EA018359B1 - Agent and method for preventing and treating intoxication by alcohol-containing liquids and alcohol substitutes - Google Patents

Abstract

The invention relates to medicine and can be used for developing agents and methods to be used in toxicological practice and by population at home for preventing and reducing risks of dangerous diseases such as intoxication by alcohol substitutes and toxic components of alcoholic beverages. The invention is based on the use of known chemical compounds in the form of vicinal dithioglycoles. They are used for new purposes, namely for developing medicinal agents, the properties of which make it possible to prevent, treat or reduce speed of pathological processes generated by alcohol substitute intoxication. The inventive agents reduce or block the pharmacological effects of alcohols and the derivatives thereof, i.e. produce a direct effect on pathogenetic mechanisms of intoxication development. Said agents are most efficient when perorally administered. Experimental data items proving that the inventive agents and the preventing method, which consists in taking the agents before and after drinking low-quality alcohol-containing beverages and alcohol substitutes, can be widely used in future are also disclosed. The use of the invention makes it possible to reduce the number of intoxication cases produced by substitutes, to decrease the severity of intoxication and the toxic effect of alcoholic beverages consumed at home.

Description

Field of Invention

The invention relates to medicine and relates to medicines used in toxicological practice, as well as for prophylactic use, including in the household use of alcoholic beverages, associated with the risk of intoxication.

The spread of intoxications associated with the voluntary use of alcoholic and alcohol-containing drinks, intentional or accidental, erroneous use of alcohol substitutes is a serious medical and social problem. Only in the Russian Federation, according to official data, from this type of poisoning, tens of thousands of people die. As a rule, recorded cases of intoxication are caused by the use of toxicants along with ethyl alcohol, which are often associated with it due to the low quality of purification of the drink or not intended for food consumption at all. It is known that non-ethanol alcohol impurities increase the toxicity of ethanol in the composition of permitted drinks.

The present invention is directed to the development of means and methods for solving problems in this field.

State of the art

For a uniform understanding of the following text, we clarify the understanding of the terms used in the field of the present invention.

Alcohols (alcohols) are derivatives of hydrocarbons formed by the substitution of hydrogen atoms by hydroxyl (OH) groups. Alcohols here means any alcohol: monohydric or polyhydric, aliphatic or alicyclic, with any length of the carbon chain, any of the possible isomers. The term alcohol can also be understood as such alcohols that have different functional groups: amino alcohols, halogenated alcohols, thioalcohols, etc.

Here, esters of a number of alcohols, for example cellosolves, will also be considered. In general, intoxication according to this invention according to the International classification of diseases of the 10th revision (ICD-10) adopted by the World Health Organization (WHO) belongs to class XIX, groups T-51, T-52.

Typical toxicants, poisoning of which are considered in this invention, in particular, are:

1) from monohydric alcohols (alkanols) methyl alcohol (methanol, carbinol, wood alcohol) CH ₃ OH; according to ICD-10, the toxic effect is assigned to group T-51.1;

ethyl alcohol (ethanol, ethyl alcohol, wine alcohol) C ₂ H ₅ OH; in the present invention, ethanol is not considered as an independent toxicant, however, in combination with other toxicants, its toxic effect is enhanced and specifically modified, in this case, intoxication caused by it together with other toxicants belongs to the field of the invention; according to ICD-10, the toxic effect is assigned to group T-51.0;

propyl alcohols (in particular, normal propyl alcohols - propanol, isopropyl alcohols - propanol2, secondary propyl, petrogol, perspirite) C ₃ H ₇ OH; according to ICD-10, the toxic effect is assigned to group T-51.2;

butyl alcohols (primary n-butyl - butanol-1 or n-propylcarbinol, secondary n-butyl - butanol-2, primary isobutyl, tertiary butyl) C ₄ H ₉ OH; according to ICD-10, the toxic effect is assigned to group T-51.3;

amyl alcohols (there are 8 isomers, the most used is normal amyl alcohol - pentanol-1 or n-butylcarbinol) C ₅ NcOH; according to ICD-10, the toxic effect is assigned to group T-51.3;

2) from dihydric alcohols (glycols, alkanediols):

ethylene glycol (ethanediol-1,2) CH ₂ ONCH ₂ OH;

propylene glycol (propanediol-1,2) CH ₃ CHONCH ₂ OH; according to ICD-10, the toxic effect is assigned to group T52.3;

3) from polyhydric alcohols, tetrahydrofurfuryl alcohol CH ₂ CH ₂ CH ₂ OH (OH) CH ₂ O (tetrahydrofuran alcohol, tetrahydrofuryl alcohol);

furfural SNSNSNS (SON) O (furanaldehyde); according to ICD-10, the toxic effect is assigned to group T51.8.

The toxic effects of other toxicants according to the invention belong to groups T-51.8 and T-51.9, as well as T-52 (according to ICD-10).

We indicate the most common areas of application of the above toxicants in industry.

Methanol is used in the paint and varnish industry, as well as for the denaturation of ethyl alcohol.

Ethanol is used (in the main way that interests us here) for the production of a wide range of alcoholic beverages.

Isopropyl alcohol is used to make antifreeze. Propyl alcohols are used in

- 1 018359 as solvents for synthetic resins, essential oils, etc.

Butyl alcohols are used for the manufacture of brake fluid, as solvents in a number of industries, in the processes of organic synthesis, etc.

Primary n-amyl alcohol is the main component of the so-called fusel oil, it is an oily liquid, an admixture of the final product of distillation of an alcohol-containing yeast fermentation product.

Tetrahydrofurfuryl alcohol is used as an anti-crystallizer, as well as in organic synthesis processes.

From the point of view of chemistry, the process of producing ethanol by yeast fermentation of sugars during their fermentation by zymase is a catalytic multi-stage decomposition of sugar into alcohols and carbon dioxide. To ensure the life cycle of yeast, sources of bioavailable nitrogen and phosphorus are added to the fermented solution (mash), which necessarily leads to the formation of, in addition to ethyl, other primary alcohols: methyl, propyl, isobutyl, isoamyl, optically active amyl (2-methylbutanol one). All of them, except the first, are collectively called fusel oil or oils. In addition to alcohols, the so-called volatile impurities associated with ethyl alcohol contain aldehydes, acids and ethers in the mash. Practically reliable is the fact that in the process of distillation and fractionation of the obtained aqueous-alcoholic solution, it is not possible to completely clear the aqueous solution of ethyl alcohol from other alcohols and some other volatile impurities. The quality of the resulting final solution of ethanol in water is determined by the amount of other remaining alcohols (the less they are, the higher the quality) and their composition. In addition, a certain amount of aldehydes, also formed during fermentation, is necessarily present in the final product. It should be borne in mind that a number of alcoholic beverages are generally not subject to distillation after fermentation (for example, beer). Thus, it should be borne in mind that the process of drinking an alcoholic beverage in many cases is accompanied, along with intoxication with ethyl alcohol and its metabolic products, the intake of concomitant toxic impurities in the form of other alcohols, their aldehydes, esters and other toxic impurities and their metabolites.

Alcohol surrogate (CA) is understood to mean defective substitutes for alcoholic beverages allowed. Conventionally, this term can mean two groups of drinks: the first group includes drinks based on edible ethyl alcohol that have not passed purification to standard quality, or liquids based on technical ethyl alcohol (the so-called true surrogates); the second group includes liquids that do not contain ethyl alcohol, or containing specially prepared mixtures of ethyl alcohol with other hydrocarbons, including alcohols and / or their derivatives.

