RU2254858C1 - Agent eliciting hepatoprotective and anti-encephalopathic property for reducing alcoholic intoxication, prophylaxis and removing alcoholic intoxication and withdrawal syndrome - Google Patents

Abstract

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

Description

The invention relates to medicine and can be used both in a food orientation in the form of a biologically active food supplement, and in a pharmacological one to solve the problem of reducing the severity of intoxication, relieving alcohol intoxication and a hangover syndrome, to reduce the craving for alcohol, relieving encephalopathies, and as a hepatoprotector, including for pathologies not related to alcohol intake.

Intoxication and, especially, alcohol intoxication and the subsequent hangover syndrome are accompanied by the development of a number of severe subjective and objectively observed symptoms: discomfort, inadequate perception, headache, impaired formation of long-term memory, thirst, apathy (and sometimes hyperactivity), agitation followed by depression, impaired coordination of movements, a decrease in the reaction rate and a number of other deviations of varying severity of a psychological, neurological and somatic nature. Particularly noteworthy is the severity of developing, and with the systematic use of alcohol, transforming into chronic forms, hepato- and encephalopathies.

Acute alcohol intoxication and even more chronic alcoholization exacerbate many chronic diseases associated with neuroendocrine imbalance and weakened immunity, new and previously hidden diseases arise or begin to progress, the body's resistance to the effects of stress and extreme environmental factors decreases. Especially often and dangerous is a violation of the functions of the cardiovascular system, manifested in the development of ischemic and spastic changes in the blood supply of not only the heart muscle, but also the brain, almost all parenchymal organs and limbs, up to the phenomena of acute heart failure and organ ischemia. Often repeated alcohol intoxications are a direct cause of the expressive malignant course of hypertension and kidney and liver diseases, exacerbation of latent and progression of existing diabetes mellitus. Due to the fact that more than 90% of ethanol is oxidized in the liver and all acetaldehyde is also oxidized by the liver, it is this organ that takes the main toxic shock. In the case of the presence of characteristic liver lesions on the background of any chronic intoxication, including alcohol, cirrhosis develops. When the apparatus of acetaldehyde dehydrogenase is overloaded, especially in Mongoloids, acetaldehyde poisoning develops, which leads to both liver damage and brain damage. Finally, fluidization of cell membranes occurs, leading to disruption of the processes of excitation, inhibition and transmission of nerve impulses, disruption of thermogenesis and sleep, as well as damage and increased permeability of the blood-brain barrier, which dramatically increases the ingress of toxic endogenous products into the brain and significantly reduces the threshold of toxic perception ethanol.

Considering that 90% of the Earth’s Caucasian population use alcohol, and in Russia up to 40% of the male population suffer from alcohol addiction to one degree or another, the severity of the above problems is obvious. Moreover, due to adverse environmental conditions and poor quality of life in childhood, more than 30% of the population of Russia acquires various forms of liver pathology. Hence, the urgent need for finding funds to reduce and eliminate the consequences of alcohol intake is clear.

To date, the arsenal of funds is quite limited. At the household level, this is, first of all, an abundant snack, which ensures a decrease in the rate of ethanol intake and facilitates the oxidation of its products to carbon dioxide and water due to the additional maintenance of the energy and plastic exchange of exogenous substrates. Further, these are, as a rule, brines, coffee, fruit drinks, kvass and other food products that help to conduct partial detoxification of the body, increase diuresis, and restore hormonal balance. But the effectiveness of household products is clearly insufficient.

In the development of special means of protecting the body from alcohol, two main trends can be distinguished:

- the search for dosage forms that allow for emergency medical care (transfusions of hemodesis, protein-salt solutions and solutions enriched with amino acids and glucose, the use of clonidine, cytochrome C, cemanthan, etc.);

- the search for food or medicinal “over-the-counter” forms of correction used without medical supervision or in the form of biologically active food additives.

Currently, there is a biologically active food supplement “Antip” (trademark “Antipohmelin” and “RU 21”), manufactured according to the patent of the Russian Federation No. 2160589 dated 12/20/2000, which solves the tasks and is the closest analogue of the proposed tool. But it has significant disadvantages:

- due to the individual characteristics of metabolism, it helps only in 70-75%;

- low effect in relation to the restoration of active detoxification function of the liver;

- there is no pronounced decrease in encephalopathy, especially with the developed hangover syndrome;

- It is not effective enough to stop the developed hangover syndrome.

