KR20090081434A - 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

Agents and methods for preventing and treating intoxication by alcohol-containing liquids and alcohol substitutes

FIELD OF THE INVENTION The present invention relates to the field of medicine and to applications as prophylatic agents in the case of the use of pharmacology used in the field of toxicology and also in the household use of alcoholic beverages at risk of poisoning.

Increased intoxication associated with voluntary use of alcoholic beverages and alcohol-containing beverages and misuse of alcohol surrogate, intentionally or accidentally, has become a serious medical-and-social problem. According to official data, tens of thousands of deaths are caused by this poisoning every year in the Russian Federation alone. Typically, medically registered addiction cases are caused by using some toxicants with ethanol, which are often added to beverages or are not intended as edible substances because of inadequate tablet quality, but are added to beverages. Non-ethanol alcohol additives are known to enhance ethanol toxicity when used in the composition of beverages that are generally acceptable for ingestion.

The present invention aims to develop a method and means for solving a problem in this field.

For clarity of understanding the following text, terms used in the field of the invention are specified herein.

Alcohols (or spirits) are hydrocarbon derivatives formed by replacing hydrogen atoms with hydroxy (OH) groups. The term "alcohol" is understood herein as all kinds of alcohols: monoatomic or polyatomic, alipathic or alicyclic, with any carbon chain length. Alcohols or their actual isomers. The term "alcohol" may refer to alcohols having different functional groups, that is, amino alcohols, halogenated alcohols, thioalcohols, and the like.

In addition, ethers of many alcohols, such as cellosovle, will be reviewed herein.

Overall, addiction contemplated herein is defined as Class XIX, Group T in accordance with the World Health Organization (WHO), Permitted International Classifications for Diseases (ICD), 10th Amendment (ICD-10). -51, T-52.

Typical toxicants to be considered in the present invention and the poisoning resulting therefrom are specifically as follows:

Monohydric alcohol (alkanol):

Methyl alcohol (methanol, carbinol, wood alcohol CH ₃ OH;

According to ICD-10, its toxic effects are classified into the T-51.1 group;

Ethyl alcohol (ethanol, wine alcohol) C ₂ H ₅ OH; Ethanol is not considered a self-dependent toxicant in the present invention, but when combined with other toxicants, its toxic effect is increased, specifically modified and caused by ethanol when combined with other toxicants. Poisoning is found to be within the field of the present invention; According to ICD-10, its toxic effects belong to the T-51.0 group;

Propyl alcohol (specifically, normal propanol, isopropanol, or propanol-2 or secondary propanol; petrohol, perspirit) C ₃ H ₇ OH;

According to ICD-10, its toxic effects belong to the T-51.2 group;

-Butyl alcohol (primary n-butanol, or butanol-1, or n-propylcarbinol; secondary n-butanol, or butanol-2, primary isobutanol, tertiary butanol) C ₄ H ₉ OH;

According to ICD-10, its toxic effects belong to the T-51.3 group;

Amyl alcohol (eight isomers are present, most suitable for application are normal amyl alcohol, or pentanol-1, or n-butylcarbinol) C ₅ H ₁₁ OH;

According to ICD-10, its toxic effects belong to the T-51.3 group.

2. Dihydric alcohols (glycol, alkanediol):

Ethylene glycol (ethanediol-1,2) CH ₂ OHCH ₂ OH;

Propylene glycol (propanediol-1,2) CH ₃ CHOHCH ₂ OH;

According to ICD-10, its toxic effects belong to the T-52.3 group.

3. polyhydric alcohol:

Tetrahydrofurfuryl alcohol

(Tetrahydrofuran spirit, tetrahydrofuryl alcohol)

CHCHCHC (OH) CH ₂ O

Furfural (furan aldehyde)

According to ICD-10, its toxic effects belong to the T-51.8 group.

Toxic effects of other toxins related to the present invention belong to groups T-51.8 and T-51.9 and to groups T-52 (all in accordance with ICD-10).

For the above toxic substances, the widest range of industrial applications are listed below:

Methanol is used in the paint and varnish industry or for the denaturation of ethyl alcohol.

 Ethanol is used for the production of alcoholic beverages in a variety of fields (the main subject of the present invention).

Isopropyl alcohol is used for the production of antifreeze. Propyl alcohol is used as a solvent for synthetic resins, essential oils and the like.

Butyl alcohol is used for the production of hydraulic fluids, and is also used as a solvent in many industrial fields and various organic synthesis.

Primary n-amyl alcohol is a basic component of the so-called fusel oil, which appears to be a kind of oily liquid, a mixture of distillation end products of alcohol-containing yeast fermentation products.

Tetrahydrofurfuryl alcohol is used as an anticrystallizer and also in various organic synthesis.

From a chemical point of view, the production of ethyl alcohol by sugar fermentation of yeast, in which sugar is fermented by zymase, is a multistage sugar decomposition process by a catalyst to form alcohol and carbon dioxide. To ensure the life cycle of the yeast, sources of biologically available nitrogen and phosphorus are added to the fermenting liquor solution (or brew), which in addition to ethyl alcohol, It results in the formation of methyl alcohol, propyl alcohol, isobutyl alcohol, and isoamyl alcohol, optionally active amyl alcohol (2-methyl butanol-1). Except for the first, all of these together are called fusel oils. In addition to alcohols, the composition of the so-called volatile admixtures with ethyl alcohol includes aldehydes, acids, and ethers in the brew. Indeed, it is practically reliable that during the distillation and fractionation of the resulting aqueous alcohol solution, it is impossible to completely purify the aqueous ethyl alcohol solution from other spirits and some other volatile mixtures. At the same time, the final ethanol solution in water obtained is determined by the quality and composition of the other residual alcohols (the lower the quantity, the higher the quality of the final product). In addition, the final product inevitably contains an amount of aldehyde which is formed simultaneously during the fermentation process. It is important to consider that many alcoholic beverages (eg beer) do not undergo any distillation step after fermentation.

Thus, in many cases, drinking alcoholic beverages is directed to ethanol itself and its metabolites by administering to the subject a toxic mixture in the form of other alcohols, their aldehydes, and toxic mixtures of ethers and other toxic mixtures and their metabolites. It will be understood that intoxication may be accompanied.

The term "alcohol surrogate" (AS) is understood as an inadequate substitute for alcoholic beverages that are acceptable for ingestion. Conditionally, this term may refer to two groups of beverages: beverages based on potable ethyl alcohol, or industrial ethyl, where the first group has not performed sufficient purification procedures to obtain quality according to the criteria. Alcohol-based liquids (so-called “true” substitutes); The second group includes liquids which do not contain ethyl alcohol or which contain a mixture of ethyl alcohol with other hydrocarbons, including alcohols and / or derivatives thereof, which are specially prepared.

The first group specifically includes:

Hydrolyzable and sulfurous alcohols (ethanol produced by hydrolysis of wood)

Denatured alcohols (technical alcohols mixed with methanol and aldehydes)

Crude alcohol (distillate of fermented biomass including ethanol and fusel oil)

Cologne water, lotions, other perfumes and cosmetic liquids (ethanol solutions with added essential oils and / or other ingredients)

-Impure alcoholic beverages made on the basis of poor quality ethyl alcohol

-Polishing liquids (a mixture of industrial ethyl alcohol and butyl and amyl spirits, chloroform, acetone, etc.)

-Other liquids (adhesives, lacquers, etc.)

The second group specifically includes:

Alcohol (alcohol other than ethyl alcohol)

-Aldehydes, ketones

Alcohol ethers

Derivatives of the aforementioned compounds

Industrial liquids prepared on the basis of compounds mentioned above.