The first group includes, in particular:

hydrolysis and sulfite alcohols (ethanol obtained by hydrolysis of wood);

denatured alcohol (industrial alcohol mixed with methanol and aldehydes);

raw alcohol (a product of the distillation of fermented biomass containing ethanol and fusel oils: propyl, butyl, amyl, and other alcohols and their isomers);

colognes, lotions, other perfumes and cosmetic liquids (ethanol solutions with the addition of essential oils and / or other components);

falsified spirits prepared on the basis of poorly refined ethyl alcohol;

polishes (mixtures of technical ethyl alcohol with butyl and amyl alcohols, chloroform, acetone, etc.);

other liquids (glues, varnishes, etc.).

The second group includes, in particular:

alcohols (except ethyl alcohol);

aldehydes, ketones;

alcohol esters;

derivatives of the above compounds;

technical fluids prepared on the basis of the above compounds.

A feature of SA poisoning is that in most cases, the products of biotransformation of the initial poison in the body are more toxic than the original compound. Such initially less toxic substances include, in particular, methanol, ethylene glycol and its esters, tetrahydrofurfuryl alcohol and others. Substances with such properties are often called toxicizable, and the process itself is toxic poisoning, which indicates the possibility of formation of more toxic substances in the metabolism than native poison , in quantities that affect the nature and severity of intoxication. According to another terminology, such a process of biotransformation of native poison is called lethal synthesis.

The toxicant in this invention is called at least one of the substances selected from the group including:

alcohol (except ethyl);

alcohol derivative;

- 2 018359 substitute for alcohol.

Intoxication (or toxicosis) is a pathological condition caused by a violation of chemical homeostasis due to the interaction of various biochemical structures of the body with toxic substances of exogenous or endogenous origin. The term intoxication refers to the entire process of development of toxicosis from its very initial symptoms to the full clinical picture of the disease, the content of which depends on the physiological role of the main toxicity receptors, i.e. certain biochemical structures with which this toxicant (poison) selectively interacts. Exogenous intoxications are usually called poisoning, in contrast to endogenous intoxications associated with the accumulation of toxic substances of one's own metabolism in the body (auto-intoxication).

The classification of intoxication as a disease of chemical etiology is based on three leading principles: etiopathogenetic; clinical; nosological.

From the point of view of the etiopathogenetic principle, intoxications considered in the present invention include:

due to development - to accidental and / or intentional;

according to the conditions of occurrence - as a rule, to household, less often - to production;

on the way the poison enters the body - to the oral, rarely to inhalation, and even less often to transdermal;

by the origin of the poison - to exogenous intoxications.

Intoxication with the poisons referred to in this patent, according to the general picture of the development, course and outcome of poisoning, can be:

sharp, i.e. after a single entry into the body of a toxic substance, the clinical picture of poisoning proceeds quickly and intensively, ending in recovery or death;

subacute, i.e. with a single (or several times in a short period of time) the introduction of a toxicant into the body, the clinical development of poisoning occurs slowly, causing more or less prolonged health problems;

chronic, such intoxications are characterized by repeated, systematic or intermittent, intake of a toxicant in the body, usually in small, toxic doses, which is naturally accompanied by its prolonged exposure and the persistence of symptoms of a health disorder, its increase with periodic exacerbations;

subchronic, differ from chronic ones by a shorter duration of the period of receipt of the toxicant, which is usually measured in weeks or months.

In terms of severity, intoxication considered here may be mild; moderate severity; heavy or fatal.

Intoxication in the present invention refers to any of the above possible intoxications caused by any of the above toxicants.

The etiological factor of the considered poisoning is alcohols and / or their derivatives, or other toxicants that accumulate in the body at a toxic concentration that can cause disturbances in chemical homeostasis, i.e. unbalance the natural system of detoxification, designed to cleanse the body of toxic substances of various origins.

The pathogenesis of poisoning by alcohols and SA is studied in two main directions: toxicokinetic (finding the answer to the question of what happens with poison in the body); toxicodynamic (what happens to the body under the influence of poison).

As part of the toxicokinetic approach, they find out:

physicochemical properties of poisons that determine their behavior in the body: molecular weight, solubility in water and fats, ability to ionize;

the ability to form bonds with proteins and certain toxicity receptors;

characterization of methods of their penetration into the body, distribution at the molecular, cellular and organ level;

biotransformation in biochemical systems;

method of excretion from the body.

In the framework of the toxicodynamic approach, they study:

toxicogenic effects of poisoning associated with a violation of the physiological functions of various biochemical structures acting as toxicity receptors, which is manifested by symptoms specific to this poison;

somatogenic effects that occur in the system of the general adaptive reaction of the body to chemical trauma (stimulation of the function of the pituitary adrenal system, shock reaction of centralization of blood circulation, etc.).

It should be borne in mind that any intoxication, like a chemical disease, always arises on the basis of certain physiological systems, but differs in the result of their activity, which acquires an inherent pathogenic character. In the pathogenesis of poisoning, several main factors are distinguished.

- 3 018359

1. The concentration factor, ie the concentration of molecules of a toxic substance in the biological environment of the body (usually μg / ml), which is the leading one, since it correlates with the appearance of clinical symptoms with a toxic concentration of poisons in the blood and with its further development up to a possible fatal outcome - at a fatal concentration.

2. Time factor - determines the residence time of a toxic dose of poison in the body, the rate of its intake and elimination. It reflects the relationship between the duration of the poison and its toxic effect. Determination of the dynamics of concentration and time factors makes it possible to distinguish between the toxicogenic and somatogenic phases of poisoning, as well as the period of resorption and elimination of the poison in the toxicogenic phase.

3. Spatial factor - determines the route of entry, elimination and space distribution of the poison, which is largely associated with the blood supply to organs and tissues.

4. Age factor - reflects the degree of sensitivity of the body to poison in various age periods of a person’s life, which varies significantly from childhood to old age, when resistance to toxic effects decreases by 10 times or more.

5. The treatment factor determines the body's response to detoxification therapy, which allows several times to increase the concentration thresholds of the development of leading symptoms of intoxication and significantly reduce the period of the toxicogenic phase.

The study of the pathogenesis of intoxication is based on the idea of the toxicity receptor as a place for a specific application and implementation of the action of the poison.

It is believed that any chemical substance, in order to produce a biological effect, should have at least two signs: affinity for the receptor and its own physicochemical activity.

By affinity is understood the degree of coupling of a substance to a receptor, which is measured by the reciprocal of the dissociation rate of a substance-receptor complex.

The degree of toxicity of a substance is determined by the minimum number of its molecules, capable of binding and disabling vital target cells. It matters not only the number of poisoned receptors, but also the degree of their significance for the life of the whole organism. The rate of formation of the poison-receptor complex, their stability, and the ability to reverse dissociation are also important, which can play a more important role than the degree of saturation of the receptors with poison.

The toxic effect does not necessarily have strict selectivity, it can occur with the whole cell as a whole. This principle is realized in the action of many poisons, common to which is that they are not electrolytes. A non-electrolytic action means all effects that are directly determined by the physicochemical properties of a substance: for example, intoxicating, narcotic, which is typical for our group of toxicants (alcohols).

For most representatives of the group of substances considered here, the presence of a specific membrane-toxic action is characteristic - these are membrane-toxins. They are characterized by the presence of phospholipase activity, which results in disorganization and destruction of the main liquid crystal structure of the membranes with subsequent cell death.

