcium channel blockers, moderately severe headaches, dizziness, and asthenic phenomena can be observed. In addition, the possibility of increasing the drug interval QT imposes certain restrictions on its clinical use (see Table 8.2).

Meldonium (mildronate) reversibly limits the rate of carnitine biosynthesis from its precursor, γ-butyrobetaine. As a result, carnitine-mediated transport of long-chain fatty acids across mitochondrial membranes is impaired without affecting the metabolism of short-chain fatty acids. This means that meldonium is practically incapable of exerting a toxic effect on mitochondrial respiration, since it cannot completely block the oxidation of all fatty acids. Partial blockade of fatty acid oxidation includes an alternative energy production system - glucose oxidation, which is much more efficient (12%) using oxygen for ATP synthesis. In addition, under the influence of meldonium, the concentration of γ-butyrobetaine, which can induce the formation of NO, increases, which leads to a decrease in the total peripheral vascular resistance (OPVR).

Meldonium, like trimetazidine, with stable angina reduces the frequency of angina attacks, increases patients' exercise tolerance and reduces the average daily intake of nitroglycerin (Table 8.3). The drug has low toxicity and does not cause significant side effects.

Carnitine (vitamin B T) is an endogenous compound and is formed from lysine and methionine in the liver and kidneys. It plays an important role in

Table 8.3. The main indications for use and schemes for prescribing meldonium

Table 8.4. The main indications for use and schemes for prescribing carnitine

transfer of long-chain fatty acids across the inner mitochondrial membrane, while activation and penetration of lower fatty acids occurs without kartinitin. In addition, carnitine plays a key role in the formation and regulation of acetyl-CoA levels.

Physiological concentrations of carnitine have a saturating effect on carnitine palmitoyl transferase-I, and an increase in the dose of the drug does not increase the transport of acyl groups of fatty acids into mitochondria with the participation of this enzyme. However, this leads to the activation of carnitine acylcarnitine translocase (which is not saturated with physiological concentrations of carnitine) and a decrease in the intramitochondrial concentration of acetyl-CoA, which is transported to the cytosol (via the formation of acetylcarnitine). In the cytosol, excess acetyl-CoA is exposed to acetyl-CoA carboxylase to form malonyl-CoA, which has the properties of an indirect inhibitor of carnitine palmitoyl transferase-I. A decrease in intramitochondrial acetyl-CoA correlates with an increase in the level of pyruvate dehydrogenase, which provides pyruvate oxidation and limits lactate production. Thus, the antihypoxic effect of carnitine is associated with blockade of the transport of fatty acids into mitochondria, is dose-dependent and manifests itself when prescribing high doses of the drug, while low doses have only a specific vitamin effect.

One of the largest studies using carnitine is CEDIM. When conducting it, it was shown that long-term carnitine therapy at sufficiently high doses in patients with myocardial infarction limits the dilatation of the left ventricle. In addition, a positive effect from the use of the drug was obtained in severe traumatic brain injuries, fetal hypoxia, carbon monoxide poisoning, etc., however, a large variability in the courses of use and not always an adequate dose policy make it difficult to interpret the results of such studies. Some indications for the use of carnitine are presented in Table. 8.4.

8.3. SUCCINATE-CONTAINING AND SUCCINATE-FORMING AGENTS

Succinate-containing products

Reamberin.

Oxymethylethylpyridine succinate (Mexidol, Mexicor).

Combined:

Cytoflavin (succinic acid + nicotinamide + riboflavin mononucleotide + inosine).

Practical use as antihypoxants began to find drugs that support the activity of the succinate oxidase link during hypoxia. This FAD-dependent link of the Krebs cycle, which is later inhibited during hypoxia compared to NAD-dependent oxidases, can maintain energy production in the cell for a certain time, provided that the mitochondria contain the oxidation substrate in this link, succinate (succinic acid).

One of the drugs created on the basis of succinic acid is Reamberin - 1.5% solution for infusion, which is a balanced polyionic solution with the addition of mixed sodium N-methylglucamine salt of succinic acid (up to 15 g / l). The osmolarity of this solution is close to that of human plasma. The study of the pharmacokinetics of reamberin showed that when administered intravenously at a dose of 5 mg/kg, the maximum level of the drug (in terms of succinate) is observed within 1 minute after administration, followed by a rapid decrease to a level of 9-10 μg/ml. 40 minutes after administration, the concentration of succinate in the blood returns to values close to the background (1-6 μg / ml), which requires intravenous drip of the drug.

Reamberin infusion is accompanied by an increase in the pH and buffer capacity of the blood, as well as alkalization of the urine. In addition to the antihypoxant activity, Reamberin has a detoxifying and antioxidant (due to the activation of the enzymatic unit of the antioxidant system) action. The main indications for the use of the drug are presented in Table. 8.5.

The use of Reamberin (400 ml of a 1.5% solution) in patients with multivessel coronary artery disease during aorto-mammary coronary artery bypass grafting with left ventricular plasty and/or valve replacement and the use of extracorporeal circulation in the intraoperative period can reduce the incidence of various complications in the early postoperative period (including reinfarctions, strokes, encephalopathy). To make a final judgment on the efficacy and safety of the drug, it is necessary to conduct large controlled clinical trials.

There are few side effects of the drug, mainly a short-term feeling of heat and redness of the upper body. Contraindicated

Table8.5. The main indications for use and schemes for prescribing Reamberin as an antihypoxant

Note:* - a single dose is given in terms of succinate; APK - heart-lung machine.

Reamberin in case of individual intolerance, conditions after craniocerebral injuries, accompanied by cerebral edema (see Table 8.2).

The combined antihypoxic effect is exerted by the drug cytoflavin (succinic acid, 1000 mg + nicotinamide, 100 mg + + riboflavin mononucleotide, 20 mg + inosine, 200 mg). The main antihypoxic effect of succinic acid in this formulation is supplemented by riboflavin, which, due to its coenzymatic properties, can increase the activity of succinate dehydrogenase and has an indirect antioxidant effect (due to the reduction of oxidized glutathione). It is assumed that nicotinamide, which is part of the composition, activates NAD-dependent enzyme systems, but this effect is less pronounced than that of NAD. Due to inosine, an increase in the content of the total pool of purine nucleotides is achieved, which is necessary not only for the resynthesis of macroergs (ATP and GTP), but also second messengers (cAMP and cGMP), as well as nucleic acids. A certain role may be played by the ability of inosine to somewhat suppress the activity of xanthine oxidase, thereby reducing the production of highly active forms and oxygen compounds. However, compared with other components of the drug, the effects of inosine are delayed in time. Cytoflavin found its main use in hypoxic and ischemic injuries of the central nervous system (Table 8.6). The drug has the greatest effect in the first 24 hours after the onset of hypoxic disorder.

In a fairly large multicenter placebo-controlled clinical trial that included 600 patients with chronic cerebral ischemia, Cytoflavin demonstrated the ability to reduce cognitive-mnestic disorders and neurological disorders; restore the quality of sleep and improve the quality of life. However, to make a final judgment on the efficacy and safety of the drug, large controlled clinical trials are required.

Side effects of cytoflavin are presented in table. 8.2.

When using preparations containing exogenous succinate, it must be taken into account that it penetrates through biological membranes rather poorly. More promising here may be oxymethylethylpyridine succinate (mexidol, mexicor), which is a complex of succinate with the antioxidant emoxipine, which has a relatively weak antihypoxic activity, but facilitates the transport of succinate through membranes. Like emoxipine, hydroxymethylethylpyridine succinate (OMEPS) is an inhibitor of

Table 8.6. The main indications for use and regimens for the appointment of Cytoflavin

free radical processes, but has a more pronounced antihypoxic effect. The main pharmacological effects of OMEPs can be summarized as follows:

Actively reacts with peroxide radicals of proteins and lipids;

Optimizes the energy-synthesizing functions of mitochondria under hypoxic conditions;

It has a modulating effect on some membrane-bound enzymes (phosphodiesterase, adenylate cyclase), ion channels, improves synaptic transmission;

It has a hypolipidemic effect, reduces the level of peroxide modification of lipoproteins, reduces the viscosity of the lipid layer of cell membranes;

Blocks the synthesis of certain prostaglandins, thromboxane and leukotrienes;

Improves the rheological properties of blood, inhibits platelet aggregation.

The main clinical trials of OMEPS were carried out to study its effectiveness in disorders of ischemic origin: in the acute period of myocardial infarction, coronary artery disease, acute cerebrovascular accidents, dyscirculatory encephalopathy, vegetovascular dystonia, atherosclerotic disorders of the brain and other conditions accompanied by tissue hypoxia. The main indications for the appointment and schemes for the use of the drug are given in Table. 8.7.

The duration of administration and the choice of an individual dose depend on the severity of the patient's condition and the effectiveness of OMEPS therapy. To make a final judgment about the efficacy and safety of the drug, it is necessary to conduct large controlled clinical trials.

The maximum daily dose should not exceed 800 mg, single - 250 mg. OMEPS is generally well tolerated. Some patients may experience nausea and dry mouth (see Table 8.2). The drug is contraindicated in severe violations of the liver and kidneys, allergies to pyridoxine.

Succinate-forming agents

Sodium/lithium oxybutyrate.

Fumarate-containing drugs (Polyoxyfumarin, Confumin). With the ability to convert to succinate in the Roberts cycle

(γ-aminobutyrate shunt) is obviously associated with the antihypoxic effect of sodium/lithium oxybutyrate, although it is not very pronounced. Transamination of γ-aminobutyric acid (GABA) with α-ketogluta-

Table 8.7. The main indications for use and prescription regimens for OMEPS as an antihypoxant

The end of the table. 8.7

Ric acid is the main pathway for the metabolic degradation of GABA. The succinic acid semialdehyde formed during the neurochemical reaction is oxidized in the brain tissue with the help of succinate semialdehyde dehydrogenase with the participation of NAD into succinic acid, which is included in the tricarboxylic acid cycle (Scheme 8.3).

This additional action is very useful when sodium oxybutyrate is used as a general anesthetic (at high doses). Under conditions of severe circulatory hypoxia, oxybutyrate in a very short time manages to launch not only cellular adaptation mechanisms, but also reinforce them by restructuring energy metabolism in vital organs. Therefore, one should not expect any noticeable effect from the introduction of small doses of anesthetic.

The average doses for the sodium salt of oxybutyrate are 70-120 mg/kg (up to 250-300 mg/kg, in which case the antihypoxic effect will be maximally expressed), for the lithium salt - 10-15 mg/kg 1-2 times a day. The action of previously introduced hydroxybutyrate prevents the activation of lipid peroxidation in the nervous system and myocardium, prevents the development of their damage during intense emotional and painful stress.