The hallmark of poisoning by AS is in general the fact that the product of the biological transformation of the first poison in the individual is found to be more toxic than the parent compound. Specifically, methanol, ethylene glycol and ethers thereof, tetrahydrofurfuryl alcohol and the like are initially referred to as initially less poisonous substances. Substances having such characteristics are often referred to as toxifiable, and the process itself is a substance that is more toxic than native poisons during metabolism, affecting addiction properties and severity. It is referred to as "poison toxification", which means the possibility of forming in an amount that affects. According to alternative terminology, the process of biological conversion of such circular poisons is called "lethal synthesis".

In the present invention, the term "toxicant" means one or more substances selected from the group comprising:

Alcohols (except ethyl alcohol, or ethanol)

Alcohol derivatives

Alcohol substitutes

Intoxication (or toxicosis) is a pathological condition caused by abnormalities in chemical homeostasis due to interactions between the individual's various biochemical structures and toxic substances of foreign or intrinsic origin. The term "intoxication" refers to a complete process of intoxication that occurs after the first symptoms and up to a complete clinical pattern of the disease, the content of which is the specific biochemical interaction of the primary receptor, that is, the toxic substance (toxic), with selective interactions. It depends on the physiological function of the toxicity of the construct. Exogenous intoxication is commonly referred to as poisoning, distinguished from endogenous intoxication (autointoxication) associated with the accumulation of toxic substances associated with its own metabolism in an individual.

The classification of addiction as a disease of etiology is based on three basic principles: etiopathogenetic, clinical and nosological principles.

In terms of causative pathology principles, the addictions examined in the present invention are:

For reasons of development, referred to as incidental and / or deliberate,

In terms of origin, it is generally referred to as domestic, more rarely industrial,

The path by which the poison enters the individual, referred to as oral administration, rarely, inhalation, even more rarely, transdermal delivery,

-By poison originating, referred to as exogenous poisoning.

Toxic poisoning, as considered in the present invention, can be classified as follows by the general pattern of onset, progression and termination of poisoning:

Acute, that is, after a single administration of a toxic substance to an individual, the pattern of clinical addiction rapidly progresses rapidly, ending with recovery or death,

Subacute, ie, after a single (or several short-term) administration of a toxic substance to an individual, the clinical development of intoxication proceeds in a decelerated manner, causing some durable damage to health. Addiction,

Chronic addiction, which addiction is repetitive, has a systemic nature, intermittently, is characterized by subtoxic dosages of less than a small level of toxic effects, naturally sustained effects and continuous Addiction, accompanied by injury-to-health symptomatology, characterized in that the symptoms are intensified and worsen periodically.

Depending on the severity, the addictions reviewed herein can be classified as follows: light, moderately severe, severe or lethal.

In the present invention, the term "intoxication" is understood to be the actual poisoning specified above, which is caused by the toxic substances described above.

The etiological factor of the corresponding intoxication can cause abnormalities in chemical homeostasis, i.e. disturb the natural system of disintoxication, which is intended to purify the individual from toxic substances of various origins. Alcohols and / or derivatives thereof, or other toxic substances that accumulate in toxic concentrations in a subject.

The pathogenesis of addiction by alcohol and alcohol substitutes (AS) is analyzed in two main aspects:

Toxicokinetic aspects (studying what is caused by toxins in an individual)

Toxicodynamic aspects (study of what happens to the individual under the action of poison)

Within the scope of toxicological studies, the following characteristics are identified:

The physicochemical properties of the poisons that determine their behavior in the individual: molecular weight, water solubility and solubility in fats, ionization capacity

A description at the molecular, cellular and organ level of the pathways entering and distributing the individual

The manner of discharge from the individual.

Within the scope of toxic epidemiological studies, the following characteristics are studied:

Toxinogenic effects of toxicosis associated with abnormalities in the physiological function of various biochemical structures that act as toxicity receptors, expressed by symptoms specific to the poison.

A somatogenic effect (systemic stimulation of the pituitary-adrenal system, shock response of blood circulation centralization) in the system of the general adaptive response of the individual to chemical trauma.

In this case, it should be taken into account that any type of intoxication, which is a chemical disease, always occurs on the basis of a clear physiological system, but depending on the result of its activity, acquires inappropriate pathological properties.

In the pathogenesis of addiction, there are several major factors selected:

1. Concentration factor, ie the molecular concentration of a toxic substance (generally, μg / ml) in an individual's biological medium, which is the expression of clinical symptoms and lethal concentrations at the toxic concentration of toxins in the blood. It is a guiding factor because it correlates with the occurrence of potential lethality in the concentration value (CL).

2. The time factor determines the dwell period, entry and rate of discharge of the toxic dose of the poison in the subject. This factor shows the relationship between the duration of toxic action and its toxic effects. Determining the kinetics of the concentration factor and time factor makes it possible to distinguish between the toxigenic phase, the somatogenic phase, and the period of absorption and removal of toxins in the toxin phase.

3. The space factor determines the space of distribution of the toxins associated with blood supply to organs and tissues, in terms of entry, exit, and many aspects.

4, age factor reflects the degree of individual's sensitivity to poisons in various age-specific periods of the human life, which susceptibility to a 10-fold decrease in resistance to toxic effects from infancy. Significantly changes until extreme old age.

5. Therapeutic factor is an individual for detoxication therapy performed that allows for a multiple increase in concentration thresholds for the development of major symptoms of intoxication and can significantly reduce the duration of the toxin generator. Determine the reaction.

Studying the pathogenesis of poisoning is based on the concept associated with toxic receptors as specific sites of poison realization and action.

In order to realize a biological action, a chemical is considered to have two or more specific properties: affinity for the receptor and inherent physicochemical activity.

The term "affinity" is understood as the degree of interaction of the substance with the receptor, which is measured by the amount, which is inversely proportional to the rate of separation of the "material-receptor" complex.

The degree of substance toxicity is defined by the minimum amount of molecules that can bind and phase out indispensable target cells. What is important is the number of receptors that become toxic and the degree of importance for the essential activity of the entire individual. Also important is the rate of formation of the "poison-receptor" complex, its stability and the ability to reverse separation, which may be a far more important factor than the degree of saturation of the receptor by the poison.

Toxic effects do not necessarily have strict selectivity, but can occur throughout the cell. This principle is confirmed in the action of many poisons, in which the common property is not an electrolyte. The term "non-electrolytic action" means any effect defined directly by the physicochemical properties of the heady or narcotic material that is characteristic of the poisons (alcohols) described herein. do.

Most of the substances belonging to the groups contemplated herein are characterized by the presence of specific membrane-toxin-actions realized by membrane-toxins. The latter feature is characterized by disorganization resulting in phospholipase activity, and disruption of the underlying liquid-crystal membrane structure, with additional cell loss.

Many studies have confirmed that under the intoxication with alkanol and alcohol substitutes, the direct mechanism of its membrane-toxic action, or the direct mechanism of its metabolites, is the peroxidation of lipids (POL). It became. The lipid peroxidation process of the intracellular membranes results in the exhaustion of the original antioxidative system (AOS) of the individual to obtain the properties of a chain reaction involving multiple cell loss.

Detoxification, one of the most important mechanisms of chemical resistance, is a complex of biochemical and biophysical reactions in individuals involved in maintaining chemical homeostasis, and includes several natural detoxification systems (exogenous and intrinsic origin), including Neutralization of toxic substances) is ensured by the cooperative action of:

Blood immune system (blood proteins and blood cells),

Liver detoxification system (microsomes and nonmicrosomal systems, comprising P-450 enzymes, in the composition of specific enzymes for the biological conversion of hydrophobic and hydrophilic substances). For the toxins of the present invention, such enzymes include alcohol dehydrogenase and hepatic acetaldehyde,

-System of secretory organs (gastrointestinal tract, kidney, lung, and skin).