In a number of studies, it has been established that in case of intoxication with alcohol and alcohol substitutes, the direct mechanism of the membrane-toxic action of themselves or their metabolites is lipid peroxidation (LPO). The process of lipid peroxidation of intracellular membranes acquires the character of a chain reaction, which is accompanied by massive cell death as a result of depletion of the body's natural antioxidant systems (AOS).

Detoxification (detoxification) - as one of the most important mechanisms of chemical resistance, it is a complex of biochemical and biophysical reactions of the body aimed at maintaining chemical homeostasis, which is provided by the cooperative function of several systems of natural detoxification (neutralization of toxic substances of exogenous and endogenous origin), including:

blood immune system (proteins and formed elements);

liver detoxification system (microsomal - with the participation of P-450 enzymes and non-microsomal - as part of specific enzymes for biotransformation of hydrophobic and hydrophilic substances). For our toxicants, such enzymes are alcohol dehydrogenase, acetaldehyde dehydrogenase of the liver.

system of excretory organs (gastrointestinal tract, kidneys, lungs, skin).

The normal function of the general system of natural detoxification provides a sufficiently reliable cleansing of the body of exo- and endogenous toxic substances when their concentration in the blood does not exceed a certain threshold level. Otherwise, the accumulation of molecules of toxic substances at toxicity receptors with the development of the picture of poisoning. The degree of its severity depends on a combination of various factors, in some cases it can be partially or largely associated with the accumulation of metabolites, which are much more toxic than the native substance (methanol, ethylene glycol, etc.), whose biotransformation proceeds along the path of toxicity. On the other hand, the intensity of exposure to toxic substances on the body increases with existing premorbid disorders with

- 4 018359 sides of the main detoxification systems, especially the functions of the liver, kidneys and immunity (situational toxicity), as well as in elderly patients. In this case, toxic effects develop when the concentration of toxin in the blood is less than the threshold.

In all cases of exceeding the threshold level of toxic load, there is a need to stimulate or additional support the work of the general system of natural detoxification of the body for its accelerated purification.

The toxicodynamic effects of intoxication are manifested by certain clinical symptoms, the content of which depends on the stage of the disease and the selective toxicity of poisons.

In the toxicogenic stage (phase) of acute poisoning, proceeding in the presence of a toxic concentration of poisons in the blood, the specific symptoms of the disease, which depend on the type and functional role of certain toxicity receptors with which the toxic substance interacts, attract attention first.

In chronic intoxication, in contrast to acute, specific toxicogenic symptoms appear much later, after a long period of general somatic disorders.

Treatment of poisoning includes the combined conduct of special therapeutic measures in two main directions:

1) cessation of further intake and accelerated elimination of toxic substances from the body (efferent methods of active detoxification), as well as, if possible, urgent neutralization of poisons by using specific (antidote) pharmacotherapy that reduces their toxicity (toxicokinetic correction);

2) pharmacological protection and maintenance of the function of the body that undergoes primary damage by a toxic substance - symptomatic therapy and resuscitation aid (toxicodynamic correction).

The use of specific antidotes (antidotes) allows for certain types of poisoning with severe selective toxicity to directly affect the toxic substance or its receptors and reduce its toxicity.

Methods of detoxification in the somatogenic stage are also aimed at eliminating endotoxemia, which develops in cases of damage to the parenchymal organs (for example, in acute renal or liver failure).

In the toxic effect of alcohols, two components are distinguished: specific and non-specific.

Nonspecific action is associated with the peculiarities of physicochemical properties and is due to the so-called non-electrolyte action (the action of a whole molecule of a substance by the mechanism of presence). The non-electrolyte effect is manifested by fluidization of the membranes and, as a consequence, a violation of their functions. The osmotic activity inherent in alcohols causes fluid movements between various organs and tissues, suppression of platelet aggregation, sensitization of the myocardium to adrenaline with the development of arrhythmias.

The clinical picture of poisoning by non-electrolytes, which include alcohols and their metabolites, is characterized by a state of intoxication, a decrease in the contractility of the myocardium, and a disorder of intracellular metabolism.

The picture of ethanol poisoning is most studied in the laboratory and clinic. A number of mechanisms of its cerebro-, hepatoto-, cardio- and nephrotoxic effects, toxic effects of synaptotropic and membranotropic nature have been established. We will give them briefly in order to further characterize the toxic effects of the toxicants considered here on the basis of the principle of analogy.

Ethanol is oxidized by oxidoreductases: alcohol dehydrogenase (ADH) in the cytosol of hepatocytes (this is a specific ΝΑΌ-dependent enzyme), microsomal ethanol oxidizing system (MEOS) of the liver, as well as by catalase, oxidase and peroxidase in tissues. As a result of oxidation, ethyl alcohol aldehyde is formed - acetaldehyde. Acetaldehyde is oxidized with the help of a печени-containing liver enzyme - acetaldehyde dehydrogenase (AcDG) to acetic acid, which is gradually metabolized further to CO ₂ and H ₂ O.

The implementation of the toxic effect of ethanol on the central nervous system (CNS) is caused by disturbances in the functioning of mediator systems caused by it, and a pronounced membrane-effect effect. It specifically affects the GABA and glutamatergic systems, changes the permeability and affinity of the ion channels of membranes, changing the functions of neurotransmitter systems.

During the biotransformation of ethanol, a large amount of acetaldehyde, acetate, and the reduced form of the ADH - фер enzyme occurs. This ultimately determines the chain of biochemical disturbances caused by the introduction of ethanol. In case of ethanol poisoning, the citric acid cycle is blocked by acetaldehyde and is not able to utilize acetyl-CoA, which leads to the formation of ketone bodies and a shift in the synthesis of fatty acids. On this basis, metabolic acidosis develops. It is also known that large amounts of acetaldehyde lead to disruptions in the work of the respiratory chain of mitochondria, distorting its energy function. On this basis, disturbances in the work of the myocardium are formed.

- 5 018359

We consider it necessary to note that, in our opinion, ADH is capable of catalyzing the redox reaction of the conversion of alcohol to aldehyde not only in the case of ethyl alcohol, but also for a number of other alcohols, which include at least those alcohols for which the phenomenon of so-called toxicity is noted. Another argument in favor of this consideration is the fact that ethanol is used as a specific antidote for poisoning with a number of alcohols, which is explained by its ability to competitively inhibit alcohol dehydrogenase, i.e., therefore, prevent the oxidation of these toxicants. Such alcohols include methanol, aliphatic alcohols with a carbon chain length of up to 5 atoms, dihydric alcohols, as well as their esters having an alcohol group - glycol monoesters, i.e. those alcohols and their derivatives that are typical toxicants of the present invention.

Thus, with poisoning by alcohols, at least by those that are oxidized to their aldehydes by means of ADH, we observe a relatively similar picture of the toxic effects of the toxicant.

The specific action of alcohols is characterized by a violation of the physicochemical properties of cell membranes, damage to membranes by the products of the biotransformation of alcohols, increasing cytoplasmic acidosis, impaired energy processes, activation of the processes of autolysis of proteins and lipids of the cell, impaired lipid metabolism, activation of peroxidation processes. On this basis, necrotic and dystrophic (fatty degeneration) changes in the cells of the most important organs develop.

The toxic effect of methanol is mainly due to its metabolites: formaldehyde and formic acid. Formaldehyde itself is the strongest poison, but also its metabolite is able to break the chain of oxidation and phosphorylation, cause metabolic acidosis, modify the normal course of a number of important biochemical processes.