In addition, the beneficial effect of sodium oxybutyrate during hypoxia is due to the fact that it activates the energetically more favorable pentose pathway of glucose metabolism with its orientation towards the path of direct oxidation and the formation of pentoses that are part of ATP. In addition, activation of the pentose glucose oxidation pathway creates an increased level of NADPH, as a necessary cofactor in hormone synthesis, which is especially important for the functioning of the adrenal glands. The change in the hormonal background during the administration of the drug is accompanied by an increase in the blood glucose content, which gives the maximum yield of ATP per unit of oxygen used and is able to maintain energy production in conditions of oxygen deficiency. Lithium oxybutyrate is additionally able to suppress thyroid activity (even at low doses up to 400 mg).

Sodium oxybutyrate neutralizes changes in the acid-base balance, reduces the amount of underoxidized products in the blood, improves microcirculation, increases the rate of blood flow through capillaries, arterioles and venules, and eliminates stasis in capillaries.

Mononarcosis with sodium hydroxybutyrate is a minimally toxic type of general anesthesia and therefore has the greatest value in patients in a state of hypoxia of various etiologies (severe acute pulmonary insufficiency, blood loss, hypoxic

Scheme 8.3.Metabolism of γ-aminobutyrate (Rodwell V. W., 2003)

and toxic myocardial damage). It is also indicated in patients with various types of endogenous intoxication accompanied by oxidative stress (septic processes, diffuse peritonitis, liver and kidney failure).

Separate indications for the use of sodium/lithium oxybutyrate as an antihypoxant are presented in Table. 8.8.

The use of lithium hydroxybutyrate during operations on the lungs is accompanied by a smoother postoperative course, mitigation of febrile reactions, and a decrease in the need for painkillers. There is an optimization of respiratory function and less pronounced hypoxemia, stability of blood circulation parameters.

and rhythm of the heart, accelerated recovery of the level of serum transaminases and the content of peripheral blood lymphocytes. Sodium oxybutyrate causes a redistribution of electrolytes (Na + and K +) between body fluids, increasing the concentration of K + in the cells of some organs (brain, heart, skeletal muscles) with the development of moderate hypokalemia and hypernatremia.

Side effects with the use of drugs are rare, mainly with intravenous administration (motor excitation, convulsive twitching of the limbs, vomiting) (see Table 8.2). These adverse events with the use of oxybutyrate can be prevented during premedication with metoclopramide or stopped with diprazine.

The exchange of succinate is also partially associated with the antihypoxic effect of polyoxyfumarin, which is a colloidal solution for intravenous administration (1.5% polyethylene glycol with a molecular weight of 17,000-26,000 Da with the addition of NaCl (6 g / l), MgCl (0.12 g / l ), KI (0.5 g / l), as well as sodium fumarate (14 g / l). Polyoxyfumarin contains one of the components of the Krebs cycle - fumarate, which penetrates well through membranes and is easily utilized in mitochondria. During the most severe hypoxia, the terminal reactions of the Krebs cycle, i.e. they begin to proceed in the opposite direction, and fumarate is converted into succinate with the accumulation of the latter. With a decrease in the depth of hypoxia, the direction of the terminal reactions of the Krebs cycle changes to the usual one, while the accumulated succinate is actively oxidized as an efficient source of energy. Under these conditions, fumarate is also predominantly oxidized after conversion to malate.

The salt component of the blood substitute is completely metabolized, while the colloid base (polyethylene glycol-20000) is not metabolized. After a single infusion of the drug, 80-85% of the polymer is excreted from the bloodstream on the first day through the kidneys, and the complete excretion of the colloidal component occurs by the 5-7th day. Repeated administration of polyoxyfumarin does not lead to the accumulation of polyethylene glycol-20000 in organs and tissues, and the body is released from it by 8-14 days.

The introduction of polyoxyfumarin leads not only to post-infusion hemodilution, as a result of which blood viscosity decreases and its rheological properties improve, but also to an increase in

Table 8.8. The main indications for use and regimens for prescribing sodium/lithium oxybutyrate as an antihypoxant

End of table 8.8

diuresis and manifestation of detoxification action. Sodium fumarate, which is part of the composition, has an antihypoxic effect. Some indications for the use of polyoxyfumarin are presented in Table. 8.9.

Table 8.9.The main indications for use and prescription regimens for polyoxyfumarin

Note:* - in terms of fumarate.

In addition, polyoxyfumarin is used as a component of the perfusion medium for primary filling of the AIC circuit (150-400 ml, which is 11%-30% of the volume) during operations for the correction of congenital and acquired heart defects under cardiopulmonary bypass. At the same time, the inclusion of polyoxyfumarin in the composition of the perfusate has a positive effect on the stability of hemodynamics in the postperfusion period, and reduces the need for inotropic support. Side effects of the drug are presented in table. 8.2.

Confumin is a 15% sodium fumarate solution for infusion, which gives a noticeable antihypoxic effect. It has a certain cardiotonic and cardioprotective effect. It is used in various hypoxic conditions, including those cases when

Yes, the introduction of large volumes of liquid is contraindicated and other infusion drugs with antihypoxic action cannot be used (Table 8.10).

Table 8.10.The main indications for use and schemes for prescribing confumin

The use of another fumarate-containing drug, mafusol, has now been discontinued.

8.4. NATURAL COMPONENTS OF THE RESPIRATORY CHAIN

Cytochrome C (Cytomac).

Ubiquinone (Ubinone, Coenzyme Q 10).

Idebenone (Noben). Combined:

Energostim (cytochrome C + NAD + inosine).

Antihypoxants, which are natural components of the mitochondrial respiratory chain involved in electron transfer, have also found practical application. These include cytochrome C and ubiquinone (Ubinone). These drugs, in essence, perform the function of replacement therapy, since during hypoxia, due to structural disorders, mitochondria lose some of their components, including electron carriers (Scheme 8.4).

Experimental studies have shown that exogenous cytochrome C during hypoxia penetrates into the cell and mitochondria, integrates into the respiratory chain and contributes to the normalization of energy-producing oxidative phosphorylation.

Cytochrome C may be a useful combination therapy for critical illness. The drug has been shown to be highly effective in poisoning with hypnotics, carbon monoxide, toxic, infectious and ischemic myocardial injuries, pneumonia, disorders of cerebral and peripheral circulation. It is also used for asphyxia of newborns and infectious hepatitis. The usual dose of the drug is 10-15 mg intravenously, intramuscularly or orally (1-2 times a day).

In patients with myocardial infarction receiving cytochrome C, the contractile and pumping functions of the heart increase, and hemodynamics stabilize. This improves the prognosis of myocardial infarction, reduces the frequency and severity of left ventricular failure. The main indications for the use of cytochrome C are presented in Table. 8.11.

The combined preparation containing cytochrome C is Energostim. In addition to cytochrome C (10 mg), it contains nicotinamide dinucleotide (0.5 mg) and inosine (80 mg). This combination gives an additive effect, where the effects of NAD and inosine complement the antihypoxic effect of cytochrome C. At the same time, exogenously administered NAD somewhat reduces the deficiency of cytosolic NAD and restores the activity of NAD-dependent dehydrogenases involved in ATP synthesis, contributes to the intensification of the respiratory

Scheme 8.4.Components of the mitochondrial respiratory chain and points of application of some antihypoxants: complex I - NADH: ubiquinone oxidoreductase; complex II - succinate: ubiquinone oxidoreductase; complex III - ubiquinone: ferricytochrome C-oxidoreductase; complex IV - ferrocytochrome C: oxygen oxidoreductase; FeS - iron-sulfur protein; FMN - flavin mononucleotide; FAD - flavin adenine dinucleotide

chains. Due to inosine, an increase in the content of the total pool of purine nucleotides is achieved. The drug is proposed to be used in myocardial infarction, as well as in conditions accompanied by the development of hypoxia (Table 8.12), however, the evidence base is currently rather weak.

Side effects of the drug are presented in table. 8.2.

Ubiquinone (coenzyme Q 10) is a coenzyme widely distributed in the cells of the body, chemically a derivative of benzoquinone. The main part of the intracellular

Table 8.11. The main indications for use and regimens for the appointment of cytochrome C

Table 8.12. The main indications for use and schemes for the appointment of energy stimulation

End of table 8.12

Table 8.13. The main indications for use and regimens for ubiquinone

The end of the table. 8.13

ubiquinone is concentrated in mitochondria in oxidized (CoQ), reduced (CoH 2 , QH 2) and semi-reduced forms (semiquinone, CoH, QH). In a small amount, it is present in the nuclei, endoplasmic reticulum, lysosomes, Golgi apparatus. Like tocopherol, ubiquinone is found in the largest quantities in organs with a high metabolic rate - the heart, liver, and kidneys.

It is a carrier of electrons and protons from the inner to the outer side of the mitochondrial membrane, a component of the respiratory chain (see Scheme 8.4). In addition, in addition to a specific redox function, ubiquinone can act as an antioxidant (see the lecture "Clinical Pharmacology of Antioxidants").

Ubiquinone is mainly used in the complex therapy of patients with coronary heart disease, with myocardial infarction, as well as in patients with CHF (Table 8.13). The average prophylactic doses of the drug are 15 mg / day, and therapeutic doses range from 30-150 to 300 mg / day. The maximum level of ubiquinone in the blood is observed after about 1 month of regular intake, after which it stabilizes.

When using the drug in patients with IHD, the clinical course of the disease improves (mainly in patients with FC I-II), the frequency of seizures decreases; increased tolerance to physical activity; the content of prostacyclin increases in the blood and thromboxane decreases. However, it must be taken into account that the drug itself does not increase coronary blood flow and does not contribute to a decrease in myocardial oxygen demand (although it may have a slight bradycardic effect). As a result, the antianginal effect of the drug appears after some, sometimes quite a long time (up to 3 months).

In the complex therapy of patients with coronary heart disease, ubiquinone can be combined with β-blockers and angiotensin-converting enzyme inhibitors. This reduces the risk of developing left ventricular heart failure, cardiac arrhythmias. The drug is ineffective in patients with a sharp decrease in exercise tolerance, as well as in the presence of a high degree of sclerotic stenosis of the coronary arteries.

In CHF, the use of ubiquinone in combination with dosed physical activity (especially in high doses, up to 300 mg /

days) allows you to increase the power of contractions of the left ventricle and improve endothelial function. At the same time, there is a significant decrease in plasma levels of uric acid and a significant increase in the content of high density lipoproteins (HDL).