The normal function of the overall system of natural detoxification provides a reasonably reliable purification of the individual from foreign and intrinsic toxicants if the blood concentration does not exceed a certain threshold level. Otherwise, accumulation of toxic substance molecules occurs in the toxic receptors, and poisoning patterns appear. The degree of manifestation, in many cases, depends on the combination of various factors and turns out to be much more toxic than the original material (methanol, ethylene glycol, etc.), and its biological conversion is toxic induction. It may be partially or wholly associated with the accumulation of metabolites that progress along the pathway of toxicity. On the other hand, the intensity of action of an toxic substance on an individual is determined by premorbid abnormality (situational toxicity) present in some of the major detoxification systems, primarily in the liver, kidney and immune system functions and in the elderly and Increased in older patients. In this case, the toxic effect develops at blood levels of toxins below the threshold.

In all cases where the threshold level of toxic load is exceeded, the need arises to stimulate or additionally maintain the function of the natural detoxification system for purification in an accelerated manner.

Toxic epidemiological effects of intoxication are expressed in specific symptomatology, the content of which depends on the clinical staging and the selective toxicity of the poison.

In the toxin production phase of acute toxicosis, which proceeds in the presence of toxic concentrations of toxins in the blood, attention is first focused on the specific symptoms of the disease, depending on the mode and functional role of the particular toxic receptor that interacts with that toxicant. do.

Under chronic intoxication, which is distinguished from acute intoxication, certain toxin symptoms appear quite late, after a long period of general somatic disorder.

Medical treatment of intoxication involves the combined performance of special therapeutic means performed in two main directions:

1) specific (detoxification action) to terminate further entry of toxic substances, to carry out accelerated release of toxic substances from the subject (efferential method of active detoxication), and if possible, to reduce the toxicity of the toxin. (C) apply pharmacotherapy to perform clear neutralization of toxins (toxicokinetic correction),

2) pharmacological protection and maintenance of the function of the individual, mainly affected by damage by toxic substances, ie symptomatic therapy and resuscitation aid (toxicodynamic correction).

The application of certain antidote (counterpoison agent) can immediately affect the toxic substance or its receptor, reducing toxicity, under certain modes of intoxication with clear selective toxicity.

The detoxification method in the somatogenic state is also aimed at eliminating endotoxicosis that occurs in the case of parenchymatous organ lesions (eg acute renal failure or liver failure).

In the toxic effects of alkanols, it is emphasized that both components are specific and nonspecific.

Nonspecific action is associated with traits of physicochemical properties and is regulated by the so-called non-electrolyte action (ie the action of the entire molecular material by the mechanism of presence). Non-electrolyte action is expressed by membrane fluidization and as a result, by showing abnormal function. Alkanol-inherent osomotic activity results in sensibilization of myocardium to adrenaline due to the displacement of liquids between different organs and tissues, inhibition of platelet aggregation, and the development of arrhythmias.

Clinical presentation of nonelectrolyte poisoning by alcohol and its metabolites is characterized by a kind of addicted (or dizzy) condition, a decrease in myocardium contractile capability, and intracellular metabolic disorders.

The most studied in laboratory and clinical conditions is the pattern of ethanol poisoning. Its ceretotoxicity, hepatotoxicity, cardiotoxicity, and nephrotoxic action, and toxic effects of synaptotropic and membranotropic nature have been established. In the following, these mechanisms will be briefly described and on the basis of which, by analogy, the characterization of the toxic effects of toxic substances contemplated in the present invention will be clarified.

Ethanol is produced by oxide reductase, that is, alcohol dehydrogenase (ADG) in the cytoplasm of liver cells (the latter being a specific NAD-dependent enzyme), liver microsomal ethanol oxidizing system, MSES), and tissue catalase, oxidase, and peroxidase. Oxidation of the alcohol results in the formation of aldehydes, ie acetic acid aldehydes. Acetic acid aldehydes are oxidized by FAD-containing liver enzymes, ie acetic acid aldehyde dehydrogenase (AcDH), to form acetic acid (ethanol acid), which is further metabolized to form CO ₂ and H ₂ O.

The implementation of ethanol toxic effects on the central nervous system (CNS) is triggered by the action and is regulated by the abnormalities of the functional mediator system, expressed as a membrane-acting event. Specific effects on gamma aminobutyric acid (GABA) and glutamatergic system alter the permeability and affinity of membrane ion channels, thereby changing the function of the neurotransmitter system.

In the biological conversion of ethanol, a large amount of recovered forms of acetic acid aldehyde, acetate and ADG-NADH enzymes are produced. Finally, that is the reason for the series of biochemical abnormalities caused by the introduction of ethanol. In the case of ethanol poisoning, the citric acid cycle is blocked by aldehyde acetate and no longer makes use of acetyl CoA, resulting in the formation of ketone species and altering the process of fatty acid synthesis. Thereby, metabolic acidosis develops. It is well known that large amounts of aldehyde acetate cause abnormalities in mitochondrial function in the respiratory chain, thereby distorting energy function. Based on this, abnormalities of myocardial function are formed.

In the opinion of the present inventors, it must be pointed out that ADG can catalyze the redox reactions that convert alcohols to aldehydes, and is useful not only for ethyl alcohol, but also for many other alcohols, and at least for them so-called toxic induction ( The phenomenon of toxication is described above. Another argument contributing to this reason is that under the toxicities of many alcohols, ethanol is used as a specific antidote, the effect of which is on the ability of ethanol to competitively inhibit alcohol dehydrogenase and consequently to prevent oxidation of this toxin. Is explained by. Such alcohols include methanol, aliphatic alcohols having a carbon chain length of up to 5 atoms, dihydric spirits, and ethers thereof having alcohol groups (glycol monoethers), ie alcohols and derivatives thereof. These are typical toxins in accordance with the present invention.

Thus, at least in the case of alcoholism by alcohol of alcohol, which is aldehyde oxidized by ADG, a relatively similar pattern of toxic effects on toxicants is observed.

Perturbation of cell membrane physicochemical properties, membrane damage by products by biological conversion of alcohol, increased cytoplasmic acid, disturbance of energy processes, activation of autolytic processes for cellular proteins and lipids, abnormal lipid metabolism, peroxide process Activation of the peroxide process is a characteristic feature of certain alcoholic actions. Based on this, necrotic and abnormal (fatal degeneration) changes occur in the cells of the most important organs.

The toxic effect of methanol is generally regulated by its metabolites, namely formaldehyde and formic acid. Formaldehyde itself is the most potent toxin, and its metabolites also disrupt the chains of oxidation and phosphorylation, causing metabolic acidosis and modifying the normal progression of many major biochemical processes.

In ethylene glycol intoxication, the products of its biological conversion, such as glyoxylic acid (after the first enzymatic conversion with ADG) appear sequentially; It is monoaldehyde, glycol aldehyde (after the second enzymatic conversion involving ADG), dialdehyde, then oxalic acid, glycolic acid. All substances in the class disrupt the function of the citric acid cycle enzymes. The aldehydes produced are toxiferous, accumulate in the subject for long periods of time, and in a system-wise manner the aldehydes can destroy essential individual functions.

This is because the ethylene glycol monoether undergoes metabolism of about the same route, and because ADG "attacks" its alcohol group, which converts the monoether to the related aldehyde. In addition, from ethylene glycol monoether, oxyacetic acid is formed, the presence of which also leads to cellular metabolic acidosis. Working together, these compounds lead to the development of hypokalemia and hypocalcemia, disrupt the normal metabolism of glucose, lactate, adenosine triphosphate (ATP) synthesis, and destroy the function of many enzyme systems.