In case of ethylene glycol poisoning, such products of its biotransformation successively arise as glyoxylic acid (after the first enzymatic conversion with the participation of ADH) - this is monoaldehyde, glycolaldehyde (after the second enzymatic conversion with the participation of ADH) - it is dialdehyde, then oxalate, glycolic acid. All substances of this series disrupt the work of the enzymes of the citric acid cycle. The resulting aldehydes are toxic and, accumulating in the body, for a long time and systemically disorganize the vital functions of the body.

Ethylene glycol monoesters follow approximately the same metabolic pathway, since ADH attacks their alcohol group, as a result of which they turn into the corresponding aldehydes. Along with this, hydroxyacetic acid is formed from the ethylene glycol monoester, the presence of which also leads to metabolic acidosis of the cell. Together, these compounds cause hypopotassemia and hypocalcemia, disrupt the normal metabolism of glucose, lactate, ATP synthesis, and disorganize the work of a number of enzyme systems.

The above processes at the cell level are triggering for the development of a number of pathogenetic disorders: homeostasis disorder (metabolic acidosis, water-electrolyte imbalance, hemocoagulation shift, etc.), as well as the formation of secondary syndromes: depression of consciousness, central and aspiration-obstructive breathing disorders, acute cardiovascular failure, damage to the parenchymal organs, etc. On their basis, a number of processes develop with the threat of mortality. These include:

acute respiratory failure (ventilating and parenchymal);

hemodynamic disorder (based on a decrease in myocardial contractility, toxic myocardial dystrophy, hypovolemic shock, etc.);

cerebral disorders;

lesions and dysfunction of parenchymal organs (liver, kidney, myocardium).

The following characteristic syndromes are distinguished in the clinical picture of SA poisoning: toxic encephalopathy;

respiratory failure;

circulatory disorders;

toxic hepatopathy;

toxic nephropathy; homeostasis disorders (water-electrolyte balance, acid-base condition); gastrointestinal disorders.

These syndromes are described in detail in the literature [source No. 1: Luzhnikov EA, Ostapenko Yu.N. and other Emergency conditions in acute poisoning, M., 2001]. To date, when poisoning with methanol, ethylene glycol and other toxicants according to the invention, ethanol is used as a specific antidote, which is administered enterally and / or intravenously as a competitive inhibitor of alcohol dehydrogenase [source No. 1, p. 155-156]. This treatment method has significant drawbacks, since ethanol itself can inhibit the work of enzyme systems and parenchymal organs, which requires careful consideration of the patient's condition, the capabilities of his natural detoxification system, premorbid factors, severity of poisoning, stage of intoxication, etc.

The present invention is the introduction into circulation of an effective means to prevent

- 6 018359 waiting or blocking or reducing the rate of development of pathological processes caused by both single and repeated, in particular, prolonged, systematic use of alcohol-containing drinks, which, in addition to ethanol itself, also contain toxicants. Toxicants appear in drinks as natural impurities that occur in the technological process of alcoholic fermentation. There may be other reasons for the appearance of toxic impurities in drinks. In addition, this invention is aimed at introducing into toxicological practice effective methods and means of preventing and treating intoxications caused by alcohols and their derivatives.

The problem is solved by means for enteral or parenteral administration, representing at least one vicinal dithioglycol of general formula (1), optionally introduced into a pharmaceutically acceptable or food carrier. Vicinal dithioglycols are substances of the general formula ₁ (CH ₂ ) СН CH (5H) CH (8HXCH2) _t K ₂ (1) in which B ₁ and B ₂ can be independently selected from the following radicals: (-H), (-OM '), (-COOM'), (-8Θ ₃ Μ '), (-О-СН ₂ -8О ₃ М'), (-РО ₃ М ' ₂ ), (-ΡΘ ₂ 8Μ' ₂ ), (- PO ₃ M), (-ΡΘ ₂ 8Μ), where M 'denotes hydrogen or an alkali metal ion, M denotes an alkaline-earth metal ion, t and η are independently selected from integers from 0 to 5,

These compounds of general formula (1) are known in the art. Their description, synthesis routes are given, for example, in the Chemical Encyclopedia [Source No. 2: Chemical Encyclopedia in 5 volumes, M .: Soviet Encyclopedia, 1990, v. 2, p. 91-92].

Vicinal dithioglycols (VD) include, but are not limited to:

1) dithioglycerol (dicaptol, dimercaprol, dimercaptopropanol, BAL, ΒπίΜι Αηΐί Bs \\ t5YS - BAB), having the formula

2) 2,3-dimercaptopropanesulfonate Να (Unitiol, ΌΜΡ8) having the formula

3) 2,3-dimercaptosuccinic acid (Succimer, ΌΜ8Α) having the formula

4) 2- (2,3-dimercaptopropoxy) ethanesulfonate Να (Oxathiol) having the formula

Vicinal dithioglycols are used as radioprotective drugs, as well as antidotes for poisoning with heavy metals and their compounds, in particular poisoning with arsenic, lead, and mercury [Source No. 3: Mashkovsky MD Medicines, M., 1993]. These are low molecular weight compounds with two adjacent mercapto groups, which makes them a good trap for heavy metals, including radionuclides.

In toxicological practice, the use of these substances is known. Dimercaprol (BAB) and Unithiol (ΌΜΡ8) are used as antidotes for poisoning by arsenic, bismuth, mercury, antimony or zinc [Source No. 4: Sheybak V.M., Panchenko L.F. et al. Fundamentals of Clinical and Analytical Toxicology (Reference Guide), ed. prof. Tomilina V.V.//Moscow, 2002, p. 46]. Unitiol (ΌΜΡ8), succimer (ΌΜ8Α) and other VDs are used as antidotes for the so-called destructive poisons, which include salts of heavy metals, arsenic and its compounds, some compounds of phosphorus and chlorine. The use of использование8 (Unithiol) for alcohol delirium, acute alcohol poisoning, drug intoxication in combination therapy with other detoxifying agents is also known [source No. 3]. It is known the use of Unithiol in the relief of withdrawal symptoms during detoxification therapy as one of the stages [source No. 5: Alcoholism, ed. G.V. Morozova, M., Medicine, 1985, p. 314-321]. It is also known to use VD to block or reduce the rate of the pathological processes of the development of addiction diseases caused by the use of ethanol or other psychoactive substances (patent VI 2229291).

We offer the use of these well-known substances for a new purpose.

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Disclosure of the invention

We first discovered that VD upon enteral administration exhibits an unexpectedly higher effect with the above known indications and, moreover, we unexpectedly found that the introduction, and especially oral administration, of VD gives a new effect, manifested primarily in blocking and / or inhibition of the development of pathological processes resulting from the use of ethanol-containing drinks containing toxic impurities and / or alcohol-containing drinks containing non-ethanol as alcohol, as well as surrogates lkogolya. This effect is based on the property of the proposed substances (VD), unexpectedly discovered by us, to bind ίη νίνο the nearest metabolites of methanol, ethylene glycol, and other monohydric and polyhydric alcohols. This effect is especially pronounced due to the features of this interaction that we have identified that are essential for this invention. The first feature is that the products of VD interaction with these toxicants cannot decompose under physiological conditions, i.e. they have chemical resistance. In other words, this reaction under the conditions of the body proceeds irreversibly. The second feature is that for a noticeable, significant manifestation of this pharmacological effect on the body, it is necessary to ensure the entry (as fast and complete as possible) of the substances of the invention (VD) into the liver. For this, the enteral route of administration is most suitable or, if it is difficult, as well as along with it, such an injection that ensures that these substances or substances enter the portal bloodstream. This effect is achieved, in particular, with intraportal administration, or, otherwise, with intraportal or transumbilical infusion of VD.