It should be noted that the effectiveness of ubiquinone in CHF largely depends on its plasma level, which in turn is determined by the metabolic needs of various tissues. It is assumed that the positive effects of the drug mentioned above appear only when the plasma concentration of coenzyme Q 10 exceeds 2.5 μg / ml (normal concentration is approximately 0.6-1.0 μg / ml). This level is achieved when prescribing high doses of the drug: taking 300 mg / day of coenzyme Q 10 gives a 4-fold increase in its blood level from the original, but not when using low doses (up to 100 mg / day). Therefore, although a number of studies in CHF were performed with the appointment of patients with ubiquinone in doses of 90-120 mg / day, apparently, the use of high-dose therapy should be considered the most optimal for this pathology.

In a small pilot study, ubiquinone treatment reduced myopathic symptoms in patients treated with statins, reduced muscle pain (by 40%), and improved daily activity (by 38%), in contrast to tocopherol, which was found to be ineffective.

To make a final judgment on the efficacy and safety of the drug, it is necessary to conduct large controlled clinical trials.

The drug is usually well tolerated. Sometimes nausea and stool disorders, anxiety and insomnia are possible (see Table 8.2), in which case the drug is stopped.

As a derivative of ubiquinone, idebenone can be considered, which, compared with coenzyme Q 10, has a smaller size (5 times), less hydrophobicity, and greater antioxidant activity. The drug penetrates the blood-brain barrier and is distributed in significant amounts in the brain tissue. The mechanism of action of idebenone is similar to that of ubiquinone (see Scheme 8.4). Along with antihypoxic and antioxidant effects, it has a mnemotropic and nootropic effect that develops after 20-25 days of treatment. The main indications for the use of idebenone are presented in Table. 8.14.

Table 8.14.The main indications for use and prescription regimens for idebenone

The most common side effect of the drug (up to 35%) is sleep disturbance (see Table 8.2), due to its activating effect, and therefore the last dose of idebenone should be taken no later than 17 hours.

8.5. ARTIFICIAL REDOX SYSTEMS

Olifen (Gypoxen).

The creation of antihypoxants with electron-withdrawing properties that form artificial redox systems is aimed at compensating to some extent the deficiency of the natural electron acceptor, oxygen, that develops during hypoxia. Such drugs should bypass the links of the respiratory chain, overloaded with electrons under hypoxic conditions, “remove” electrons from these links and thereby restore to a certain extent the function of the respiratory chain and associated phosphorylation. In addition, artificial electron acceptors can provide oxidative

synthesis of pyridine nucleotides (NADH) in the cytosol of the cell, preventing, as a result, inhibition of glycolysis and excessive accumulation of lactate.

Preparations capable of forming artificial redox systems must meet the following basic requirements:

Have optimal redox potential;

Have conformational accessibility for interaction with respiratory enzymes;

Have the ability to carry out both one- and two-electron transfer.

Of the agents that form artificial redox systems, sodium polydihydroxyphenylene thiosulfonate (olifen, hypoxen), which is a synthetic polyquinone, has been introduced into medical practice. In the interstitial fluid, the drug apparently dissociates into a polyquinone cation and a thiol anion. The antihypoxic effect of the drug is associated primarily with the presence in its structure of the polyphenolic quinone component involved in the transfer of electrons along the respiratory chain.

Olifen has a high electron-volume capacity associated with the polymerization of phenolic nuclei in the ortho position, and the antihypoxic effect of the drug is due to the shunting of electron transport in the mitochondrial respiratory chain (from complex I to III) (see Scheme 8.4). In the posthypoxic period, the drug leads to a rapid oxidation of the accumulated reduced equivalents (NADP H 2 , FADH). The ability to easily form semiquinone provides it with a noticeable antioxidant effect necessary to neutralize lipid peroxidation products.

When taken orally, the drug has a high bioavailability and is fairly evenly distributed in the body, accumulating somewhat more in the brain tissue. The half-life of oliphena is approximately 6 hours. The minimum single dose that causes a distinct clinical effect in humans when taken orally is about 250 mg.

The use of the drug is allowed for severe traumatic lesions, shock, blood loss, and major surgical interventions. In patients with IHD, it reduces ischemic manifestations, normalizes hemodynamics, reduces blood clotting and total oxygen consumption. Clinical studies have shown that

with the inclusion of oilen in the complex of therapeutic measures, the lethality of patients with traumatic shock decreases, there is a more rapid stabilization of hemodynamic parameters in the postoperative period.

In patients with CHF, the manifestations of tissue hypoxia decrease while taking oliphena, but there is no particular improvement in the pumping function of the heart, which limits the use of the drug in acute heart failure. The absence of a positive effect on the state of impaired central and intracardiac hemodynamics in myocardial infarction does not allow one to form an unambiguous opinion about the effectiveness of the drug in this pathology. In addition, oliven does not give a direct antianginal effect and does not eliminate rhythm disturbances that occur during myocardial infarction.

Course use of the drug after surgery is accompanied by faster stabilization of the main hemodynamic parameters and restoration of circulating blood volume in the postoperative period. In addition, the antiaggregatory effect of the drug was revealed.

Olifen is used in the complex therapy of acute destructive pancreatitis (ADP). With this pathology, the effectiveness of the drug is higher, the earlier treatment is started. When prescribing Olifen regionally (intra-aortically) in the early phase of ADP, the moment of onset of the disease should be carefully determined, since after the period of controllability and the presence of already formed pancreatic necrosis, the use of the drug is contraindicated. This is due to the fact that olifen, by improving microcirculation around the zone of massive destruction, contributes to the development of reperfusion syndrome, and the ischemic tissue through which blood flow resumes becomes an additional source of toxins, which can provoke the development of shock. Regional therapy with oliven in ADP is contraindicated: 1) with clear anamnestic indications that the duration of the disease exceeds 24 hours; 2) with endotoxic shock or the appearance of its precursors (hemodynamic instability); 3) in the presence of hemolysis and fibrinolysis.

Local use of drying oil in patients with generalized periodontitis eliminates bleeding and inflammation of the gums, and normalizes the functional resistance of capillaries.

The question of the effectiveness of olifen in the acute period of cerebrovascular diseases (decompensation of dyscirculatory encephalopathy, ischemic stroke) remains open. The absence of the effect of the drug on the state of the main cerebral and the dynamics of systemic blood flow was shown.

The drug is used orally (before a meal or during a meal with a small amount of water), intravenous drip or intra-aortic (after transfemoral catheterization of the abdominal aorta to the level of the celiac trunk. Average single doses for adults are 0.5-1.0 g, daily - 1.5-3.0 g. For children, a single dose of 0.25 g, a daily dose of 0.75 g. Some indications for the use of drying oil are given in Table 8.15.

To make a final judgment on the efficacy and safety of the drug, it is necessary to conduct large controlled clinical trials.

Among the side effects of oliven, undesirable vegetative changes can be noted, including a prolonged increase in blood pressure or collapses in some patients, allergic reactions and phlebitis; rarely short-term feeling of drowsiness, dry mouth; with myocardial infarction, the period of sinus tachycardia may be somewhat prolonged (see Table 8.2). With long-term course use of oliven, two main side effects predominate - acute phlebitis (in 6% of patients) and allergic reactions in the form of hyperemia of the palms and pruritus (in 4% of patients), intestinal disorders are less common (in 1% of patients).

8.6. MACROERGIC COMPOUNDS

Creatine phosphate (Neoton).

Neoton is an antihypoxant created on the basis of a macroergic compound natural for the body - creatine phosphate. In the myocardium and in the skeletal muscle, creatine phosphate acts as a reserve of chemical energy and is used for the resynthesis of ATP, the hydrolysis of which provides the energy necessary for the contraction of actomyosin. The action of both endogenous and exogenously administered creatine phosphate is to directly phosphorylate ADP and thereby increase the amount of ATP in the cell. In addition, under the influence of the drug, the sarcolemmal membrane of ischemic cardiomyocytes is stabilized, platelet aggregation decreases and plasma increases.

Table 8.15. The main indications for use and schemes for the appointment of olifen

The end of the table. 8.15

ity of erythrocyte membranes. The most studied is the normalizing effect of neoton on the metabolism and functions of the myocardium, since in case of myocardial damage there is a close relationship between the content of high-energy phosphorylating compounds in the cell, cell survival and the ability to restore contraction function.

The main indications for the use of creatine phosphate are myocardial infarction (acute period), intraoperative myocardial or limb ischemia, chronic heart failure (Table 8.16). It should be noted that a single infusion of the drug does not affect the clinical status and the state of the contractile function of the left ventricle.

The effectiveness of the drug in patients with acute cerebrovascular accident was shown. In addition, the drug can also be used in sports medicine to prevent the adverse effects of physical overexertion. Doses of the intravenous drip of the drug vary depending on the type of pathology. The inclusion of neoton in the complex therapy of CHF allows, as a rule, to reduce the dose of cardiac glycosides and diuretics.

To make a final judgment on the efficacy and safety of the drug, it is necessary to conduct large controlled clinical trials. The economic feasibility of using creatine phosphate also requires additional study, given its high cost.

Side effects are rare (see Table 8.2), sometimes a short-term decrease in blood pressure is possible with a rapid intravenous injection at a dose of more than 1 g.

Sometimes ATP (adenosine triphosphoric acid) is considered as a macroergic antihypoxant. The results of the use of ATP as an antihypoxant have been contradictory, and the clinical prospects are doubtful, which is explained by the extremely poor penetration of exogenous ATP through intact membranes and its dephosphorylation in the blood.

At the same time, the drug still has a certain therapeutic effect, not associated with a direct antihypoxic effect, which is due both to its neurotransmitter properties (influence on adreno-, choline-, purine receptors) and to the effect on the metabolism and cell membranes of the detoxification products. -

Table 8.16. The main indications for use and prescription regimens for creatine phosphate

gradations of ATP-AMP, cAMP, adenosine, inosine. Under oxygen-deficient conditions, new properties of adenine nucleotides may appear as endogenous intracellular regulators of metabolism, the function of which is aimed at protecting the cell from hypoxia.

Dephosphorylation of ATP leads to the accumulation of adenosine, which has a vasodilator, antiarrhythmic, antianginal and antiaggregation effect and realizes its effects through P 1 -P 2 -purinergic (adenosine) receptors in various tissues. The main indications for the use of ATP are presented in Table. 8.17.