At the cellular level, the processes described above are intended to cause a series of pathological abnormalities: homeostasis disorder (metabolic acidosis, water-electrolyte imbalance, hemocoagulation shift, and other disorders). Considered as a starting point, secondary syndromes: forming consciousness depression, central and aspiration-obturation breathing abnormalities, acute cardiovascular insufficiency, damage to parenchymatous organs, etc. do. On this basis, a number of processes are carried out with the risk of lethality. These processes include:

Acute respiratory distress (lack of ventilation and parenchymal failure),

Circulatory embarassment (decreased myocardial contractile capacity, toxic cardiomyopathy, hypopovolemic shock, and other reasons),

Cerebral disorder,

Damage and dysfunction of the parenchymal organs (liver, kidney, myocardium)

In the clinical pattern of AS-addiction, the following characteristic syndromes are selected:

Toxic encephalopathy,

-Abnormal breathing,

-Abnormal blood circulation,

-Addictive liver disease,

-Addictive nephropathy,

Homeostasis disorders (water-electrolyte balance, acid-base balance),

-Gastrointestinal disorders.

These syndromes are described in detail in the literature [Source 1: Luzhnikov E.A., Ostapenko Yu.N., et al. "Emergency status under acute poisonings" M., 2001). To date, in addiction caused by methanol, ethylene glycol, and other toxicants according to the present invention, ethanol has been applied as a specific antidote administered enterally and / or intravenously as a competitive inhibitor of alcohol dehydrogenase. [Source 1, pp. 155-156]. This method of treatment has significant drawbacks, as ethanol itself can degrade the function of the enzyme system and the parenchymal organs, which may lead to patient conditions, the ability of the patient's natural detoxification system, premorbid factor, and addiction. Requires thorough monitoring of severity and addiction stages.

It is an object of the present invention to prevent or block the occurrence of or reduce the rate of pathological processes caused by single use and repetitive, in particular prolonged systemic use, of alcohol-containing beverages containing toxic substances, in addition to ethanol itself. An efficacious agent is administered into the circulation. These toxins are present as a natural mixture in the production of alcoholic fermentation in the beverage. There may also be some other reasons for the presence of toxic mixtures in the beverage. It is also an object of the present invention to introduce into the field of toxicology effective methods and agents for the prevention and drug treatment of addiction caused by alcohols and their derivatives.

A given task is one or more vicinal dithioglycols of the general formula (I) and, if necessary, a pharmaceutically acceptable or alimentary agent, formulated with a carrier, designed for enteral or parenteral administration. Bisinal dithioglycols have R ₁ and R ₂ independently of radicals (-H), (-OM '), (-COOM'), (-SO ₃ M '), and (-O-CH). ₂ -SO ₃ -M '), (-PO ₃ M' ₂ ), (-PO ₂ SM ' ₂ ), (-PO ₃ M "), (-PO ₂ SM") and the symbol above M 'represents hydrogen or an alkali metal ion, symbol M "represents an alkaline earth metal ion, and m and n are independently selected from an integer of 0 to 5, meaning a substance of formula (1):

R ₁ (CH ₂ ) _n CH (SH) CH (SH) (CH ₂ ) _m R ₂ (1).

Compounds of formula (1) are known from the prior art available. His explanations and synthetic routes are described, for example, in Chemical Encyclopedia [Source 2: "Chemical Encyclopedia", M .: Soviet Encyclopedia Publishing House, 1990, v.2, p. 91-92. For vicinal dithioglycol (VD), the following compounds are specifically mentioned:

1. Dithioglycerol (dicaptol, dimercaptol, dimercaptopropanol, BAL (British anti-Lewisite) [BAL]) having the following formula:

(1)

(One)

2. 2,3-dimercaptopropanesulfonate Na ("Unithiol", DMPS) having the formula:

(2)

(2)

3. 2,3-dimercaptosuccinic acid ("Succimer", DMSA) having the formula:

(3)

(3)

4. 2- (2,3-dimercaptopropoxy) ethanolsulfonate Na ("Oxathiol") having the formula:

(4)

(4)

Bisinal dithioglycol is applied as a medicament with antiradiation activity and also as an antidote under poisoning with heavy metals and compounds thereof, in particular with poisoning with arsenic, lead, mercury [Source 3: Mashkovsky M.D. "Medications". M., 1993]. These are low-molecular weight compounds with two adjacent mercapto groups and because of this they are excellent traps for heavy metals, including radionuclides.

The use of these materials is known in the field of toxicology. Dimercaptol (BAL) and Unityol (DMPS) are applied as antidote under arsenic, bismuth, mercury, antimony, or zinc poisoning [Source 4: Shiebak VM, Panchenko LF, et al., "The Fundamentals of Clinical and Analytical Toxicology "(reference manual), edited by Prof. Tomilin V. V.// Moscow, 2002, p. 46]. Unityol (DMPS), succimer (DMSA), and other bisinal dithioglycols (VD) are antidote to so-called destructive poisons, including heavy metal salts, arsenic and compounds thereof, some phosphorus and chlorine compounds Is used. In the case of delirium alcoholism, acute alcoholism, and drug addiction, there is a known application of DMPS (unthiol) in combination therapy in combination with other antidote [Source 3]. In order to carry out a rapid alleviation of withdrawal syndrome of detoxification therapy, the application of unityol as one of his sweets is known [Source 5: "Alcoholism", edited by G.V. Morozov, M., Medicina Publishing House, 1985, pp. 314-321. VD applications are known to block or reduce the development of pathological processes in the progression of dependence diseases caused by the use of ethanol or other psychoactive substances (Russian Patent No. 2229221).

The present invention provides for the novel purpose of known materials.

Applicants have found that, after the initial enteral administration, bisinal dithioglycol (VD) unexpectedly shows a stronger effect under the known indicators listed above, and also after administration, in particular after oral administration, Visinal dithioglycols block the development of pathological processes, which appear to be due, among other things, to the use of ethanol-containing beverages and / or spirits with toxic mixtures, as well as alcohol-containing beverages containing alcohol substitutes. And / or unexpectedly found a new effect on inhibition. This effect is an unexpectedly discovered property of the proposed bisinal dithioglycol (VD) substance binding to the immediate metabolite of methanol, ethylene glycol, and other monohydric and polyhydric alcohols in vivo. Caused by. This effect is particularly strongly expressed because of the discovery of the specificity of this interaction, which is a substantial feature of the present invention.

The first feature is that the product of the interaction of the VD with the specified toxin cannot be separated under physiological conditions. That is, they have chemical resistance. In other words, in the body, the reaction proceeds irreversibly.

A second feature is the need for providing (as fast as possible, complete) administration of the substance (VD) proposed by the invention to the liver for significant and substantial expression of said pharmacological effect on the subject. In order to carry out this action, a suitable method is the enteral route of administration, or if the latter is disturbed, and equivalently, such as injection administration, which provides for the administration of the specified substance into the portal bloodstream. something to do. This effect is obtained in particular under intraportal infusion of VD or under intraportal or transumbilical infusion.

A third additional feature is that when a toxic substance such as an aldehyde derived from alcohol reacts with the water-soluble bisinal dithioglycol, the reaction product becomes water soluble and obtains the ability to be excreted from the kidney into urine. This is very important for carbon chain lengths having three or more atoms, starting with propanol, so that the water solubility of this aldehyde is low and decreases with increasing chain length. Because of this behavior, the agents and methods proposed herein have become active agents and methods of centrifugal detoxification, apart from the fact that they are agents and methods of detoxification pharmacotherapy; They not only accelerate the removal of toxins, but also allow to carry out toxic emissions through the kidneys. The same process applies to the release of ketones. Inclusion of the kidneys in the process of toxic excretion advantageously affects the concentration factor of the onset.