The third, additional feature is that if a water-soluble vicinal dithioglycol enters into a reaction with a toxicant such as alcohol aldehyde, then the reaction product also becomes water-soluble and acquires the ability to be excreted through the kidneys with urine. This is very important for carbon chain lengths starting from 3 atoms, since, starting from propanal, the water solubility of the aldehydes of these alcohols is not complete and decreases with increasing chain length. Due to this property, the proposed agent and method, in addition to being an antidote pharmacotherapy agent and method, become an active agent and method of efferent detoxification: they not only accelerate the elimination of the toxicant, but also allow the excretion of poison through the kidneys. The same applies to the removal of ketones. The inclusion of kidneys in the excretion of a toxicant affects the concentration factor of pathogenesis in a favorable direction.

The fourth, also optional, feature is as follows. Owing to their physicochemical properties, alcohols easily overcome histohematological barriers and are fairly evenly distributed over organs and tissues. Further, alcohols undergo biotransformation in them, turning at the first stage into aldehydes. Aldehydes are more toxic than alcohols and have greater reactivity. They interact with the terminal groups of plasma proteins and blood cells, enzymes, etc., modifying their functions (immunity, hemostasis, respiration, central nervous system, myocardium, energy functions and much more). In other words, aldehyde toxicity receptors are much more diverse than alcohol toxicity receptors. Aldehydes, unlike alcohols, overcome histohematological barriers much worse, which leads to their accumulation in those organs and tissues where the metabolism (first stage of oxidation) of alcohol began. At the same time, the oxidation of aldehyde occurs under the influence of the hepatic enzyme aldehyde dehydrogenase. In view of the foregoing, further oxidation of the aldehyde in organs and tissues outside the liver is difficult, which enhances its exposure (time factor) and toxic effect. This problem is especially acute in persons belonging to the Mongoloid race, since they have a genetically predetermined reduced activity of aldehyde dehydrogenase. The use of the means and method according to the invention allows to find a new solution to this problem. Namely, when the active substance of the invention (VD) enters the liver, aldehyde binding occurs there. This leads to a shift in equilibrium in the reversible reaction of alcoholaldehyde. As a result of this, according to the Le Chatelier principle, the system responds to this by increasing the oxidation of alcohol and, consequently, reducing its concentration in the liver. This, in turn, according to the same principle, causes the outflow of alcohol from other organs and tissues and its entry into the liver to restore concentration. If the presence of VD is maintained in the liver, then a new amount of aldehyde, obtained by oxidation from the alcohol entering the liver, binds again and the cycle repeats. Therefore, the use of substances according to the invention reduces the toxic load on all organs and tissues, since it helps to accelerate the release of the toxicant from vital organs and tissues. From the point of view of the pathogenesis of intoxication, it is critically important to start the implementation of this type of treatment as soon as possible. The cycle described here, which is realized under conditions of maintaining the intake of the active substances of the invention (VD) into the liver, is called by us the cycle of alcohol-aldehyde detoxification of the body (CSAD). We also point out that CSAD is also implemented with the prophylactic administration of VD. Thus, CSAD has a favorable effect on the temporal and spatial factors of the pathogenesis of intoxication.

Thus, we have discovered a new type of pharmacological activity of vicinal dithioglycols, consisting in their ability to detoxify the body from alcohols and their metabolites, ίη νίνο

- 8 018359 which are heavy poisons, such as methanol and formaldehyde, propyl, butyl and amyl alcohols and their aldehydes, dihydric alcohols and aldehydes of their monoesters, their dialdehydes, and to use them on this basis as specific antidotes for these poisonings (the first essential sign ) The second significant sign of the use for this new purpose is the method of administering vicinal dithioglycols, in which they should be provided to the liver as completely and as quickly as possible, since it is in this organ that the poison is metabolized and toxic. In this case, it is optimal to use enteral administration, and if the patient's condition requires this, then along with this or instead, introduction into the portal bloodstream or transumbilical administration. On this basis, we offer a tool and method for the prevention and treatment of intoxication with the above toxicants.

Description of technical results.

The following are characterized by groups of effects that are achieved by the proposed tool and method (technical results), manifested primarily in connection with the use of typical toxicants contained in ethanol solutions for domestic use, or with abuse of alcohol-containing drinks containing toxic impurities, as well as in connection with the use of the toxicants considered here.

Group: treatment - toxicokinetic correction:

chemical binding of the toxicant; preventing the toxicant from binding to the toxicity receptor; acceleration of the elimination of the toxicant and / or its toxic metabolite from the body; accelerated release of toxicant from organs and tissues occupied by it (brain, lungs, etc.); prevention of toxicosis of a native toxicant;

increasing the water solubility of the reaction products of the toxicant or its metabolite with the active substance of the agent according to the invention;

reduction of ethanol toxicity caused by the presence of a toxicant or toxicants of surrogate alcohol;

improved toxicant excretion;

prevention or reduction of toxic effects on the functioning of the respiratory chain of mitochondria.

Group: treatment - toxicodynamic correction: restoration of the functions of parenchymal organs; restoration of the functioning of neurotransmitter systems; restoration of central nervous system functions;

restoration of energy functions of cells.

Group: Prevention:

prevention of the occurrence or development of acute or subacute intoxication caused by a toxicant when it may enter the body;

preventing the occurrence or reduction of the rate of development of subchronic or chronic intoxication with repeated or regular intake of alcohol-containing liquids containing a toxicant in a toxic dose or alcohol substitutes;

reduction in the severity of intoxication with the possible intake of a toxicant;

increase in the threshold level of concentration toxicity; effect on the concentration factor in the direction of reducing toxic concentration;

effect on the concentration factor in the direction of reducing the amount of toxicant in the brain; reduction in toxicant exposure (time factor);

decreased sensitivity of the body to a toxicant;

strengthening detoxification functions of the liver and kidneys with their premorbid lesions (reduction in situational toxicity);

reduced risk of the occurrence and severity of the development of endotoxic shock.

Since we have discovered new properties of the compounds of general formula (1), another aspect of the present invention is the use of at least one vicinal dithioglycol as an agent for preventing the onset or development of intoxication when taking at least one toxicant according to this invention. This appointment is new, it is not based on the known detoxification, antioxidant properties of these substances. Also new is the appointment for the use of VD as active agents for the preparation of drugs made in the dosage or non-drug form, used to prevent or treat intoxication caused by toxicants according to the invention. Such agents may be compositions, including other active ingredients as well. According to the form of execution, they can be liquid or solid means for oral administration or parenteral administration.

Vicinal dithioglycols are able to stop the process of free-radical destruction of the biomembrane, in particular they protect the axial myelin sheaths from damage, protect hepatocytes, blood vessels, and brain structures. Based on the above properties of their vicinal dithioglycols,

- 9 018359 introduction allows you to block or reduce the level of damaging effects on myocardial tissue, pancreas, vascular system, central nervous system and other organs and systems of the body.

These and other effects of vicinal dithioglycols on the processes associated with the pharmacological effects of the introduction of toxicants, determine the presence of those effects that are listed above and which are the technical results of the proposed solution.