We can conclude that today there is no affordable non-infusion drug or food supplement that can not only remove the problems associated with an overdose of alcohol, but also effectively prevent the development of these problems before, during or after alcohol intake, while effective liver protection and preventing or removing encephalopathy. This is especially important when drinking low-quality drinks or mixtures of vodka with beer, etc.

In reality, this leads to the use as the most effective means of repeated use of alcohol (hangover), which is an obligatory step in the development of alcoholism.

The first problem solved by the present invention is to create a food composition in the form of a biologically active food supplement, suitable for reducing the degree of intoxication, prevention and removal of alcohol intoxication. The second task is to reduce the development and elimination of the pathological phenomena of the hangover syndrome. The third task is the possibility of effective exposure to the supplement before, during and after drinking alcohol at home, without qualified medical supervision. At the same time, the task of improving alcohol tolerance is being addressed. The fourth task is to increase the tolerance of the mixture of drinks. The fifth task is to increase the percentage of the population that responds adequately to the action of the additive. The sixth task is to increase the effectiveness of the action against the background of alcohol intoxication and a hangover syndrome, activation of the body's detoxification process. The seventh task is to protect the liver in case of any pathological effects, including alcohol. The eighth task is to reduce the severity of the phenomenon of encephalopathy.

These problems are solved by the proposed tool designed to reduce alcohol intoxication, prevent and relieve alcohol intoxication and a hangover syndrome, as well as prevent adverse effects on the liver and brain, containing components based on succinic, fumaric and glutamic acids, as well as at least one a component from B-group vitamins and a number of extracts and amino acids.

Compared with the closest analogue, the proposed drug acts on at least 90% of people, has higher detoxification properties, is able to quickly stop alcohol intoxication and a hangover syndrome, is a highly effective hepatoprotector, and not only with alcohol intoxication, but also with any pathological effects on the liver, as well as an antencephalopathic remedy. In addition, the new composition can significantly increase the stability of the product during storage, which is due, inter alia, to the exclusion of ascorbic acid.

It should be noted that the use of the described components separately, even in shock doses, did not lead to an equally tangible effect.

According to the claimed invention, a means for reducing alcohol intoxication, preventing and removing alcohol intoxication and a hangover syndrome, as well as for preventing adverse effects on the liver and brain, contains, as an active substance, in addition to components based on succinic, fumaric and glutamic acids, at least one vitamin B groups.

The tool may further comprise

up to 30.0 wt.% (in terms of dry extract) of at least one extract of medicinal plants selected from the group: extract of Schisandra Chinensis), Eleutherococcus (Eleutherococcus senticosus), sweet clover (Melilotus Officinalis), Rhodiola rosea (Rodiola rosea ), ginseng (Pulanna schin-seng Nees) and / or a mixture thereof;

up to 80 wt.% a substance selected from the group: L-carnitine, glycine, L-arginine, taurine and / or a mixture thereof;

up to 80 wt.% a substance selected from the group: methylsulfonylmethane, dihydroquercytin, dimethyl sulfoxide or a mixture thereof;

nicotinamide or nicotinic acid in amounts authorized by WHO.

The tool may further comprise a component selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, ammonium bicarbonate, ammonium carbonate, or a mixture thereof in an amount equimolar to the acid content.

The tool is a powder mixture, or granular mixture, or tablet, or capsule, or dragee.

The tool may also be a drink or an effervescent drink, while the components of the tool can be diluted in juice or a drink, including carbonated.

The tool may additionally contain up to 1000 wt.% Sweetener and energizer and / or filler selected from the group: sucrose, glucose, sorbose, sorbitol, fructose, saccharin, aspartame, xylitol, other sweeteners, aspartic acid, sodium aspartate, amino acids, sorbic acid , potato starch, corn starch and / or a mixture thereof.

The tool is used to reduce alcohol intoxication, prevent and relieve alcohol intoxication and a hangover syndrome by oral administration before, and / or during and / or after taking alcohol in the form of a powder, or granules, or tablets, or capsules, or dragees, or a drink , or bubbly.