A fourth, additional feature is below. Because of suitable physicochemical properties, alcohol overcomes the histohematogenous barrier and is uniformly distributed throughout the organs and tissues. The alcohol then undergoes biotransformation therein, whereby the aldehyde is converted in the first step. Aldehydes are more toxic and have greater reactivity than alcohols. Aldehydes react with plasma proteins and terminal groups of blood cells, enzymes and other elements to modify their function (by which immunity, hemostasis, respiration, CNS, myocardium, energy function and many others are affected). In other words, the toxic receptors of aldehyde are much more diverse than the toxic receptors of alcohol. Unlike alcohols, aldehydes are much slower in overcoming the tissue-blood barrier, resulting in their accumulation in organs and tissues, where alcohol metabolism is initiated (ie, the first stage of alcohol oxidation). At the same time, aldehyde oxidation takes place under the action of liver enzyme-aldehyde dehydrogenase. As mentioned above, further aldehyde oxidation is hindered in organs and tissues outside the liver, which enhances exposure to aldehydes (time factor) and toxic effects. This problem is particularly expressed in people in the Mongoloid race, in an acute manner, because they have genetically predetermined lowered aldehyde dehydrogenase activity. Application of the medicaments and methods according to the invention makes it possible to find new solutions to the problem. It is noted that after administration of the active substance (VD) according to the invention to the liver, binding of aldehyde occurs. This leads to an equilibrium shift in the reversible reaction "alcohol-aldehyde". Then, according to the Le Chatelier principle, the system reacts to it by enhancing alcohol oxidation and consequently by reducing its concentration in the liver. According to the same principle, this leads to additional outflow of alcohol and inflow into the liver from other organs and tissues to restore concentration. If the presence of VD is maintained in the liver, the new aldehyde obtained by oxidation of the alcohol introduced into the liver is bound again and the cycle is repeated. The application of the substances according to the invention thus lowers the toxic load on all organs and tissues, since these substances promote the rapid release of toxic substances from vital organs and tissues. In view of the development of intoxication, it is important to start this kind of pharmaceutical treatment as soon as possible. The cycles disclosed herein, which are realized under conditions that maintain the entry of the active substance (VD) according to the invention into the liver, are referred to by the applicant as the 'cycle of alcohol-aldehyde detoxication'. It is referred to. It is noted that CAAD is realized even after prophylactic VD administration. Thus, CAAD exerts a beneficial effect on both temporal and spatial factors in the pathogenesis of intoxication.

Accordingly, Applicants have the ability to detoxify an individual in the body from alcohol and its metabolites, known as serious poisons such as methanol and aldehydes, propyl, butyl and amyl alcohols and their aldehydes, dihydric alcohols and their aldehydes and monoethers, and dialdehydes. And based on this, a new class of pharmacological activity of bisinal dithioglycols has been discovered (first essential feature) in the ability to use them as specific antidote under this poisoning. A second essential feature of this new purpose of use is the method of administering bisinal dithioglycol, and the liver is the place where toxic metabolism and its toxicity are mainly induced, so full and rapid administration to the liver should be ensured. . The optimal solution is then directed to enteral administration, or where the patient condition requires with or instead of the drug administration into the portal bloodstream or economic versus administration. Based on this, the applicant provides a method and a medicament for the prevention and drug treatment of intoxication caused by the above-described toxic substances.

Explanation of Technical Results

In the following, the use of typical poisons contained in ethanol solutions intended for home use, specified by group, or the malusage of alcohol-containing beverages, which also contain toxic mixtures, and also the use of poisons contemplated herein. Listed are the effects (i.e. technical results) achieved by the proposed medicaments and methods identified as being associated with.

Group 1: Toxicokinetic correction theory

-Chemically binds toxins;

Prevent the binding of toxic and toxic receptors;

Accelerate the secretion of toxicants and / or their toxic metabolites from the individual;

Accelerate the release of toxins from organs and tissues (brain, lungs, etc.) occupied by them;

Prevent toxication of circular toxins;

Increase the water solubility of the reaction products of the toxic or metabolites thereof and the active substances of the agents according to the invention;

Reduce ethanol toxicity, caused by the presence of toxins of alternative alcohols;

-Increase toxic emissions;

Prevent or reduce the toxic effects on the function of the respiratory chain mitochondria.

Group 2: Toxicodynamic correction theory

Recovery of functional parenchymal organs;

Restoration of a functional neurotransmitter system;

Recovery of CNS function;

Restoration of the energy-energetic function of the cell.

Group 3: Prevention

To prevent the development or progression of acute or subacute intoxication caused by toxic substances after potential entry into the subject;

Subtoxic doses prevent or reduce the rate of progression of subchronic or chronic poisoning upon repeated or regular use of toxic or alcohol containing liquids with alcohol substitutes; ;

-Reduce the severity of intoxication under possible ingestion of poisons;

Increases the threshold level of concentration toxicity;

-Influence concentration factors to reduce toxic concentration values;

Affect concentration factors to reduce the amount of toxins in the brain;

Reduce toxic exposure (time factor);

Reduce the individual susceptibility to toxicants;

Enhance liver and kidney detoxification function (preventing situational toxicity) under premorbid damages;

Reduces the risk and severity of the occurrence of endotoxin shock.

Since Applicant has discovered novel properties of the compounds of formula (1), one further aspect of the invention is one or more visi as an agent which prevents the occurrence or progression of intoxication after ingestion of one or more toxic substances according to the invention. Application of raw dithioglycol. This object is novel because it is not based on the known detoxification, antioxidant properties of these substances. In addition, the use of VD as an active agent for the preparation of a medicament, formulated in a dosage form or in a non-dosage form, which is applied for the prevention or medical treatment of poisoning caused by the toxin according to the invention. The purpose of things is also new. Such medicament means a composition and may also include other active ingredients. By formulated form, they may be liquid or solid medicaments for dose or parenteral administration.

Bisinal dithioglycol can terminate the free-radical destruction process of the biomembrane, in particular, they protect the myeline oxone layer from damage, hepatocytes, blood vessels, and Protect brain structures. Based on the aforementioned behavior of bisinal dithioglycol, its administration would block or reduce the damaging effects on myocardial tissue, pancreatic gland, vasculature, CNS, and other organs and systems of the individual. Can be.

The foregoing and other effects on the process associated with the pharmacological effects of toxic administration of bisinal dithioglycol enable the presence of effects listed above and representative of the technical results of the claimed solutions.

According to the invention, the toxic effect of toxic administration is expressed by the effect on the individual's multiple organs and systems, ie these toxic effects result in the simultaneous initiation or activation of a series of pathological processes. Since the aforementioned properties or behavior of bisinal dithioglycol are possible, the latter may have a beneficial effect on all such pathological processes, but this effect may be exerted or implemented simultaneously but by different degrees of expression. Can be. The degree of manifestation of his influence on a particular pathological process depends first of all on the stage of performance. The occurrence of certain processes can be blocked by prophylactic administration of a medicament according to the invention and other pathological processes already disclosed can be inhibited by administering these medicaments. The influence of expression on a particular pathological process, controlled by the toxic effects of toxic administration, is also dependent on the dosage, individual physical and other properties of the drug according to the invention, the tactic of the drug, the toxic load. , And other factors.

Applicants have found that the physiologically beneficial effects described above are expressed to a particularly strong extent upon oral administration of the medicament. This phenomenon appears to be associated with a high rate of entry of the active substance into the liver and some features of the interaction between the substance and the liver enzymes. Less important effects can also be observed in topical administration via oral mucosa, nasal and inhalation administration.