Table 8.17.The main indications for use and schemes for the appointment of ATP

Concluding the characterization of antihypoxants, it is necessary to emphasize once again that the use of these drugs has the broadest prospects, since antihypoxants normalize the very basis of cell vital activity - its energy, which determines all other functions. Therefore, the use of antihypoxic drugs in critical conditions can prevent the development of irreversible changes in organs and make a decisive contribution to saving the patient.

The practical use of drugs of this class should be based on the disclosure of their mechanisms of antihypoxic action, taking into account pharmacokinetic features (Table 8.18), the results of large randomized clinical trials and economic feasibility.

Table 8.18. Pharmacokinetics of some antihypoxants

End of table 8.18

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S.V. Okovity 1 , D.S. Sukhanov 2 , V.A. Zaplutanov 1 , A.N. Smagina 3

1 St. Petersburg State Chemical Pharmaceutical Academy
2 North-Western State Medical University named after N.N. I.I. Mechnikova
3 St. Petersburg State Medical University named after acad. I.P. Pavlova

Hypoxia is a universal pathological process that accompanies and determines the development of a wide variety of pathologies. In the most general form, hypoxia can be defined as a discrepancy between the energy demand of a cell and energy production in the system of mitochondrial oxidative phosphorylation. The reasons for the violation of energy production in a hypoxic cell are ambiguous: disorders of external respiration, blood circulation in the lungs, oxygen transport function of the blood, disorders of the systemic, regional blood circulation and microcirculation, endotoxemia. At the same time, insufficiency of the leading cellular energy-producing system, mitochondrial oxidative phosphorylation, underlies the disorders characteristic of all forms of hypoxia. The immediate cause of this deficiency in the overwhelming majority of pathological conditions is a decrease in the supply of oxygen to the mitochondria. As a result, inhibition of mitochondrial oxidation develops. First of all, the activity of NAD-dependent oxidases (dehydrogenases) of the Krebs cycle is suppressed, while the activity of FAD-dependent succinate oxidase, which is inhibited during more pronounced hypoxia, is initially preserved.
Violation of mitochondrial oxidation leads to inhibition of phosphorylation associated with it and, consequently, causes a progressive deficiency of ATP, the universal energy source in the cell. Energy deficiency is the essence of any form of hypoxia and causes qualitatively similar metabolic and structural changes in various organs and tissues. A decrease in the concentration of ATP in the cell leads to a weakening of its inhibitory effect on one of the key enzymes of glycolysis, phosphofructokinase. Glycolysis, which is activated during hypoxia, partially compensates for the lack of ATP, but quickly causes the accumulation of lactate and the development of acidosis with the resulting autoinhibition of glycolysis.

Hypoxia leads to a complex modification of the functions of biological membranes, affecting both the lipid bilayer and membrane enzymes. The main functions of membranes are damaged or modified: barrier, receptor, catalytic. The main reasons for this phenomenon are energy deficiency and activation against its background of phospholipolysis and lipid peroxidation (LPO). The breakdown of phospholipids and the inhibition of their synthesis lead to an increase in the concentration of unsaturated fatty acids and an increase in their peroxidation. The latter is stimulated as a result of the suppression of the activity of antioxidant systems due to the breakdown and inhibition of the synthesis of their protein components, and first of all, superoxide dismutase (SOD), catalase (CT), glutathione peroxidase (GP), glutathione reductase (GR), etc.

Energy deficiency during hypoxia contributes to the accumulation of Ca 2+ in the cytoplasm of the cell, since the energy-dependent pumps that pump Ca 2+ ions out of the cell or pump it into the cisterns of the endoplasmic reticulum are blocked, and the accumulation of Ca 2+ activates Ca 2+ -dependent phospholipases. One of the protective mechanisms preventing the accumulation of Ca 2+ in the cytoplasm is the uptake of Ca 2+ by mitochondria. At the same time, the metabolic activity of mitochondria increases, aimed at maintaining the constancy of the intramitochondrial charge and pumping protons, which is accompanied by an increase in ATP consumption. A vicious circle closes: lack of oxygen disrupts energy metabolism and stimulates free radical oxidation, and activation of free radical processes, damaging the membranes of mitochondria and lysosomes, exacerbates energy deficiency, which, as a result, can cause irreversible damage and cell death.

In the absence of hypoxia, some cells (for example, cardiomyocytes) obtain ATP through the breakdown of acetyl-CoA in the Krebs cycle, and glucose and free fatty acids (FFA) are the main sources of energy. With an adequate blood supply, 60-90% of acetyl-CoA is formed due to the oxidation of free fatty acids, and the remaining 10-40% is due to the decarboxylation of pyruvic acid (PVA). Approximately half of PVC inside the cell is formed due to glycolysis, and the other half is formed from lactate entering the cell from the blood. FFA catabolism requires more oxygen than glycolysis to produce an equivalent amount of ATP. With a sufficient supply of oxygen to the cell, the glucose and fatty acid energy supply systems are in a state of dynamic equilibrium. Under conditions of hypoxia, the amount of incoming oxygen is insufficient for the oxidation of fatty acids. As a result, underoxidized activated forms of fatty acids (acylcarnitine, acyl-CoA) accumulate in mitochondria, which are able to block adenine nucleotide translocase, which is accompanied by suppression of the transport of ATP produced in mitochondria to the cytosol and damage cell membranes, having a detergent effect.

Several approaches can be used to improve the energy status of a cell:

increasing the efficiency of the use of deficient oxygen by mitochondria due to the prevention of uncoupling of oxidation and phosphorylation, stabilization of mitochondrial membranes
weakening the inhibition of Krebs cycle reactions, especially maintaining the activity of the succinate oxidase link
replacement of lost components of the respiratory chain
formation of artificial redox systems shunting the respiratory chain overloaded with electrons
economizing the use of oxygen and reducing the oxygen demand of tissues, or inhibiting the ways of its consumption that are not necessary for emergency maintenance of life in critical conditions (non-phosphorylating enzymatic oxidation - thermoregulatory, microsomal, etc., non-enzymatic lipid oxidation)
increased ATP production during glycolysis without increasing lactate production
reduction in ATP consumption for processes that do not determine emergency life support in critical situations (various synthetic reduction reactions, the functioning of energy-dependent transport systems, etc.)
external introduction of high-energy compounds

Currently, one of the ways to implement these approaches is the use of drugs - antihypoxants.

Classification of antihypoxants(Okovity S.V., Smirnov A.V., 2005)

Fatty acid oxidation inhibitors
Succinate-containing and succinate-forming agents
Natural components of the respiratory chain
Artificial redox systems
macroergic compounds

The pioneer in the development of antihypoxants in our country was the Department of Pharmacology of the Military Medical Academy. Back in the 60s, under the guidance of Professor V.M. Vinogradov, the first antihypoxants with a polyvalent effect were created on it: gutimine, and then amtizol, which were subsequently actively studied under the guidance of professors L.V. Pastushenkov, A.E. Alexandrova, A. V. Smirnova. These drugs have shown high efficiency, but, unfortunately, they are not currently produced and are not used in medical practice.

1. Fatty acid oxidation inhibitors

Means similar in pharmacological effects (but not in structure) to gutimine and amtizol are drugs - inhibitors of fatty acid oxidation, currently used mainly in the complex therapy of coronary heart disease. Among them are direct inhibitors of carnitine palmitoyltransferase-I (perhexelin, etomoxir), partial inhibitors of fatty acid oxidation (ranolazine, trimetazidine, meldonium), and indirect inhibitors of fatty acid oxidation (carnitine).

Perhexelin and etomoxir able to inhibit the activity of carnitine palmitoyltransferase-I, thus disrupting the transfer of long-chain acyl groups to carnitine, which leads to blockade of the formation of acylcarnitine. As a result, the intramitochondrial level of acyl-CoA decreases and the NAD H 2 /NAD ratio decreases, which is accompanied by an increase in the activity of pyruvate dehydrogenase and phosphofructokinase, and therefore stimulation of glucose oxidation, which is more energetically beneficial compared to fatty acid oxidation.

Perhexelin is administered orally in doses of 200-400 mg per day for up to 3 months. The drug can be combined with antianginal drugs, however, its clinical use is limited by adverse effects - the development of neuropathy and hepatotoxicity. Etomoxir is used at a dose of 80 mg per day for up to 3 months, however, the issue of drug safety has not been finally resolved, given the fact that it is an irreversible inhibitor of carnitine palmitoyltransferase-I.

Trimetazidine, ranolazine and meldonium are classified as partial inhibitors of fatty acid oxidation. Trimetazidine(Preductal) blocks 3-ketoacylthiolase, one of the key enzymes in fatty acid oxidation. As a result, the oxidation of all fatty acids in the mitochondria is inhibited - both long-chain (the number of carbon atoms is more than 8) and short-chain (the number of carbon atoms is less than 8), however, the accumulation of activated fatty acids in mitochondria does not change in any way. Under the influence of trimetazidine, pyruvate oxidation and glycolytic production of ATP increase, the concentration of AMP and ADP decreases, the accumulation of lactate and the development of acidosis are inhibited, and free radical oxidation is suppressed.

Currently, the drug is used for ischemic heart disease, as well as other diseases based on ischemia (for example, with vestibulocochlear and chorioretinal pathology). Evidence of the effectiveness of the drug in refractory angina pectoris has been obtained. In the complex treatment of coronary artery disease, the drug is prescribed in the form of a sustained-release dosage form in a single dose of 35 mg 2 times a day, the duration of the course can be up to 3 months.

In a European randomized clinical trial (RCT) of trimetazidine (TEMS) in patients with stable angina, the use of the drug contributed to a decrease in the frequency and duration of episodes of myocardial ischemia by 25%, which was accompanied by an increase in patients' exercise tolerance. The appointment of the drug in combination with?-blockers (BAB), nitrates and calcium channel blockers (CCBs) helps to increase the effectiveness of antianginal therapy.

Early inclusion of trimetazidine in the complex therapy of the acute period of myocardial infarction (MI) helps to limit the size of myocardial necrosis, prevents the development of early postinfarction left ventricular dilatation, increases the electrical stability of the heart without affecting ECG parameters and heart rate variability. At the same time, within the framework of a large RCT EMIR-FR, the expected positive effect of a short course of intravenous administration of the drug on long-term, in-hospital mortality and the frequency of the combined end point in patients with MI was not confirmed. However, trimetazidine significantly reduced the incidence of prolonged anginal attacks and recurrent MI in patients undergoing thrombolysis.

In post-MI patients, the additional inclusion of modified-release trimetazidine in standard therapy can achieve a reduction in the number of angina attacks, a reduction in the use of short-acting nitrates, and an increase in quality of life (PRIMA study).