The toxic effects of the administration of toxicants according to this invention are manifested by the effect on many organs and systems of the body, i.e. lead to the simultaneous launch or activation of a number of pathological processes. Given the above properties of vicinal dithioglycols, it can be argued that they favorably affect a number of such pathological processes, but this effect can manifest itself or be carried out, although at the same time, but with a different degree of severity. The severity of the impact on a particular pathological process depends, first of all, on the stage of its course. The occurrence of certain processes may be blocked by the prophylactic administration of the agents of the invention. In this case, other pathological processes that have already begun can be inhibited by taking these agents. The severity of the impact on a specific pathological process, due to the toxic effects of the introduction of a toxicant, also depends on the dose of the agent according to the invention, somatic and other characteristics of the individual, tactics of taking the agent, toxic load and other factors.

We found that the above physiologically beneficial effects are manifested, and especially strongly manifested, when administered orally. Apparently, this is due to the high rate of penetration of the active substance into the liver and the characteristics of the interaction of the substance with liver enzymes. A less significant effect can also be observed with local administration through the oral mucosa, nasal and inhalation.

The effects indicated above significantly expand the previously known properties of vicinal dithioglycols. Their well-known detoxification activity was used to stop acute withdrawal symptoms, i.e. for the treatment of people affected by alcoholism. Treatment with Unithiol for alcoholic delirium is carried out in relation to patients suffering from alcoholism in the initial (third) stage of the disease, which is characterized by the presence of severe mental disorder. Known antioxidant activity also well complements the new possibilities of vicinal dithioglycols. We previously revealed the ability of vicinal dithioglycols to alleviate the severity of a hangover at the household level, which was understood as the adverse effects of ethanol consumption occurring on the first day after its use. This effect is due to the activity of the substance with respect to acetaldehyde ίη νίνο (KP patent No. 2157647 C1, 2000). Currently, on the basis of newly discovered effects in experiments, it can be argued that the effects of vicinal dithioglycols as an active substance are manifested when they are administered in isolation from the fact of using SA, for example, with prophylactic administration several weeks (course) or days or hours before use of CA. The same applies to other toxicants. It is important to note that we have established the effect of vicinal dithioglycols on the general pathogenesis of intoxication with alcohols and their metabolites of heterogeneous origin.

Thus, there is every reason to conclude about the synergism of the known properties of vicinal dithioglycols with their above properties, which allow us to recommend their use for a new purpose.

The pharmaceutical form of the proposed funds may include forms suitable for enteral, in particular oral, administration, administration via a probe, nasal, local (including buccal and sublingual) administration through the oral mucosa, or for administration by inhalation, or by injection. The proposed funds may be in the form of a solution for injection. In this case, an infusion solution is prepared by combining the active substances according to the invention with suitable liquid components and dosing using suitable means. The pharmaceutical forms can be compositions and can be presented in the form of convenient discrete dosage units and can be prepared by any means well known in the art of pharmacy. All of these pharmaceutical methods include the step of combining the active substance with liquid carriers or finely divided solid carriers, or both, if necessary, and then, if necessary, molding the product in the desired form.

Pharmaceutical forms suitable for oral administration may be presented as discrete units such as tablets, capsules, cachets, each containing a predetermined amount of the active ingredient; or in the form of powders or granules; or in the form of a solution, suspension or emulsion. The active ingredient may also be presented as a bolus or paste or in pure form, i.e. without carrier. Tablets and capsules for oral administration, in addition to additional physiologically active components, may also contain conventional additives, such as binders, fillers, lubricants, disintegrants, moisturizers. Tablets may be made by compression or molding in a mold, optionally with one or more additional ingredients. Compressed tablets may be made by compressing, in suitable machines, the active ingredient in a free flowing form, such as

- 10 018359 shock or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surface active or dispersing agent. Molded tablets may be prepared by casting in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Tablets may be coated according to methods well known in the art. Liquid oral preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as dry products for constitution with water or another suitable solvent before use. Such liquid preparations, in addition to additionally introduced physiologically active components, may also contain conventional additives, such as suspending agents, non-aqueous solvents (which may include edible oils), flavoring, aromatic, coloring agents or preservatives. The listed forms may optionally be made to provide a slow or controlled release of the active substance contained therein.

Forms for topical administration through the oral mucosa, for example buccally or sublingually, include lozenges containing the active ingredient in a flavoring base such as carbohydrate, for example sucrose, acacia or tragacanth, and lozenges containing the active ingredient in such a base as gelatin, glycerin, carbohydrate, acacia, etc. For intranasal administration of the above active substances, forms such as aerosol or nebulized powder or drops may be used. Drops can be formulated on an aqueous or non-aqueous basis, also containing one or more dispersing agents, solubilizing agents or suspending agents. Liquid aerosols are conveniently obtained from pressure packs. For administration by inhalation, the compounds of the present invention are conveniently formulated from insufflators, pressurized inhaler packs, or other convenient means of preparing aerosol sprays. Pressurized packages may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for supplying the measured quantity.

Alternatively, for administration by inhalation or insufflation of the substances of the invention, a dry powder form may be used, for example a powder mixture of the active substance and a suitable powder base, such as, for example, lactose, starch, talc. The powder composition may be presented in unit dose form, for example, in capsules, cartridges, gelatin or patch packs, from which the powder may be administered by inhaler or insufflator.

If necessary, the above forms adapted to provide continuous release of the active ingredient may be used.

The pharmaceutical agents of the present invention may also contain one or more other active ingredients, the addition of which, as a rule, enhances the action of the substance according to the invention, and can also serve to achieve synergies between the added ingredients and compounds of the present invention. The active ingredients to be added may be those selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid, amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative , coenzyme precursor, carbohydrate, mineral, source of metal ions, protein and mixtures thereof. For example, it may be advantageous to add amino acids that are neurotransmitters, such as glycine, aminobutyric acid (GABA). It is favorable to add metal ion sources, since poisoning with methanol, ethylene glycol and a number of other toxicants disrupts the water-electrolyte balance, causes hypocalcemia, on the basis of which tetanic muscle contractions develop. Moreover, the addition of sources of divalent metal ions is also favorable, since some of them, such as magnesium, calcium, manganese, play an important role in enzymatic catalysis and are part of coenzymes. Calcium deficiency, which is a modulator of a number of processes, as described above, as well as toxic inhibition of its metabolism accelerates the development of many pathological processes. Favorable additions to the compositions of the invention can also be sources of lipids, in particular phospholipids, for example lecithin, glycolipids, other hepatoprotectors, in particular vitamins, for example α-tocopherol, their precursors, their derivatives, physiologically active peptides, for example neuropeptides, as well as many other known physiologically active substances.

It should be understood that, in addition to the ingredients partially listed above, the agents of the present invention may include other ingredients, agents customary for the field of application and used for the form of the agent in question. For example, agents for oral administration may contain flavoring or structure-forming agents. In particular, the preparations according to the invention, especially those aimed at the prevention of intoxication, can be made in pharmaceutical form or in non-pharmaceutical form, for example, in the form of a food product, in particular a beverage.

- 11 018359

Preferred fractional dosage forms are those containing an effective dose of the active substance of the invention, as set forth below, or an appropriate fraction of the indicated dose.

In order to achieve the recommended objectives of the invention, the aforementioned agent containing the active ingredient in an effective amount can be administered orally or in another convenient way at a dose of 0.1 to 250 mg / kg (per kilogram of recipient weight) per day. The dose level for a normal adult typically ranges from about 5 mg to about 10 g per day, typically even more narrowly from about 50 mg to about 2 g per day, most preferably from 100 to 1000 mg per day. Tablets or other forms of manufacture of the agent, presented as discrete units, may conveniently contain an amount that is effective at such a dosage, or a multiple amount, for example, units containing from 50 to 1000 mg, usually about 200-500 mg.