The effects described above greatly expand the properties of bisinal dithioglycol known until the present invention. Their known detoxification activity is used for the relief of acute abstinen conditions, ie for the treatment of people suffering from alcoholism. Unityol treatment of delirium alcoholism is being performed on patients suffering from alcoholism of the third stage characterized by the presence of severe psychogenic diseases. Known antioxidant activity also well complements the novel ability of bisinal dithioglycol. Previously, Applicants have shown that bisinal dithioglycol may alleviate the severity of a dometic level hangover (or alcohol withdrawal syndrome) condition, which indicates a detrimental effect of ethanol use, which occurs the day after ethanol administration. Confirmed. This effect is caused by the activity of VD on aldehydes in vivo (Russian patent 2157647 C1, 2000). Currently, based on the newly discovered effects in experiments, the effect of bisinal dithioglycol as the active ingredient is expressed after their administration, for example, several weeks before taking AS (medication course), or This occurs separately from the fact that the AS is used for prophylactic administration for days or hours. The same applies to other toxics. It is important to note that the applicant has established the action of bisinal dithioglycol on the common link of the development of intoxication by alcohol and its metabolites of various origins.

Thus, there is ample reason to draw conclusions about the properties of known bisinal dithioglycols and the synergies of the above-mentioned properties, which makes it possible to recommend applications for novel purposes of bisinal dithioglycols. .

Pharmaceutical formulations of the proposed medicaments include enteral administration, specifically oral administration, administration via probes, nasal administration, topical (including transbuccal administration and subligual administration) through the oral mucosa, Or formulations suitable for administration by inhalation or by injection. The proposed medicament may have a formulation of a solution for administration by injection. In this case, an infusion solution is prepared by combining the proposed active substance according to the invention with suitable liquid components and by mixing them by a suitable manufacturing facility. Pharmaceutical formulations may be in composition, may be presented in the form of convenient separate dosage units, and may be prepared by methods well known in the art of pharmacy. All such pharmaceutical methods include the step of combining the active substance with a liquid carrier or a finely divided solid carrier or both if necessary, and then, if necessary, shaping the product into the desired form. Is followed.

Pharmaceutical formulations suitable for oral administration may be in the form of discrete unit dosage forms, such as tablets, capsules, cachets, or formulations of powders or granules, or solutions, suspensions or emulsions, each containing a predetermined amount of the active ingredient. It may be provided in the formulation of an emulsion. The active ingredient may also be provided in the form of a bolus or paste, or in its pure form, ie, in a carrier-free form. Except for the additional physiologically active ingredients, tablets and capsules for oral administration may also include generally acceptable additives such as binders, fillers, lubricants, fluffs, moistening substances. Tablets may be made by compression or casting, optionally with one or more additional ingredients. Compressed tablets are suitable by pressing the active ingredient into a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, dispersant, etc. in a suitable machine. Can be manufactured in a machine. Molded tablets may be prepared by mold-casting a mixture of powdered compounds in a wet state with an inert liquid diluent. Tablets may be coated by a shell according to methods well known in the art. Liquid oral formulations can be, for example, in the form of aqueous suspensions, oil suspensions, solutions, emulsions, syrups or elixirs, or in the form of dried products for mixing with water or other suitable solvent prior to use. Can be. Apart from the additionally introduced physiologically active ingredients, this liquid preparation also contains suspending agents, non-aqueous solvents (which may include edible oils), flavor additives, fragrances, colorants, or preservatives. It may include generally acceptable additives such as. The formulations described above may optionally be prepared to provide slow excretion or controlled excretion of the active substance contained therein.

Formulations intended for topical administration via the oral mucosa, eg, via the buccal mucosa or by sublingual route, may be carbohydrates such as saccharose, acacia, or tragacanth. Lozenge containing the active ingredient in the base) and pastille containing the active material in the base such as gelatin, glycerol, carbohydrates, acacia and the like. For intranasal administration of the active ingredients described above, they may be used in formulations such as aerosols, pulverizable powders, or drops. This drop may be prepared on an aqueous or non-aqueous base comprising one or more dispersing agents, solvating agents or suspending agents. Liquid aerosols are conveniently obtained from pressurized packages. For administration by inhalation, the compounds according to the invention can be obtained from convenient facilities for obtaining insufflators, inhalable pressurized packages, or other aerosol sprays. The package under pressure may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable gas. In the case of aerosols under pressure, the dosage unit can be determined by providing a valve for supplying a metered quantity to the spray.

Alternatively, for administration by inhalation or blowing of the substance according to the invention, a dry powder mixture, for example an active substance and a suitable powder-like base such as lactose, starch, Formulations of powder mixtures of talc may be applied. The powder composition may be provided in a single dosage form, for example in the form of a capsule, cartridge, gelatin or adhesive plaster package, into which the powder may be introduced therefrom by an inhaler or blower.

If desired, the above-described formulations adapted to provide sustained release of the active ingredient can be used.

The pharmaceutical agents according to the invention may also comprise one or more other active ingredients, and in general, their addition may enhance the action of the substances proposed by the invention, and in addition to the added ingredients and the invention Can contribute to elicit synergistic action of the compound. Active ingredients added include vitamins, vitamin precursors, vitamin derivatives, organic acids, organic acid derivatives, lipids, physiologically active peptides, amino acids, amino acid derivatives, enzymes, enzyme derivatives, enzyme precursors, coenzymes, coenzyme derivatives, coenzyme precursors, carbohydrates , Mineral substances, sources of metal ions, proteins, and mixtures thereof. For example, it may be advantageous to add amino acids, which are neurotransmitters such as glycine, γ-aminobutyric acid (GABA). It may be advantageous to add a source of metal ions because addiction by methanol, ethylene glycol and many other toxicants can cause hypocalcemia, disrupting the water-electrolyte balance and inducing tetanus in muscles. In this case, it is advantageous to add a source of divalent metal ions because some divalent metal ions such as magnesium, calcium and manganese play an important role by forming part of the coenzyme composition in the catalytic reaction by the enzyme. As mentioned above, the lack of modulator calcium and its metabolism toxic depression in many processes accelerate the development of many disease processes. Advantageous additives in the composition of the medicament according to the invention are lipids, in particular phospholipids such as lecithin, glycolipids, other hepatoprotectors, in particular vitamins such as α-tocopherol, Precursors, derivatives thereof, physiologically active peptides such as neuropeptides, and many other physiologically active substances known in the art to which this invention pertains.

Apart from the components partially listed above, a medicament according to the invention may include other ingredients, agents, which are considered to be conventional in this application and which are used for the formulation of a medicament specifically examined herein. . For example, a medicament for oral administration may include a flavourant or a structure-formative agent. In particular, preparations according to the invention with an emphasis on the prevention of intoxication can be prepared in pharmaceutical or non-pharmaceutical formulations, for example in alimentary products, in particular in the form of beverages.

Preferred formulations with small dosages are formulations containing an effective amount of the active ingredient according to the invention, or a suitable portion of the specified dosage, as described below.

In accordance with the present invention, in order to obtain a recommended subject, the above-mentioned medicament comprising an active ingredient in an effective amount is administered orally or in another convenient route at a daily dosage of 0.1 to 250 mg / kg (per kg of patient's body weight). Can be introduced. The level of daily dosage for the average adult is typically in the range of about 5 mg to about 10 g, and generally within the much closer limits of about 50 mg to about 2 g, with the most preferred range of 100 to 1 day. 1000 mg. For convenience of use, tablets or other formulations of medicaments, provided in separate units, contain such effective amounts or amounts in multiple amounts, for example, a unit from 50 mg to 1000 mg, generally about 200 It contains -500 g.