A small RCT provided the first data on the efficacy of trimetazidine in patients with CHF. It has been shown that long-term administration of the drug (20 mg 3 times a day for approximately 13 months) improves the functional class and contractile function of the left ventricle in patients with heart failure. In the Russian study PREAMBLE in patients with comorbidities (IHD+CHF II-III FC), trimetazidine (35 mg 2 times a day) demonstrated the ability to slightly reduce CHF FC, improve clinical symptoms and exercise tolerance in such patients. However, to finally determine the place of trimetazidine for the treatment of patients with CHF, additional studies are required.

Side effects when taking the drug are rare (discomfort in the stomach, nausea, headache, dizziness, insomnia).

Ranolazine(Ranexa) is also an inhibitor of fatty acid oxidation, although its biochemical target has not yet been established. It has an anti-ischemic effect by limiting the use of FFA as an energy substrate and increasing the use of glucose. This leads to the production of more ATP per unit of oxygen consumed.

Ranolazine is usually used in combination therapy in patients with coronary artery disease along with antianginal drugs. Thus, the RCT ERICA showed the antianginal efficacy of ranolazine in patients with stable angina who had attacks, despite taking the maximum recommended dose of amlodipine. In women, the effect of ranolazine on the severity of angina symptoms and exercise tolerance is lower than in men.
The results of the MERLIN-TIMI 36 RCT, conducted to clarify the effect of ranolazine (intravenously, then orally 1 g per day) on the incidence of cardiovascular events in patients with acute coronary syndrome, showed that ranolazine reduces the severity of clinical symptoms, but does not affect the long-term risk of death and MI in patients with CAD.

In the same study, the antiarrhythmic activity of ranolazine was found in patients with non-ST elevation ACS during the first week after their hospitalization (reduction in the number of episodes of ventricular and supraventricular tachycardia). It is assumed that this effect of ranolazine is associated with its ability to inhibit the late phase of sodium flow into the cell during repolarization (late I Na current), which causes a decrease in intracellular Na + concentration and Ca 2+ overload of cardiomyocytes, preventing the development of both mechanical myocardial dysfunction accompanying ischemia. , and to its electrical instability.

Ranolazine usually does not cause pronounced side effects and does not have a significant effect on heart rate and blood pressure, however, when using relatively high doses and when combined with BAB or BCC channels, moderately severe headaches, dizziness, and asthenic phenomena may be observed. In addition, the possibility of increasing the QT interval by the drug imposes certain restrictions on its clinical use.

Meldonium(Mildronate) reversibly limits the rate of carnitine biosynthesis from its precursor, γ-butyrobetaine. As a result, carnitine-mediated transport of long-chain fatty acids across mitochondrial membranes is impaired without affecting the metabolism of short-chain fatty acids. This means that meldonium is practically incapable of exerting a toxic effect on mitochondrial respiration, since it cannot completely block the oxidation of all fatty acids. Partial blockade of fatty acid oxidation includes an alternative energy production system - glucose oxidation, which is much more efficient (12%) using oxygen for ATP synthesis. In addition, under the influence of meldonium, the concentration of γ-butyrobetaine, which can induce the formation of NO, increases, which leads to a decrease in the total peripheral vascular resistance (OPVR).

Meldonium and trimetazidine, with stable angina, reduces the frequency of angina attacks, increases patient exercise tolerance and reduces the consumption of short-acting nitroglycerin. The drug has low toxicity, does not cause significant side effects, however, when using it, skin itching, rashes, tachycardia, dyspepsia, psychomotor agitation, and a decrease in blood pressure may occur.

Carnitine(vitamin B t) is an endogenous compound and is formed from lysine and methionine in the liver and kidneys. It plays an important role in the transport of long-chain fatty acids across the inner mitochondrial membrane, while activation and penetration of lower fatty acids occurs without kartinitin. In addition, carnitine plays a key role in the formation and regulation of acetyl-CoA levels.

Physiological concentrations of carnitine have a saturating effect on carnitine palmitoyltransferase I, and an increase in the dose of the drug does not increase the transport of fatty acid acyl groups into mitochondria with the participation of this enzyme. However, this leads to the activation of carnitine acylcarnitine translocase (which is not saturated with physiological concentrations of carnitine) and a drop in intramitochondrial concentration of acetyl-CoA, which is transported to the cytosol (via formation of acetylcarnitine). In the cytosol, excess acetyl-CoA is exposed to acetyl-CoA carboxylase to form malonyl-CoA, which has the properties of an indirect inhibitor of carnitine palmitoyltransferase I. A decrease in intramitochondrial acetyl-CoA correlates with an increase in the level of pyruvate dehydrogenase, which ensures the oxidation of pyruvate and limits the production of lactate. Thus, the antihypoxic effect of carnitine is associated with blockade of the transport of fatty acids into mitochondria, is dose-dependent and manifests itself when prescribing high doses of the drug, while low doses have only a specific vitamin effect.

One of the largest RCTs using carnitine is CEDIM. It was shown that long-term carnitine therapy at sufficiently high doses (9 g 1 time per day for 5 days, followed by the transition to oral administration of 2 g 3 times a day for 12 months) in patients with MI limits the dilatation of the left ventricle. In addition, a positive effect from the use of the drug was obtained in severe traumatic brain injuries, fetal hypoxia, carbon monoxide poisoning, etc., however, a large variability in the courses of use and not always an adequate dose policy make it difficult to interpret the results of such studies.

2. Succinate-containing and succinate-forming agents

2.1. Succinate-containing products
Practical use as antihypoxants is found in drugs that support the activity of the succinate oxidase link during hypoxia. This FAD-dependent link of the Krebs cycle, which is later inhibited during hypoxia compared to NAD-dependent oxidases, can maintain energy production in the cell for a certain time, provided that the mitochondria contain an oxidation substrate in this link, succinate (succinic acid). The comparative composition of the preparations is given in table.1.

Table 1.
Comparative composition of succinate-containing preparations

Component of the drug	Reamberin (400 ml)	Remaxol (400 ml)	Cytoflavin (10 ml)	Hydroxymethylethylpyridine succinate (5 ml)
parenteral forms
succinic acid	2112 mg	2112 mg	1000 mg	-
	-	-	-	250 mg
N-methylglucamine	3490 mg	3490 mg	1650 mg	-
Nicotinamide	-	100 mg	100 mg	-
Inosine	-	800 mg	200 mg	-
Riboflavin mononucleotide	-	-	20 mg	-
Methionine	-	300 mg	-	-
NaCl	2400 mg	2400 mg	-	-
KCl	120 mg	120 mg	-	-
MgCl	48 mg	48 mg	-	-
oral forms
succinic acid	-	-	300 mg	100-150 mg
Hydroxymethylethylpyridine succinate	-	-	-	-
Nicotinamide	-		25 mg	-
Inosine	-		50 mg	-
Riboflavin mononucleotide	-		5 mg	-

In recent years, it has been established that succinic acid realizes its effects not only as an intermediate in various biochemical cycles, but also as a ligand of orphan receptors (SUCNR1, GPR91) located on the cytoplasmic membrane of cells and coupled to G-proteins (G i /G o and G q). These receptors are found in many tissues, primarily in the kidneys (the epithelium of the proximal tubules, cells of the juxtaglomerular apparatus), as well as in the liver, spleen, and blood vessels. Activation of these receptors by succinate present in the vascular bed increases the reabsorption of phosphate and glucose, stimulates gluconeogenesis, and increases blood pressure (through an indirect increase in renin formation). Some effects of succinic acid are shown in Fig.1.

One of the drugs created on the basis of succinic acid is reamberin- which is a balanced polyionic solution with the addition of mixed sodium N-methylglucamine salt of succinic acid (up to 15 g / l).

Reamberin infusion is accompanied by an increase in the pH and buffer capacity of the blood, as well as alkalization of the urine. In addition to antihypoxic activity, Reamberin has detoxification (with various intoxications, in particular, alcohol, anti-tuberculosis drugs) and antioxidant (due to activation of the enzymatic link of the antioxidant system) action. Prerat is used for diffuse peritonitis with multiple organ failure syndrome, severe concomitant trauma, acute cerebrovascular accidents (by ischemic and hemorrhagic type), direct revascularization operations on the heart.

The use of Reamberin in patients with multivessel lesions of the coronary arteries during aorto-mammary coronary artery bypass grafting with left ventricular plasty and/or valve replacement and the use of extracorporeal circulation in the intraoperative period can reduce the incidence of various complications in the early postoperative period (including reinfarctions, strokes, encephalopathy). ).

The use of Reamberin at the stage of withdrawal from anesthesia leads to a shortening of the period of awakening of patients, a reduction in the recovery time of motor activity and adequate breathing, and an acceleration of the recovery of brain functions.

Reamberin was shown to be effective (reducing the duration and severity of the main clinical manifestations of the disease) in infectious diseases (influenza and SARS complicated by pneumonia, acute intestinal infections), due to its high detoxifying and indirect antioxidant effect.
There are few side effects of the drug, mainly a short-term feeling of heat and redness of the upper body. Reamberin is contraindicated in conditions after traumatic brain injury, accompanied by cerebral edema.

The drug has a combined antihypoxic effect cytoflavin(succinic acid, 1000 mg + nicotinamide, 100 mg + riboflavin mononucleotide, 20 mg + inosine, 200 mg). The main antihypoxic effect of succinic acid in this formulation is supplemented by riboflavin, which, due to its coenzymatic properties, can increase the activity of succinate dehydrogenase and has an indirect antioxidant effect (due to the reduction of oxidized glutathione). It is assumed that nicotinamide, which is part of the composition, activates NAD-dependent enzyme systems, but this effect is less pronounced than that of NAD. Due to inosine, an increase in the content of the total pool of purine nucleotides is achieved, which is necessary not only for the resynthesis of macroergs (ATP and GTP), but also second messengers (cAMP and cGMP), as well as nucleic acids. A certain role may be played by the ability of inosine to somewhat suppress the activity of xanthine oxidase, thereby reducing the production of highly active forms and oxygen compounds. However, compared to other components of the drug, the effects of inosine are delayed in time.

Cytoflavin found its main application in hypoxic and ischemic CNS injuries (ischemic stroke, toxic, hypoxic and dyscirculatory encephalopathy), as well as in the treatment of various pathological conditions, including in the complex treatment of critically ill patients. Thus, the use of the drug provides a decrease in mortality in patients with acute cerebrovascular accident to 4.8-9.6%, against 11.7-17.1% in patients who did not receive the drug.

In a fairly large RCT that included 600 patients with chronic cerebral ischemia, cytoflavin demonstrated the ability to reduce cognitive-mnestic disorders and neurological disorders; restore the quality of sleep and improve the quality of life.