The agent according to the invention is preferably administered orally, and the exact amount of agent, respectively, the dose of the substance, should be taken in accordance with the instructions for use or the recommendations of a specialist. However, the actual dose used will depend on many factors, including gender, age, body weight, risk factors associated with the toxicant, somatic and neuropsychiatric characteristics of the individual, etc. Factors of the same plan should be taken into account when determining the time of administration and duration (frequency ) the introduction of funds. The tool can be recommended for administration in the form of a course, it can be prescribed before the possible use of an alcohol-containing drink, associated with a risk or threat of intoxication, and / or other possible route of entry of a toxicant into the body (aspiration, inhalation), or after a certain period of time after drinking drink (or the implementation of the ingestion of a toxicant into the body in another way), either before and after use, or in other combinations with the use of a drink containing a toxicant. At the same time, both the listed and other possible options regulating the relationship in time between the moment (or moments) of the administration of the drug and the moment (moments) of the use of an alcohol-containing drink or CA or other administration of a toxicant can partially be combined with each other.

For parenteral administration, specially prepared infusion solutions are usually used. For their preparation, the active substances of the invention are combined with a suitable solvent. Such solvent may be specially prepared water.

The following examples illustrate the essence of the invention, but do not limit the scope of the claims.

Example 1. Tablets of Unithiol.

Mix 25 g of Unithiol (substances in powder), 5 g of lactose, 10 g of aerosil, 30 g of starch, 5 g of sodium starch glycolate, 5 g of magnesium stearic acid, 1 g of calcium pantothenate, 7 g of folic acid, moisten the mixture, mix thoroughly , homogenize and tablet, getting tablets of 0.5 g.

Composition of the tablets wt.% mg Unitiol 28 140 Lactose 5.5 25 Aerosil eleven fifty Corn starch 34 150 Sodium Glycolate Starch 5.5 25 Magnesium stearate 5.5 25 Calcium pantothenate 1,2 5 Folic acid 8 35

Moisturizing agent rest

- 12 018359

Example 2. Instant capsules filled with granules containing:

Dicaptolus 50 mg Succimer 50 mg Unitiol 100 mg succinic acid 100 mg Calcium citrate 100 mg Lecithin 50 mg Magnesium oxide 50 mg Pyridoxine hydrochloride 20 mg

The granules were obtained according to the technology known in pharmacy.

The ability to use for the above purposes has been tested on laboratory animals. The study of the antidote properties of vicinal dithioglycols (on the example of Unitiol) was carried out on the initiative of the author.

Example 3. The experimental part of the work was performed on male rats of the A181ag-100 line with an initial weight of 150-250 g. Animals were kept under artificial lighting (12 hours per day) and constant access to standard combined feed and water.

The animals were divided into 4 groups (3 experimental and one control), before each experiment, blood biochemical parameters were determined in each group: triglycerides, liver enzymes: alanine aminotransferase (AlAT) and aspartate aminotransferase (AsAT), the rates of peroxide processes are TBA-positive products (according to the test with thiobarbituric acid), as well as indicators of the antioxidant system of the body: urate, vitamins E, A; 8H groups.

In the 1st experimental group (1OG), the animals were toxic without prophylaxis and treatment, an hour later they were given a dummy in the form of a gelatin capsule. In the 2nd experimental group (2OG), animals were administered orally Unitiol in a gelatin capsule in an amount of 150 mg per kilogram of weight one hour before toxicity. In the 3rd experimental group (3OG), animals received the same amount of Unithiol in the capsule 30 minutes after toxicity.

To create acute methanol intoxication, rats were once orally administered methanol in a dose of 1 ml in an aqueous solution.

The results of an animal experiment showed that the concentration of the end products of lipid peroxidation - TBA-positive compounds in the blood plasma of toxic rats (1OG) takes on values that are significantly different from similar groups with the use of Unithiol (2OG, 3OG) upward. The content of the main endogenous antioxidants - vitamins E, A, 8H-groups in rats from 1OG was significantly reduced. A comparison of the span diagrams for all three groups of animals shows that a sharp decrease in vitamin E levels occurred in animals that received only methanol and placebo. Animals treated with Unithiol along with methanol retained the average value of vitamin E at the level of values in the control group. The same picture was observed in changes in other endogenous antioxidants: vitamin A and 8H groups.

The activity of enzymes-markers of hepatocyte damage (AlAT, AsAT) also turned out to be significantly higher in 1OG than in the groups that received Unitiol. A comparison of the biochemical parameters of 2OG and 3OG showed that animals of the 2nd group treated with Unitiol prophylactically tolerated intoxication much better. This also manifested itself when observing animals, their behavior, and reactions.

The results of the study of animal tissues decapitated in compliance with biological ethics 12 days after intoxication showed that the greatest damage was found in the tissues of animals of the 1OG group. Focal infiltration, thickening of the alveolar septa, and areas of emphysema are clearly visible in the tissues of the lung. In the myocardium, there is a sharp plethora of endocardial vessels, fragmentation of individual fibers. In the liver there is granular and droplet degeneration of hepatocytes, sharp plethora of the central vein, there are binuclear cells, the beam structure is blurred. The kidneys are least affected by changes in them, there is some plethora of capillaries, small changes in the cerebral layer. In animals of the 3OG group, similar changes in tissues are observed, but they are less pronounced: the liver is more preserved, the beam structure is preserved; dystrophic changes in cardiomyocytes are less noticeable; there are no areas of emphysema in the lungs. The smallest changes in the tissues were recorded in animals of the 2OG group that received Unitiol prophylactically. In the liver, with plethora of the central vein, hepatocytes are more preserved, although granular dystrophy is also noted. In the lungs there is focal infiltration. Thinning of myocytes is noted in myocardial tissues.

The results of histological studies in this experiment allow us to conclude that vicinal dithiols exhibit therapeutic and prophylactic properties in acute methanol intoxication.

Example 4. The experimental part of the work was performed on male rats of the A181ag-100 line with a starting weight of 150-250 g. Animals were kept under artificial lighting (12 hours a day) and constant access to standard combined feed and water.

The animals were divided into 4 groups (3 experimental and one control), before each experiment, blood biochemical parameters were determined in each group: triglycerides, liver enzymes: alanine aminotransferase (AlAT) and aspartate aminotransferase (AsAT), the rates of peroxide processes are TBA-positive products (according to the test with thiobarbituric acid), alkaline phosphatase, as well as indicators of the antioxidant system of the body: urate, vitamins E, A; 8H groups.

In the 1st experimental group (1OG), the animals were toxic without prophylaxis and treatment, an hour later they were given a dummy in the form of a gelatin capsule. In the 2nd experimental group (2OG), animals were administered orally Unitiol in a gelatin capsule in an amount of 150 mg per kilogram of weight one hour before toxicity. In the 3rd experimental group (3OG), animals also received Unithiol in a capsule 30 minutes after toxicity.

To create acute intoxication with ethylene glycol, ethylene glycol was once orally administered to rats at a dose of 1 ml in an aqueous solution.

The results of an animal experiment showed that the concentration of the end products of lipid peroxidation, TBA-positive compounds in the blood plasma of toxic rats (1OG), takes values significantly different from the same results for groups using Unitiol (2OG, 3OG) upward. The content of the main endogenous antioxidants of vitamins E, A, 8H groups in rats from 1OG was significantly reduced. Comparison of the span diagrams for all three groups of animals shows that a sharp decrease in vitamin E levels occurred in animals that received only ethylene glycol and placebo. Animals treated with Unithiol along with ethylene glycol kept the average value of vitamin E at the level of values in the control group. The same picture was observed in changes in other endogenous antioxidants: vitamin A and 8H-groups. Alkaline phosphatase in animals of the first group 1OG is increased.