The medicaments according to the invention are preferably introduced orally in the correct dosages, and the respective substance dosages are administered according to the application instructions or expert recommendations. However, the amount actually applied will depend on a number of factors, including the individual's sex, age, weight, risk factors, concomitant conditions for ingesting toxicants, physical and psychological characteristics, and the like. Factors of the same kind are considered when determining the frequency and duration (rate) of administration of a medicament. The medicament may be used before or by another potential route (inhalation, inhalation) for the possible use of alcohol-containing beverages and / or for the administration of toxins to the individual, including the risk of poisoning, or by the use (or otherwise) of such beverages. Administration at regular intervals after the influx of toxic substances into the subject, or before and after the use of the beverage containing the toxic substances, or in different combinations, may be given in the form of courses. Can be. In this case, the aforementioned alternatives and other possible alternatives for adjusting the time relationship between the moment of administration of the medicament and the moment of using other administration of the alcohol-containing beverage or AS or toxicant may be partially combined with each other.

For parenteral administration, specially prepared infusion solutions are generally used. For their preparation, the active substances according to the invention are combined with a suitable solvent. As such a solvent, specially conditioned water can be used.

The following examples illustrate the nature of the invention but do not limit the scope of the invention as claimed.

Example 1. Unithiol tablet.

25 g of unityol (powder material), 5 g of lactose, 10 g of aerosil, 30 g of starch, 5 g of sodium starch glycolate, 5 g of magnesium stearate, 1 g of calcium pantothenate , 7 g of folic acid were mixed, the resulting mixture was wetted with water, thoroughly mixed, homogenized and compressed to give 0.5 g tablets.

Tablet formulation

ingredient weight% mg Unityol 28 140 Lactose 5.5 25 Aerosil 11 50 Corn starch 34 150 Starch sodium glycolate 5.5 25 Magnesium stearate 5.5 25 Calcium pantothenate 1.2 5 Folic acid 8 35 Wetting agent Balance

Example 2: Quick-dissolving capsules filled with granules, comprising

ingredient mg Dicaptol 50 Succimer 50 Unityol 100 Succinic acid 100 Calcium citrate 100 lecithin 50 Magnesium oxide 50 Pyridoxine Hydrochloride 50

Granules are prepared by techniques known in the art of pharmacology.

Applicability for the specified purpose was tested in laboratory animals. At the initiative of the applicant, a study of bisinal dithioglycol antidotal behavior (using unityol as an example) was performed.

Example 3 Experiments were performed on male rats of Wister-100 lineage having an initial body weight of 150-250 g. Animals were kept under conditions of artificial illumination (12 hours per day) and allowed free access to standard combination feed and water.

Animals were separated into four groups (three experimental groups and one control group). In each group, the following biochemical indicators were measured before the start of the experiment: biochemical blood indicators: triglycerides, liver enzymes: alanine aminotransferase (AlAT), or serum glutamic pyruvic transaminase (serum glutamic pyruvic) transaminase, SGPT), and aspartate aminotransferase (AsAT) indices of peroxidase process strength-thiobarbituric acid (TBA) -positive products (by test with thiobarbituric acid), individual's antioxidant system Indices of: urate, vitamin E, A; SH-group.

In the first experimental group (EG1), animals were intoxicated without prevention or treatment (toxicate); Placebo in gelatin capsule formulations were administered to these animals within 1 hour. In the second experimental group (EG2), 1 hour prior to induction of toxicity, animals received 150 mg of unityol per kg of body weight contained in gelatin capsules. In the third experimental group (EG3), animals received the same amount of unityol in capsules within 30 minutes after toxicity induction.

To induce acute poisoning with methanol, rats were orally administered with methanol in a 1 ml dose of aqueous solution.

Experimental results for these animals showed that the concentration of lipid peroxidation end products, TBA-positive compounds in plasma of toxic rats (EG1) was increased, and the concomitant group receiving unityol was applied. It has been shown to have a value that is reliably different from (EG2, EG3). The contents of major endogenous antioxidants-vitamin E, A, SH- groups were significantly reduced in EG1 rats. Comparison of the range graphs for all three groups of animals showed that a sharp reduction in vitamin E levels occurred in animals receiving only methanol and placebo. Animals receiving unityol with methanol maintained the average value of vitamin E at the value level in the control group. The same pattern was observed for changes in other endogenous antioxidants: vitamin A and SH-groups.

The activity of enzyme-markers (AlAT, AsAT) on injured liver cells proved to be significantly higher in EG1 than in the group receiving unityol. Comparison of the biochemical markers of EG2 and EG3 showed that EG2 animals that received Unitiol as a prophylaxis survived far better in toxicity. This was also confirmed in the observation of the animal, its behavior and reaction.

Twelve days after toxicity induction, the tissues of decapitate animals following the biological ethical guidelines showed that the greatest damage occurred in the tissues of EG1 animals. In lung tissue, focal infiltration, alveolar partition thickening and emphysema sites were clearly observed. In the myocardium, severe hyperemia of endocardial vessels, fragmentation of individual fibers was observed. In the liver, granular and drop dystrophy of liver cells, drastic hyperemia of central vein were observed, bicyclic cells, diffuse beam structure There was. The kidneys were least affected by the change, with some changes in the blood vessels and brain layers of some blood vessels.

In EG3 animals, similar changes were observed in tissues, but these changes were less pronounced: the liver was more intact and the ditrophic changes in cardiomyocytes were less pronounced; In addition, there was no site of emphysema in the lung. The largest change in tissue was identified in EG2 animals receiving Unityol as a preventive measure. In the liver under central venous hyperemia, granulotrophy was observed, but liver cells were more intact. There was local invasion in the lungs. Muscle cell wearing has been noted in myocardial tissue.

In this experiment, the results of histological studies enabled us to derive the effect that bisinal dithiol has therapeutic and prophylactic properties for acute intoxication with methanol.

Example 4 Experiments were performed on male rats of the Wister-100 lineage having an initial weight of 150-250 g. Animals were kept under conditions of artificial illumination (12 hours per day) and allowed free access to standard combination feed and water.

Animals were separated into four groups (three experimental groups and one control group). In each group, the following biochemical indicators were measured before the start of the experiment: biochemical blood indicators: triglycerides, liver enzymes: alanine aminotransferase (AlAT), or serum glutamic pyruvate transaminase (SGPT), And aspartate aminotransferase (AsAT) indicators of peroxidase process strength—by test by thiobarbituric acid—TBA-positive products, alkaline phosphatase, indicators of the antioxidant system of the individual: urate, vitamin E , A; SH-group.

In the first experimental group (EG1), animals were induced to toxicity without prevention or treatment; Placebo in gelatin capsule formulations were administered to these animals within 1 hour. In the second experimental group (EG2), 1 hour prior to induction of toxicity, animals received 150 mg of unityol per kg of body weight contained in gelatin capsules. In the third experimental group (EG3), animals received the same amount of unityol in capsules within 30 minutes after toxicity induction.

To induce acute intoxication with ethylene glycol, rats were orally administered single doses of ethylene glycol in 1 ml doses of aqueous solution.

Experimental results for the animals were obtained for the experimental group (EG2, EG3) subjected to unityol in the direction of increasing the concentration of lipid peroxidation end product, TBA-positive compound in plasma of toxic rats (EG1). It was shown that the result was reliably different from the results of the same experiment. The contents of major endogenous antioxidants-vitamin E, A, SH- groups were significantly reduced in EG1 rats. Comparison of range graphs for all three groups of animals showed a sharp decrease in vitamin E levels in animals receiving only ethylene glycol and placebo. Animals receiving unityol with ethylene glycol maintained the average value of vitamin E at the value level in the control group. The same pattern was observed for changes in other endogenous antioxidants: vitamin A and SH-groups. Alkali phosphatase levels were increased in EG1 animals.

The activity of enzyme-markers (AlAT, AsAT) on injured liver cells proved to be significantly higher in EG1 than in the group receiving unityol. Comparison of the biochemical markers of EG2 and EG3 showed that EG2 animals that received Unitiol as a prophylaxis survived far better in toxicity. In control animals, the indicators proved stable.