The clinical use of Cytoflavin for the prevention and treatment of posthypoxic CNS lesions in premature infants with cerebral hypoxia/ischemia can reduce the frequency and severity of neurological complications (severe forms of periventricular and intraventricular hemorrhages, periventricular leukomalacia). The use of cytoflavin in the acute period of perinatal CNS damage allows achieving higher indices of mental and motor development of children in the first year of life. The effectiveness of the drug in children with purulent bacterial meningitis and viral encephalitis has been shown.

Side effects of Cytoflavin include hypoglycemia, hyperuricemia, hypertensive reactions, infusion reactions with rapid infusion (feeling hot, dry mouth).

Remaxol- an original drug that combines the properties of a balanced polyionic solution (in which methionine, riboxin, nicotinamide and succinic acid are additionally introduced), an antihypoxant and a hepatotropic agent.

The antihypoxic effect of Remaxol is similar to that of Reamberin. Succinic acid has an antihypoxic effect (maintaining the activity of the succinate oxidase link) and an indirect antioxidant effect (preserving the pool of reduced glutathione), while nicotinamide activates NAD-dependent enzyme systems. Due to this, both the activation of synthetic processes in hepatocytes and the maintenance of their energy supply occur. In addition, it is assumed that succinic acid can act as a paracrine agent released by damaged hepatocytes (for example, during ischemia), affecting pericytes (Ito cells) in the liver through SUCNR1 receptors. This causes the activation of pericytes, which provide the synthesis of extracellular matrix components involved in the metabolism and regeneration of hepatic parenchyma cells.

Methionine is actively involved in the synthesis of choline, lecithin and other phospholipids. In addition, under the influence of methionine adenosyltransferase from methionine and ATP, S-adenosylmethionine (SAM) is formed in the body.
The effect of inosine was discussed above, however, it is worth mentioning that it also has the properties of a non-steroidal anabolic that accelerates the reparative regeneration of hepatocytes.

Remaxol has the most noticeable effect on manifestations of toxemia, as well as cytolysis and cholestasis, which allows it to be used as a universal hepatotropic drug for various liver lesions in both therapeutic and preventive treatment regimens. The effectiveness of the drug has been established in viral (CVHC), drug (anti-tuberculosis agents) and toxic (ethanol) liver damage.

Like exogenously administered SAM, remaxol has a mild antidepressant and antiasthenic effect. In addition, in acute alcohol intoxication, the drug reduces the incidence and duration of alcoholic delirium, reduces the length of stay of patients in the ICU and the total duration of treatment.

As a combined succinate-containing drug can be considered hydroxymethylethylpyridine succinate(mexidol, mexicor) - which is a complex of succinate with the antioxidant emoxipin, which has a relatively weak antihypoxic activity, but increases the transport of succinate through membranes. Like emoxipin, hydroxymethylethylpyridine succinate (OMEPS) is an inhibitor of free radical processes, but has a more pronounced antihypoxic effect. The main pharmacological effects of OMEPs can be summarized as follows:

actively reacts with peroxide radicals of proteins and lipids, reduces the viscosity of the lipid layer of cell membranes
optimizes the energy-synthesizing functions of mitochondria under hypoxic conditions
has a modulating effect on some membrane-bound enzymes (phosphodiesterase, adenylate cyclase), ion channels, improves synaptic transmission
blocks the synthesis of certain prostaglandins, thromboxane and leukotrienes
improves the rheological properties of blood, inhibits platelet aggregation

The main clinical trials of OMEPS were carried out to study its effectiveness in disorders of ischemic origin: in the acute period of myocardial infarction, coronary artery disease, acute cerebrovascular accident, dyscirculatory encephalopathy, vegetovascular dystonia, atherosclerotic disorders of the brain and other conditions accompanied by tissue hypoxia.

The maximum daily dose should not exceed 800 mg, a single dose - 250 mg. OMEPS is generally well tolerated. Some patients may experience nausea and dry mouth.

The duration of administration and the choice of an individual dose depend on the severity of the patient's condition and the effectiveness of OMEPS therapy. To make a final judgment on the efficacy and safety of the drug, large RCTs are needed.

2.2. Succinate-forming agents

The ability to convert to succinate in the Roberts cycle (γ-aminobutyrate shunt) is also associated with the antihypoxic effect of sodium hydroxybutyrate, although it is not very pronounced. Transamination of γ-aminobutyric acid (GABA) with α-ketoglutaric acid is the main pathway for the metabolic degradation of GABA. The succinic acid semialdehyde formed during the neurochemical reaction is oxidized with the help of succinate semialdehyde dehydrogenase with the participation of NAD into succinic acid, which is included in the tricarboxylic acid cycle. This process occurs mainly in the nervous tissue, however, under conditions of hypoxia, it can also be realized in other tissues.

This additional action is very useful when using sodium oxybutyrate (OH) as a general anesthetic. In conditions of severe circulatory hypoxia, hydroxybutyrate (in high doses) in a very short time manages to launch not only cellular adaptation mechanisms, but also reinforce them by restructuring energy metabolism in vital organs. Therefore, one should not expect any noticeable effect from the introduction of small doses of anesthetic.

The favorable effect of OH during hypoxia is due to the fact that it activates the energetically more favorable pentose pathway of glucose metabolism with its orientation towards the path of direct oxidation and the formation of pentoses that are part of ATP. In addition, activation of the pentose pathway of glucose oxidation creates an increased level of NADP H, as a necessary cofactor in hormone synthesis, which is especially important for the functioning of the adrenal glands. The change in the hormonal background during the administration of the drug is accompanied by an increase in the blood glucose content, which gives the maximum yield of ATP per unit of oxygen used and is able to maintain energy production in conditions of oxygen deficiency.

OH mononarcosis is a minimally toxic type of general anesthesia and therefore has the greatest value in patients in a state of hypoxia of various etiologies (severe acute pulmonary insufficiency, blood loss, hypoxic and toxic myocardial damage). It is also indicated in patients with various types of endogenous intoxication accompanied by oxidative stress (septic processes, diffuse peritonitis, liver and kidney failure).

Side effects with the use of drugs are rare, mainly with intravenous administration (motor excitation, convulsive twitching of the limbs, vomiting). These adverse events with the use of hydroxybutyrate can be prevented during premedication with metoclopramide or stopped with promethazine (diprazine).

The antihypoxic effect is also partially associated with the exchange of succinate. polyoxyfumarin, which is a colloidal solution for intravenous administration (polyethylene glycol with the addition of NaCl, MgCl, KI, as well as sodium fumarate). Polyoxyfumarin contains one of the components of the Krebs cycle - fumarate, which penetrates well through membranes and is easily utilized in mitochondria. Under the most severe hypoxia, the terminal reactions of the Krebs cycle are reversed, that is, they begin to proceed in the opposite direction, and fumarate is converted into succinate with the accumulation of the latter. This provides conjugated regeneration of oxidized NAD from its reduced form during hypoxia, and, consequently, the possibility of energy production in the NAD-dependent link of mitochondrial oxidation. With a decrease in the depth of hypoxia, the direction of the terminal reactions of the Krebs cycle changes to the usual one, while the accumulated succinate is actively oxidized as an effective energy source. Under these conditions, fumarate is also predominantly oxidized after conversion to malate.

The introduction of polyoxyfumarin leads not only to post-infusion hemodilution, as a result of which blood viscosity decreases and its rheological properties improve, but also to an increase in diuresis and the manifestation of a detoxification effect. Sodium fumarate, which is part of the composition, has an antihypoxic effect.

In addition, polyoxyfumarin is used as a component of the perfusion medium for the primary filling of the circuit of the heart-lung machine (11%-30% of the volume) during operations to correct heart defects. At the same time, the inclusion of the drug in the composition of the perfusate has a positive effect on the stability of hemodynamics in the postperfusion period, and reduces the need for inotropic support.

Konfumin- 15% sodium fumarate solution for infusion, which has a noticeable antihypoxic effect. It has a certain cardiotonic and cardioprotective effect. It is used in various hypoxic conditions (hypoxia with normovolemia, shock, severe intoxication), including in cases where the administration of large volumes of fluid is contraindicated and other infusion drugs with antihypoxic action cannot be used.

3. Natural components of the respiratory chain

Antihypoxants, which are natural components of the mitochondrial respiratory chain involved in electron transfer, have also found practical application. These include cytochrome C (Cytomac) and ubiquinone(Ubinon). These drugs, in essence, perform the function of replacement therapy, since during hypoxia, due to structural disorders, mitochondria lose some of their components, including electron carriers.

Experimental studies have shown that exogenous cytochrome C during hypoxia penetrates the cell and mitochondria, integrates into the respiratory chain and contributes to the normalization of energy-producing oxidative phosphorylation.

A combination drug containing cytochrome C is energostim. In addition to cytochrome C (10 mg), it contains nicotinamide dinucleotide (0.5 mg) and inosine (80 mg). This combination has an additive effect, where the effects of NAD and inosine complement the antihypoxic effect of cytochrome C. At the same time, exogenously administered NAD somewhat reduces the deficiency of cytosolic NAD and restores the activity of NAD-dependent dehydrogenases involved in ATP synthesis, contributes to the intensification of the respiratory chain. Due to inosine, an increase in the content of the total pool of purine nucleotides is achieved. The drug is proposed for use in MI, as well as in conditions accompanied by the development of hypoxia, however, the evidence base is currently rather weak.

Ubiquinone (coenzyme Q10) is a coenzyme widely distributed in the cells of the body, which is a derivative of benzoquinone. The main part of intracellular ubiquinone is concentrated in mitochondria in oxidized (CoQ), reduced (CoH2, QH2) and semi-reduced forms (semiquinone, CoH, QH). In a small amount, it is present in the nuclei, endoplasmic reticulum, lysosomes, Golgi apparatus. Like tocopherol, ubiquinone is found in the largest quantities in organs with a high metabolic rate - the heart, liver, and kidneys.

It is a carrier of electrons and protons from the inner to the outer side of the mitochondrial membrane, a component of the respiratory chain, and is also capable of acting as an antioxidant.

Ubiquinone(Ubinon) can mainly be used in the complex therapy of patients with coronary heart disease, with myocardial infarction, as well as in patients with chronic heart failure (CHF).
When using the drug in patients with IHD, the clinical course of the disease improves (mainly in patients with functional class I-II), the frequency of seizures decreases; increased tolerance to physical activity; the content of prostacyclin increases in the blood and thromboxane decreases. However, it should be taken into account that the drug itself does not lead to an increase in coronary blood flow and does not contribute to a decrease in the oxygen demand of the myocardium (although it may have a slight bradycardic effect). As a result, the antianginal effect of the drug appears after some, sometimes quite a long time (up to 3 months).