The activity of enzymes-markers of hepatocyte damage (AlAT, AsAT) also turned out to be significantly higher in 1OG than in the groups that received Unitiol. A comparison of the biochemical parameters of 2OG and 3OG showed that animals of the 2nd group who received Unitiol prophylactically tolerated intoxication much better. In animals of the control group, the indicators were stable.

The results of the study of animal tissues decapitated in compliance with biological ethics 12 days after intoxication showed that the greatest damage was found in the tissues of animals of the 1OG group. Focal infiltration, thickening of the alveolar septa, and separate sections of emphysema are clearly visible in the tissues of the lung. In the myocardium, there is a sharp plethora of blood vessels, dystrophic changes. In the liver there is granular and drip dystrophy of hepatocytes, sharp plethora of the central vein, slight blurring of the beam structure. There are no visible changes in the kidneys, small intestine, or pancreas. In animals of the 3OG group, similar changes in tissues are observed, however, they are less pronounced in comparison with the 1OG group: the liver is more preserved, the beam structure is preserved; dystrophic changes in cardiomyocytes are less noticeable, although hypertrophy of individual myocytes is also observed; there are no areas of emphysema in the lungs, although the alveolar septa are thickened.

The smallest changes in the tissues were recorded in animals of the 2OG group that received Unitiol prophylactically. In the liver with plethora of the central vein, hepatocytes are more preserved, although granular dystrophy is also noted. In the lungs there is focal infiltration, the pulmonary pattern is strengthened. Thinning of myocytes is noted in myocardial tissues.

The results of histological studies of animal tissue in this experiment allow us to conclude that vicinal dithiols exhibit therapeutic and prophylactic properties in acute ethylene glycol intoxication.

Claims (23)

CLAIM 1. The use of at least one vicinal dithioglycol of the formula CH ₂ CH (8H) CH (8H) CH ₂ 8OzNA (1) for the treatment of intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1 carbon atom 1 , or 3, or 4, or 5. 2. The use according to claim 1, characterized in that at least one vicinal dithioglycol of formula (1) is administered by enteral and / or intraportal or transumbilical infusion. 3. The use according to claim 1, characterized in that at least one vicinal dithioglycol of formula (1) is used as a specific antidote in the treatment of intoxication caused by at least one toxic component of an alcohol-containing liquid and / or alcohol substitute. 4. The use according to claim 3, characterized in that at least one vicinal dithioglycol of formula (1) is administered by enteral and / or intraportal or transumbilical infusion. 5. The use according to any one of claims 1 to 4, providing at least one effect - 14 018359 that associated with toxicodynamic correction of intoxication, selected from the group including: restoration of the functions of parenchymal organs; restoration of the functioning of neurotransmitter systems; restoration of central nervous system functions; restoration of energy functions of cells; and / or ensuring the achievement of at least one effect associated with toxicokinetic correction of intoxication selected from the group including: chemical binding of the toxic component; preventing the toxic component from binding to the toxicity receptor; accelerating the elimination of the toxic component and / or its toxic metabolite from the body; acceleration of the release of the toxic component from the organs and tissues occupied by it (brain, lungs, etc.); prevention of toxicity of the native toxic component; increasing the water solubility of the reaction products of the toxic component or its metabolite with the active substance of the agent according to the invention; reduction of ethanol toxicity caused by the presence of a toxic component or toxic components of surrogate alcohol; improved excretion of the toxic component; prevention or reduction of toxic effects on the functioning of the respiratory chain of mitochondria. 6. The use according to any one of claims 1 to 5, in which at least one active substance is selected, selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid , amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral, metal ion source, protein, and mixtures thereof. 7. The use of at least one vicinal dithioglycol of formula (1) for the prevention of intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1 or 3 carbon atoms , or 4, or 5. 8. The use according to claim 7, characterized in that at least one vicinal dithioglycol of formula (1) is administered enterally. 9. The use according to claim 7, characterized in that at least one vicinal dithioglycol of formula (1) is used as an antidote for the prevention of intoxication caused by at least one toxic component of an alcohol-containing liquid and / or alcohol substitute. 10. The use according to any one of claims 7 to 9, providing at least one effect associated with the risk of intoxication selected from the group including: prevention of the occurrence or development of acute or subacute intoxication caused by a toxic component when it may enter the body; preventing the occurrence or reduction of the rate of development of subchronic or chronic intoxication with repeated or regular intake of alcohol-containing liquids containing a toxic component in a toxic dose or alcohol substitutes; reduction in the severity of intoxication with the possible intake of a toxic component; increase in the threshold level of concentration toxicity; effect on the concentration factor in the direction of reducing toxic concentration; effect on the concentration factor in the direction of reducing the amount of toxic component in the brain; decreased exposure to the toxic component (time factor); decreased body sensitivity to a toxic component; strengthening detoxification functions of the liver and kidneys with their premorbid lesions (reduction in situational toxicity); reduced risk of the occurrence and severity of the development of endotoxic shock. 11. The use according to any one of claims 7 to 10, in which at least one active substance is selected, selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid , amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral substance, metal ion source, protein, and mixtures thereof. 12. A method for the prevention of intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1, 3, 4, or 5 carbon atoms, comprising enteral administration of at least one vicinal dithioglycol of formula (1). 13. The method according to item 12, in which at least one active substance is added, you - 15 018359 selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid derivative, organic acid derivative, lipid, physiologically active peptide, amino acid, amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral, source of metal ions, protein and mixtures thereof. 14. A method of treating intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1, 3, 4, or 5 carbon atoms, comprising enteral administration of at least one vicinal dithioglycol of formula (1). 15. The method according to 14, in which additionally introducing at least one active substance selected from the group comprising vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid, amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral, metal ion source, protein, and mixtures thereof. 16. A method of treating intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1, 3, 4, or 5 carbon atoms, including enteral and parenteral the introduction of at least one vicinal dithioglycol of the formula (1). 17. The method according to clause 16, in which at least one active substance selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid, amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral, metal ion source, protein, and mixtures thereof. 18. A method of treating intoxication caused by at least one toxic component of an alcohol-containing liquid and / or an alcohol substitute, said toxic component being an alcohol or an alcohol derivative having 1, 3, 4, or 5 carbon atoms, comprising parenteral administration of at least one vicinal dithioglycol of formula (1). 19. The method according to p. 18, in which at least one active substance is selected, selected from the group consisting of vitamin, vitamin precursor, vitamin derivative, organic acid, organic acid derivative, lipid, physiologically active peptide, amino acid, amino acid derivative, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivative, coenzyme precursor, carbohydrate, mineral, metal ion source, protein, and mixtures thereof. 20. A method of treating intoxication according to any one of claims 16-19, comprising introducing at least one vicinal dithioglycol of formula (1) into the portal vein and / or umbilical vein by intraportal or transumbilical infusion. 21. The method according to any one of claims 12-17, wherein the enteral administration is by oral administration of the dosage form. 22. The method according to any one of paragraphs.14-17, in which the enteral administration is carried out using a probe. 23. The treatment method according to any one of paragraphs.14-19, in which additionally carry out a complex of detoxification measures: toxicokinetic correction and / or toxicodynamic correction. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2