Twelve days after toxicity induction, the examination of the tissues of beheaded animals according to the biological ethical guidelines showed that the largest damage occurred in the tissues of EG1 animals. In lung tissue, local infiltration, alveolar wall thickening and distinct emphysema sites were clearly observed. In myocardium, severe hyperemia of endocardial vessels, and dystrophic changes have been observed. In the liver, granular and drop dystrophy of liver cells, central venous hyperemia were observed, but no largely diffused beam structure was observed. No visible changes were observed in the kidney, small intestine and pancreatic glands.

In EG3 animals, similar changes were observed in tissues, but these changes were less pronounced than in the EG1 group: the liver remained more intact and the beam structure was preserved; Dystrophic changes were less pronounced in cardiomyocytes; individual myocyte hypertrophy was observed, but there was no site of emphysema in the lungs, and the alveolar wall was thickened. The smallest changes in tissues were recorded in EG2 animals receiving Unityol as a prophylactic. In the liver under central venous hyperemia, granulotrophy was also observed, but liver cells were more intact. There was local invasion in the lungs. Muscle cell breakdown has been noted in myocardial tissue.

The results of histological studies in experiments with animal tissues have led to conclusions about the effect that bisnal dithiol has obvious therapeutic and prophylactic properties for acute intoxication with ethylene glycol.

Claims (25)

Has the following general formula (1) for the treatment of intoxication caused by one or more toxic components of the alcohol-containing liquid and / or alcohol surrogate, R ₁ (CH ₂ ) _n CH (SH) CH (SH) (CH ₂ ) _m R ₂ (1) In the above, R ₁ and R ₂ are independently a radical (-H), (-OM '), (-COOM'), (-SO ₃ M '), (-O-CH ₂ -SO ₃ M'), (-PO ₃ M ' ₂ ), (-PO ₂ SM' ₂ ), (-PO ₃ M "), (-PO ₂ SM"), wherein the symbol M 'is hydrogen or an alkali metal ion And the symbol M " represents an alkaline earth metal ion, and m and n are independently selected from integers from 0 to 5. The use of at least one vicinal dithioglycol. Use according to claim 1, characterized in that the at least one bisinal dithioglycol of formula (1) is administered enterally and / or by intra-portal or transumblical infusion. The method of claim 1, wherein the at least one bisinal dithioglycol of formula (1) is treated with a specific antidote in the treatment of intoxication caused by one or more toxic components of the alcohol containing liquid and / or alcohol substitute. Use, characterized in that used. 4. Use according to claim 3, characterized in that the at least one bisinal dithioglycol of formula (1) is administered by intestinal and / or by intra-portal infusion or by inflation. The method according to any one of claims 1 to 4, which ensures the achievement of one or more effects associated with toxicodynamic correction, selected from the group comprising: Recovery of function of parenchymal organs; Restore function of the neurotransmitter system; Restoration of central nervous system (CNS) function; Restoration of the energy energetic function of the cell; And / or to ensure the achievement of one or more effects associated with toxicokinetic correcction, selected from the group consisting of: Chemical bonding of toxicants; Prevention of binding of toxins and toxic receptors; -Accelerating the secretion of toxic and / or toxic metabolites thereof from the individual; Accelerating the release of toxins from organs and tissues (brain, lungs, etc.) occupied by the toxin; Prevention of toxicity of native toxicants; Increased water solubility of the reaction product of the toxic or metabolite thereof and the active substance of the agent according to the invention; Reduction in ethanol toxicity, caused by the presence of toxins of substitute alcohols; -Increase the emission of toxic substances; Prevention or reduction of toxic effects on mitochondrial respiratory chain function. Use of one or more bisinal dithioglycols of the general formula (1) of claim 1 for the prevention of poisoning caused by one or more toxic components of an alcohol containing liquid and / or alcohol substitute. Use according to claim 6, characterized in that at least one bisinal dithioglycol of formula (1) of claim 1 is administered to the intestine. 7. A specific antidote for the prevention of poisoning according to claim 6, wherein the bisinal dithioglycol of formula (1) of claim 1 is caused by one or more toxic components of the alcohol containing liquid and / or alcohol substitute. Use, characterized in that applied as. Use according to claim 8, characterized in that at least one bisinal dithioglycol of formula (1) of claim 1 is administered to the intestine. Use according to any one of claims 6 to 9 to ensure attainment of at least one effect associated with the risk of intoxication expression, selected from the group comprising: Prevention of the occurrence or progression of acute or subacute intoxication caused by toxic substances after potential entry into the subject; Preventing the occurrence of or decreasing the rate of progression of subchronic or chronic poisoning upon repeated or regular use of toxic substances at doses below the toxic dose, or alcohol containing liquids with alcohol substitutes; -Reduction of the severity of intoxication under possible use of toxicants; An increase in the threshold level of concentration toxicity; Reduction in concentration toxicity due to effects on concentration factors; Reduction in the amount of toxins in the brain due to effects on concentration factors; Reduction in toxic exposure (time factor); Reduction in susceptibility to toxicants; -Enhancement of liver and kidney detoxification function (pre-reduction of situational toxicity) under premorbid damages; And Reduction in the risk and severity of the development of endotoxin shock. A method of preventing intoxication caused by one or more toxic components of an alcohol-containing liquid and / or an alcohol substitute, comprising enteral administration of bisinal dithioglycol of formula (1) of claim 1. A method of drug treatment of intoxication caused by one or more toxic components of an alcohol-containing liquid and / or an alcohol substitute, comprising enteral administration of bisinal dithioglycol of formula (1) of claim 1 . A method of drug treatment of intoxication caused by one or more toxic components of an alcohol-containing liquid and / or alcohol substitute, comprising enteral and parenteral administration of bisinal dithioglycol of formula (1) of claim 1. A method of drug treatment of intoxication caused by one or more toxic components of an alcohol containing liquid and / or alcohol substitute, comprising parenteral administration of bisinal dithioglycol of formula (1) of claim 1. 15. The method of any one of claims 13 and 14, comprising administering one or more of the bisinal dithioglycols of formula (1) to the portal vein and / or the umbilical vein, i. E. A method of drug treatment of intoxication comprising intraportal injection or transumbilical injection. 14. The method of any one of claims 11, 12 and 13, wherein enteral administration is performed by application of an oral dosage form. The method of claim 12, wherein intestinal administration is performed by a probe. 18. The method according to any one of claims 12 to 17, wherein a combination of disintoxication means known in the art, ie toxicokinetic correction and / or toxicodynamic correction, The method of drug treatment further performed by. A pharmaceutical agent for the prevention of poisoning caused by one or more toxic components of an alcohol-containing liquid and / or an alcoholic substitute, comprising one or more active ingredients, wherein the medicament comprises one or more active ingredients A medicament comprising bisinal dithioglycol of 1). 20. A medicament according to claim 19, wherein said medicament is prepared in a dosage form suitable for oral administration. 21. A medicament according to claim 20, wherein said medicament is prepared in a dosage form or a non-dosage form. A pharmaceutical agent for the treatment of intoxication caused by one or more toxic components of an alcohol-containing liquid and / or an alcoholic substitute, comprising one or more active ingredients, wherein the medicament comprises one or more active ingredients of formula (1) A medicament comprising bisinal dithioglycol. 23. A medicament according to claim 22, wherein said medicament is prepared in a dosage form suitable for oral administration. 24. A medicament according to any one of claims 22 and 23, wherein said medicament is prepared in the form of a solid drug or in the form of a liquid drug. The method according to any one of claims 19 to 24, wherein the 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 ), A coenzyme derivative, coenzyme precursor, carbohydrates, minerals, sources of metal ions, proteins, and mixtures thereof.