In the complex therapy of patients with coronary artery disease, ubiquinone can be combined with beta-blockers and angiotensin-converting enzyme inhibitors. This reduces the risk of developing left ventricular heart failure, cardiac arrhythmias. The drug is ineffective in patients with a sharp decrease in exercise tolerance, as well as in the presence of a high degree of sclerotic stenosis of the coronary arteries.

In CHF, the use of ubiquinone in combination with dosed physical activity (especially in high doses, up to 300 mg per day) can increase the power of left ventricular contractions and improve endothelial function. The drug has a significant positive effect on the functional class of patients with CHF and the number of hospitalizations.

It should be noted that the effectiveness of ubiquinone in CHF largely depends on its plasma level, which in turn is determined by the metabolic needs of various tissues. It is assumed that the positive effects of the drug mentioned above appear only when the plasma concentration of coenzyme Q10 exceeds 2.5 μg / ml (normal concentration is approximately 0.6-1.0 μg / ml). This level is achieved when prescribing high doses of the drug: taking 300 mg per day of coenzyme Q10 gives a 4-fold increase in its blood level from the initial one, but not when using low doses (up to 100 mg per day). Therefore, although a number of studies in CHF were performed with the appointment of patients with ubiquinone in doses of 90–120 mg per day, it seems that the use of high-dose therapy should be considered the most optimal for this pathology.

In a small pilot study, ubiquinone treatment reduced myopathic symptoms in statin patients, reduced muscle pain (by 40%), and improved daily activity (by 38%), in contrast to tocopherol, which was found to be ineffective.

The drug is usually well tolerated. Sometimes nausea and stool disorders, anxiety and insomnia are possible, in which case the drug is stopped.

As a derivative of ubiquinone, idebenone can be considered, which, compared with coenzyme Q10, has a smaller size (5 times), less hydrophobicity, and greater antioxidant activity. The drug penetrates the blood-brain barrier and is distributed in significant amounts in the brain tissue. The mechanism of action of idebenone is similar to that of ubiquinone. Along with antihypoxic and antioxidant effects, it has a mnemotropic and nootropic effect that develops after 20-25 days of treatment. The main indications for the use of idebenone are cerebrovascular insufficiency of various origins, organic lesions of the central nervous system.

The most common side effect of the drug (up to 35%) is sleep disturbance due to its activating effect, and therefore the last intake of idebenone should be carried out no later than 17 hours.

4. Artificial redox systems

Of the agents that form artificial redox systems, sodium polydihydroxyphenylene thiosulfonate has been introduced into medical practice - drying oil(hypoxene), which is a synthetic polyquinone. In the interstitial fluid, the drug apparently dissociates into a polyquinone cation and a thiol anion. The antihypoxic effect of the drug is associated, first of all, with the presence in its structure of the polyphenolic quinone component, which is involved in the shunting of electron transport in the respiratory chain of mitochondria (from complex I to III). In the posthypoxic period, the drug leads to a rapid oxidation of the accumulated reduced equivalents (NADP H2, FADH). The ability to easily form semiquinone provides it with a noticeable antioxidant effect, which is necessary for the neutralization of LPO products.

The use of the drug is allowed for severe traumatic lesions, shock, blood loss, extensive surgical interventions. In patients with coronary heart disease, it reduces ischemic manifestations, normalizes hemodynamics, reduces blood clotting and total oxygen consumption. Clinical studies have shown that the inclusion of drying oil in the complex of therapeutic measures reduces the lethality of patients with traumatic shock, there is a more rapid stabilization of hemodynamic parameters in the postoperative period.

In patients with heart failure against the background of Olifen, the manifestations of tissue hypoxia are reduced, but there is no particular improvement in the pumping function of the heart, which limits the use of the drug in acute heart failure. The absence of a positive effect on the state of impaired central and intracardiac hemodynamics in MI does not allow one to form an unambiguous opinion about the effectiveness of the drug in this pathology. In addition, oliven does not give a direct antianginal effect and does not eliminate rhythm disturbances that occur during MI.

Among the side effects of oliven, undesirable vegetative changes can be noted, including a prolonged increase in blood pressure or collapses in some patients, allergic reactions and phlebitis; rarely short-term feeling of drowsiness, dry mouth; with MI, the period of sinus tachycardia may be somewhat prolonged. With long-term course use of oliven, two main side effects prevail - acute phlebitis (in 6% of patients) and allergic reactions in the form of hyperemia of the palms and pruritus (in 4% of patients), intestinal disorders are less common (in 1% of people).

5. Macroergic compounds

An antihypoxant, created on the basis of a macroergic compound natural for the body - creatine phosphate, is Neoton. In the myocardium and in the skeletal muscle, creatine phosphate acts as a reserve of chemical energy and is used for the resynthesis of ATP, the hydrolysis of which provides the energy necessary for the contraction of actomyosin. The action of both endogenous and exogenously administered creatine phosphate is to directly phosphorylate ADP and thereby increase the amount of ATP in the cell. In addition, under the influence of the drug, the sarcolemmal membrane of ischemic cardiomyocytes is stabilized, platelet aggregation decreases and the plasticity of erythrocyte membranes increases. The most studied is the normalizing effect of neoton on the metabolism and functions of the myocardium, since in case of myocardial damage there is a close relationship between the content of high-energy phosphorylating compounds in the cell, cell survival and the ability to restore contraction function.

The main indications for the use of creatine phosphate are MI (acute period), intraoperative myocardial or limb ischemia, CHF. It should be noted that a single infusion of the drug does not affect the clinical status and the state of the contractile function of the left ventricle.

The effectiveness of the drug in patients with acute cerebrovascular accident was shown. In addition, the drug can also be used in sports medicine to prevent the adverse effects of physical overexertion. The inclusion of neoton in the complex therapy of CHF allows, as a rule, to reduce the dose of cardiac glycosides and diuretics. Doses of the intravenous drip of the drug vary depending on the type of pathology.

To make a final judgment on the efficacy and safety of the drug, large RCTs are needed. The economic feasibility of using creatine phosphate also requires additional study, given its high cost.

Side effects are rare, sometimes a short-term decrease in blood pressure is possible with a rapid intravenous injection at a dose of more than 1 g.

Sometimes ATP (adenosine triphosphoric acid) is considered as a macroergic antihypoxant. The results of the use of ATP as an antihypoxant have been contradictory and the clinical prospects are doubtful, which is explained by the extremely poor penetration of exogenous ATP through intact membranes and its rapid dephosphorylation in the blood.

At the same time, the drug still has a certain therapeutic effect that is not associated with a direct antihypoxic effect, which is due both to its neurotransmitter properties (modulating effect on adreno-, choline-, purine receptors) and to the effect on metabolism and cell membranes of products degradation of ATP - AMP, cAMP, adenosine, inosine. The latter has a vasodilatory, antiarrhythmic, antianginal and antiaggregatory effect and implements its effects through P 1 -P 2 -purinergic (adenosine) receptors in various tissues. The main indication for the use of ATP at present is the relief of paroxysms of supraventricular tachycardia.

Concluding the characterization of antihypoxants, it is necessary to emphasize once again that the use of these drugs has the widest prospects, since antihypoxants normalize the very basis of cell vital activity - its energy, which determines all other functions. Therefore, the use of antihypoxic drugs in critical conditions can prevent the development of irreversible changes in organs and make a decisive contribution to saving the patient.

The practical use of drugs of this class should be based on the disclosure of their mechanisms of antihypoxic action, taking into account pharmacokinetic features, the results of large randomized clinical trials and economic feasibility.

Description of the drug

Means "Trimetazidine" instructions for use refers to the pharmacological group of antihypoxic drugs with characteristic antianginal and cytoprotective effects. The action of this drug is based on the optimization of the metabolism of neurons and cardiomyocytes of the brain, the activation of oxidative decarboxylation, the arrest of the process of fatty acid oxidation, and the stimulation of aerobic glycolysis. Prolonged use of the drug "Trimetazidine", instructions for the use of which is always attached, prevents the activation of neutrophils and a decrease in the content of phosphocreatinine and ATP, allows you to normalize the functioning of ion channels and reduce intracellular acidosis. In addition, this tool maintains the integrity of cell membranes, reduces the release of creatine phosphokinase and the severity of ischemic damage. With regard to the pharmacokinetics of this antihypoxic drug, the time to reach the highest plasma concentration is about two hours, and the elimination half-life varies from four to five hours.

Features of the dosage form

The medicine "Trimetazidine" is produced in the form of round tablets, which contain twenty milligrams of trimetazidine hydrochloride as an active ingredient.

The main indications for the appointment

Doctors recommend taking this drug mainly for the treatment of coronary disease and the prevention of angina attacks. With chorioretinal vascular disorders, the appointment of Trimetazidine tablets is also indicated. Instructions for use advises using them for the treatment of dizziness of vascular origin. In addition, this antihypoxic agent is often prescribed for the treatment of cochleovestibular disorders accompanied by hearing loss and tinnitus.

Features of the use of the drug

Take the drug "Trimetazidine", as a rule, should be two, maximum three times a day, one to two tablets. The duration of treatment is determined only by the doctor on the basis of certain tests.

List of medical contraindications

The instructions for use strictly do not recommend using the antihypoxic agent "Trimetazidine" for persons who have an allergic reaction to trimetazidine hydrochloride, as well as people with severe renal insufficiency. During gestation, similarly, you should not start taking this drug. In addition, the list of strict contraindications includes lactation and the presence of significant violations in the liver. Due to the lack of sufficient experience in clinical trials, Trimetazidine should also not be taken by persons under the age of eighteen.

Side effects

Prolonged use of this remedy may cause vomiting, nausea, headaches, itchy skin, and increased heart rate. Gastralgia can also be observed as a result of long-term use of Trimetazidine tablets.

To The key role of thrombosis of the arteries of the heart in the formation of acute coronary syndrome, up to the development of acute myocardial infarction (AMI), has now been postulated. To replace the traditionally established conservative therapy of coronary pathology, aimed at preventing complications: dangerous arrhythmias, acute heart failure (AHF), limiting the zone of myocardial damage (by increasing collateral blood flow), radical methods of treatment have been introduced into clinical practice - recanalization of the branches of the coronary arteries by pharmacological effects (thrombotic agents), and invasive intervention - percutaneous transluminal balloon or laser angioplasty with or without stent(s) installation.

The accumulated clinical and experimental experience indicates that the restoration of coronary blood flow is a "double-edged sword", i.e. in 30% or more, a “reperfusion syndrome” develops, manifesting additional damage to the myocardium, due to the inability of the cardiomyocyte energy system to utilize the “surging” oxygen supply. As a result, the formation of free-radical, reactive oxygen species (AA) increases, contributing to damage to membrane lipids - lipid peroxidation (LPO), additional damage to functionally important proteins, in particular, the cytochrome respiratory chain and myoglobin, nucleic acids and other structures of cardiomyocytes. This is a simplified model of the postperfusion metabolic cycle of development and progression of ischemic myocardial damage. In this regard, pharmacological preparations of anti-ischemic (antihypoxants) and antioxidant (antioxidants) protection of the myocardium have been developed and are being actively introduced into clinical practice.

Antihypoxants - drugs that improve the utilization of oxygen by the body and reduce the need for it in organs and tissues, in total increasing resistance to hypoxia. At present, the antihypoxic and antioxidant role of Actovegin (Nycomed) in the clinical practice of treating various urgent CVS conditions is the most studied.

Actovegin - highly purified hemodialysate obtained by ultrafiltration from the blood of calves, containing amino acids, oligopeptides, nucleosides, intermediate products of carbohydrate and fat metabolism (oligosaccharides, glycolipids), electrolytes (Mg, Na, Ca, P, K), microelements (Si, Cu).

The basis of the pharmacological action of Actovegin is the improvement of transport, glucose utilization and oxygen uptake:

Increases the exchange of high-energy phosphates (ATP);

Enzymes of oxidative phosphorylation (pyruvate and succinate dehydrogenases, cytochrome C-oxidase) are activated;

The activity of alkaline phosphatase increases, the synthesis of carbohydrates and proteins accelerates;

The influx of K+ ions into the cell increases, which is accompanied by the activation of potassium-dependent enzymes (catalases, sucrases, glucosidases);

The breakdown of anaerobic glycolysis products (lactate, b-hydroxybutyrate) is accelerated.

The active components that make up Actovegin have an insulin-like effect. Actovegin oligosaccharides activate the transport of glucose into the cell, bypassing insulin receptors. At the same time, Actovegin modulates the activity of intracellular glucose carriers, which is accompanied by an intensification of lipolysis. What is extremely important - the action of Actovegin is insulin-independent and persists in patients with insulin-dependent diabetes mellitus, helps to slow down the progression of diabetic angiopathy and restore the capillary network due to neovascularization.

The improvement of microcirculation, which is observed under the action of Actovegin, is apparently associated with an improvement in the aerobic metabolism of the vascular endothelium, which promotes the release of prostacyclin and nitric oxide (biological vasodilators). Vasodilation and a decrease in peripheral vascular resistance are secondary to the activation of oxygen metabolism in the vascular wall.

Thus, the antihypoxic effect of Actovegin is summarized through improved glucose utilization, oxygen uptake and a decrease in oxygen consumption by the myocardium as a result of a decrease in peripheral resistance.

The antioxidant effect of Actovegin is due to the presence in this drug of high superoxide dismutase activity, confirmed by atomic emission spectrometry, the presence of magnesium preparations and trace elements that are part of the prosthetic group of superoxide dismutase. Magnesium is an obligatory participant in the synthesis of cellular peptides, it is part of 13 metalloproteins, more than 300 enzymes, including glutathione synthetase, which converts glutamate to glutamine.

The accumulated clinical experience of intensive care units allows us to recommend the introduction of high doses of Actovegin: from 800-1200 mg to 2-4 g. Intravenous administration of Actovegin is advisable:

For the prevention of reperfusion syndrome in patients with AMI, after thrombolytic therapy or balloon angioplasty;

Patients in the treatment of various types of shock;

Patients suffering from circulatory arrest and asphyxia;

Patients with severe heart failure;

Patients with metabolic syndrome X.

Antioxidants - block the activation of free radical processes (formation of AK) and lipid peroxidation (LPO) of cell membranes that occur during the development of AMI, ischemic and hemorrhagic strokes, acute disorders of regional and general circulation. Their action is realized through the reduction of free radicals into a stable molecular form that is not able to participate in the autoxidation chain. Antioxidants either directly bind free radicals (direct antioxidants) or stimulate the antioxidant system of tissues (indirect antioxidants).

Energostim - a combined preparation containing nicotinamide adenine dinucleotide (NAD), cytochrome C and inosine in the ratio: 0.5, 10 and 80 mg, respectively.

With AMI, disturbances in the energy supply system occur as a result of the loss of NAD by the cardiomyocyte - the coenzyme of glycolysis dehydrogenase and the Krebs cycle, cytochrome C - the enzyme of the electron transport chain, with which ATP synthesis is associated in mitochondria (Mx) through oxidative phosphorylation. In turn, the release of cytochrome C from Mx leads not only to the development of energy deficiency, but also contributes to the formation of free radicals and the progression of oxidative stress, ending in cell death by apoptosis. After intravenous administration, exogenous NAD, penetrating through the sarcolemma and Mx membranes, eliminates the deficiency of cytosolic NAD, restores the activity of NAD-dependent dehydrogenases involved in the synthesis of ATP by the glycolytic pathway, and promotes the intensification of the transport of cytosolic proton and electrons in the respiratory chain of Mx. In turn, exogenous cytochrome C in Mx normalizes the transfer of electrons and protons to cytochrome oxidase, which in total stimulates the ATP-synthesizing function of Mx oxidative phosphorylation. However, the elimination of NAD and cytochrome C deficiency does not completely normalize the "conveyor" of cardiomyocyte ATP synthesis, since it does not significantly affect the content of individual components of adenyl nucleotides involved in the respiratory chain of cells. Restoration of the total content of adenyl nucleotides occurs with the introduction of inosine, a metabolite that stimulates the synthesis of adenyl nucleotides. At the same time, inosine enhances coronary blood flow, promotes the delivery and utilization of oxygen in the area of microcirculation.

In this way, it is advisable to combine the introduction of NAD, cytochrome C and inosine for effective impact on metabolic processes in cardiomyocytes subjected to ischemic stress.

Energostim, according to the mechanism of pharmacological effects on cellular metabolism, has a combined effect on organs and tissues: antioxidant and antihypoxic. Due to the composite composition of Energostim, according to various authors, in terms of the effectiveness of treating MI as part of traditional treatment, it is many times greater than the effect of other antihypoxants recognized in the world: 2-2.5 times lithium oxybutyrate, riboxin (inosine) and amitazole, 3- 4 times - carnitine (mildronate), piracetam, oliven and solcoseryl, 5-6 times - cytochrome C, aspisol, ubiquinone and trimetazidine. Recommended doses of Energostim in the complex therapy of MI: 110 mg (1 bottle) in 100 ml of 5% glucose 2-3 times a day for 4-5 days. All of the above allows us to consider Energostim the drug of choice in the complex therapy of MI, for the prevention of complications resulting from metabolic disorders in cardiomyocytes.

Coenzyme Q10 - a vitamin-like substance, was first isolated in 1957 from the mitochondria of a bovine heart by the American scientist F. Crane. K. Folkers in 1958 determined its structure. The second official name for coenzyme Q10 is ubiquinone (the ubiquitous quinone), as it is found in various concentrations in almost all tissues of animal origin. In the 1960s, the role of Q10 as an electron carrier in the Mx respiratory chain was shown. In 1978, P. Mitchell proposed a scheme explaining the participation of coenzyme Q10 both in electron transport in mitochondria and in the coupling of electron transport and oxidative phosphorylation processes, for which he received the Nobel Prize.

Coenzyme Q10 effectively protects lipids of biological membranes and blood lipoprotein particles (phospholipids - "membrane glue") from the destructive processes of peroxidation, protects DNA and body proteins from oxidative modification as a result of the accumulation of reactive oxygen species (AA). Coenzyme Q10 is synthesized in the body from the amino acid tyrosine with the participation of B and C vitamins, folic and pantothenic acids, and a number of trace elements. With age, the biosynthesis of coenzyme Q10 progressively decreases, and its consumption during physical, emotional stress, in the pathogenesis of various diseases and oxidative stress increases.

More than 20 years of experience in clinical studies of the use of coenzyme Q10 in thousands of patients convincingly prove the role of its deficiency in the pathology of the cardiovascular system, which is not surprising, since it is in the cells of the heart muscle that the energy needs are greatest. The protective role of coenzyme Q10 is due to its participation in the processes of energy metabolism of cardiomyocytes and antioxidant properties. The uniqueness of the drug under discussion is in its regenerative ability under the action of the enzyme systems of the body. This distinguishes coenzyme Q10 from other antioxidants, which, while performing their function, irreversibly oxidize themselves, requiring additional administration.

The first positive clinical experience in cardiology on the use of coenzyme Q10 was obtained in the treatment of patients with dilated cardiomyopathy and mitral valve prolapse: convincing data were obtained in improving the diastolic function of the myocardium. The diastolic function of a cardiomyocyte is an energy-intensive process and, under various pathological conditions, the CCC consumes up to 50% or more of all the energy contained in ATP synthesized in the cell, which determines its strong dependence on the level of coenzyme Q10.

Clinical studies in recent decades have shown Therapeutic efficacy of coenzyme Q10 in the complex treatment of coronary artery disease , arterial hypertension, atherosclerosis and chronic fatigue syndrome. The accumulated clinical experience allows us to recommend the use of Q10 not only as an effective drug in the complex therapy of CV diseases, but also as a means of preventing them.

The prophylactic dose of Q10 for adults is 15 mg/day, the therapeutic dose is 30-150 mg/day, and in cases of intensive care, up to 300-500 mg/day. It should be taken into account that high therapeutic doses with oral intake of coenzyme Q10 are associated with difficulty in the absorption of fat-soluble substances, therefore, a water-soluble form of ubiquinone has now been created to improve bioavailability.

Experimental studies have shown the preventive and therapeutic effect of coenzyme Q10 in reperfusion syndrome, documented by the preservation of subcellular structures of cardiomyocytes subjected to ischemic stress, and the function of oxidative phosphorylation of Mx.

Clinical experience with the use of coenzyme Q10 is so far limited to the treatment of children with chronic tachyarrhythmias, long QT syndrome, cardiomyopathies, and sick sinus syndrome.

Thus, a clear understanding of the pathophysiological mechanisms of damage to cells of tissues and organs subjected to ischemic stress, which are based on metabolic disorders - lipid peroxidation, occurring in various CV diseases, dictates the need to include antioxidants and antihypoxants in the complex therapy of urgent conditions.

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