The drug is administered by mouth no later than an hour before drinking or while taking alcohol, 25-5000 mg of powder or granules, or 1-10 tablets, or dragees, or capsules, or one glass of effervescent drink, and after taking alcohol, 50-10000 mg of powder or granules, or 1-20 tablets, or dragees, or capsules, or 1-3 glasses of a drink or an effervescent drink.

All constituent components are well understood and are standard components of food and pharmaceutical products.

The following examples do not limit the claimed invention, but merely illustrate it.

Example 1. (By the closest analogue). ANTIP tablets of 500 mg of 100 mg succinic acid, 100 mg sodium mono-L-glutaminate, 37.5 mg fumaric acid, 25 mg ascorbic acid and 237.5 mg glucose corresponding to RF patent 2160589 were used.

Example 2. Used tablets of the proposed product in 1000 mg of the composition:

- 300 mg succinic acid

- 200 mg of fumaric acid

- 200 mg sodium mono-L-glutaminate

- 150 mg of taurine

- 50 mg of L-arginine

- 25 mg L-carnitine

- 7 mg of dry Schisandra extract

- 45 mg glycine

- 0.5 mg of vitamin B1

- 0.6 mg of vitamin B2

- 0.6 mg of vitamin B6

- 21.3 mg of aspartame

The method of preparation is direct mixing followed by dry pressing.

Example 3. Used effervescent drink containing a mixture of 3000 mg:

- 600 mg of succinic acid

- 400 mg of fumaric acid

- 400 mg sodium mono-L-glutaminate

- 300 mg of taurine

- 100 mg L-arginine

- 50 mg of L-carnitine

- 15 mg of lemongrass extract

- 85 mg glycine

- 0.5 mg of vitamin B 1

- 0.6 mg of vitamin B2

- 0.6 mg of vitamin B6

- 300 mg of ammonium bicarbonate

- 723.3 mg of soda

- 25 mg of aspartame

The method of obtaining - direct dry mixing to obtain a mixture in a mixer type "drunk barrel". If necessary, the mixture is tabletted, or granulated, or packaged in powder form.

Example 4. Used dragee composition per 1000 mg of active principle:

- 150 mg potassium succinate

- 100 mg of fumaric acid

- 150 mg of a mixture of 2 parts of glutaminate sodium and 1 part of glutamic acid

- 150 mg of taurine

- 25 mg L-carnitine

- 25 mg glycine

- 300 mg sorbitol

- 0.2 mg of vitamin B1

- 0.3 mg of vitamin B6

- 99.5 mg fructose

The mixture is obtained by direct mixing, then moistened to 10 wt.% And granulated. The granules obtained are dried, calibrated and granules of average weight 100 mg are obtained. The resulting granules are pelleted using conventional technology.

Example 5. Used a powder composition weighing 1000 mg of the active components of the composition:

- 250 mg of ammonium succinate

- 200 mg of ammonium fumarate

- 50 mg of glutamic acid

200 mg methylsulfonylmethane

- 150 mg of taurine

- 50 mg of L-carnitine

- 30 mg of aspartame

- 0.5 mg of vitamin B1

- 0.8 mg of vitamin B2

- 10 mg of a mixture of nicotinic acid and nicotinamide 1: 1

- 8.7 mg of Rhodiola rosea extract

- 50 mg glucose

The mixture is obtained by direct mixing, then dissolved in grape juice to a mixture concentration of 5% per 1 liter.

Example 6. Used capsule containing 400 mg of the composition according to example 5.

Example 7. Studies of the proposed funds were carried out in two stages: preclinical (in animals) and clinical.

To compare the effectiveness of the proposed means and dietary supplements ANTIP, a study was conducted on rats of male Wistar breed weighing 190-230 g.

Test 1.

Initially, each animal was landed in a sealed exchange cage with a given air flow, and exhaled air was collected for 5 minutes for subsequent analysis for the content of endogenous 13CO ₂ . Then, 2.5 ml of water was intragastrically administered to each animal, supplemented with 1 mg of 13C-ethanol, and 8 air samples were collected over 120 minutes to determine the metabolic rate of the introduced ethanol to carbon dioxide using 13CO ₂ labeled carbon dioxide. The isotopic composition was measured by mass spectrometry. The data obtained were normalized by the maximum content of 13CO ₂ in exhaled air. An experimental curve was constructed for each animal and, using the Sigma-Plot nonlinear regression program, an approximation was made of the curve with a regression coefficient of at least 0.9967, and the parameters a, b, c were determined from the equation describing the 13CO ₂ excretion curve as a function of time t:

f = a · t ^b · e ^-ct

To illustrate the accuracy of the method, we give the values of the indicated parameters for one of the curves indicating the standard error of each parameter, the Student's t value and the level of p-probability (in this case, reliability) of determining each parameter:

a = 0.7272; Art. error 0.1653; t = 4.3985; p = 0.0046

b = 1.3195; Art. error 0.0842; t = 15,6798; p <0.0001

c = 0.0346; Art. error 0.0019; t = 17.7988; p <0.0001

For the subsequent characterization of the ethanol metabolism in each animal, the most reliable parameter c was used, which has the meaning of the coefficient of the rate of ethanol oxidation in animals: the higher the value of c, the higher the rate of ethanol metabolism.

The next day, the animal was injected into the stomach with 2.5 ml of an aqueous solution containing ethanol at the rate of 0.25 g per kg of body weight and 1 mg of 13C-ethanol (test with load). And again we determined the dynamics of exhalation and the curve of the removal of 13CO ₂ for the subsequent calculation of the value of s.

Then the animals were divided into groups.

In the first group, animals received an intragastric ethanol solution for 7 days at the rate of 2.5 g of ethanol per kg of body weight daily with a solution volume of 2.5 ml.

In the second group, animals were also sealed for 7 days, but Antipochmelin dietary supplement was added to the ethanol solution at the rate of 200 mg per kg of body weight.

In the remaining groups, animals were also sealed for 7 days, but the proposed compositions (one composition — one group) were added to the ethanol solution at a rate of 200 mg per kg of body weight.

After 7 days, the study described above was repeated - ethanol metabolism without load, and the next day, the study of ethanol metabolism with load was repeated.

The data obtained are summarized in table 1.

As can be seen from table 1, there is a significant decrease in liver function on the background of chronic sealing, however, when taking funds according to examples 2-6, liver function on the background of ethanol loading is restored completely, and partially without load (from 30 to 60%), while Antipohmelin does not have a significant effect.

Test 2.

With a normal liver, animals sleep an average of 18-20 minutes from the usual therapeutic dose of hexenal administered intraperitoneally. After double administration of 0.1 dose of LD50 of tetrachoride carbon, the duration of hexenal sleep increases by 2–3 times. Such a decrease in the detoxification function of the liver lasts about 1.5-2 months, if the animal does not die before. Carbon tetrachloride was injected into two groups of rats at the described dose, after which the animals were divided into groups: 12 rats, for each example, a group of 12 animals. In the experiment for each of the examples, hepatoprotector was started on the next day after the administration of carbon tetrachloride at a dose of 25 mg / kg body weight and the period of liver recovery after toxic hepatitis was determined by the duration of hexenal sleep. As can be seen from table 2, in the control and after 21 days its duration averaged 53.2 minutes, for example 1 the situation is better, but not significantly - 44.2 minutes. Examples 2-6 show the high efficiency of the proposed hepatoprotector, fully restoring liver function. At the same time, the restoration of animal appetite in the experiments of examples 2-6 was noted.

Test 3.

An isolated perfused Krebs-Henselight solution (all salts, as in plasma and 10 mM glucose), a section of the rat brain hypocampus was subjected to two types of damaging effects:

anoxic - by stopping the supply of oxygen to the perfusate,

and toxic - by adding 12 mM ethanol and 0.1 mM acetaldehyde to the perfusate.

After 10 minutes of perfusion, these effects caused a suppression of 60% (on average) of the electrical activity of the slices of the hypocampus. After 20 minutes of “damaging perfusion”, the initial composition of the perfusate was restored and the kinetics of restoration of electrical activity was observed for 60 minutes. After anoxic exposure after 30 minutes, 90% recovery was observed, after toxic exposure after 45-50 minutes, 80% recovery of electrical activity was observed.

When testing the drugs according to the examples, the final concentration of the drug in the perfusate was 0.2% (based on the fact that when taking 2 g of the drug and dissolving it in 5 l of circulating blood, the maximum concentration of the drug in plasma with hematocrit 40 can reach 0.5-0, 6%). The anoxic effect against the background of Antipochmelin caused 57% inhibition of the electrical activity of the slices of the hypocampus, while the toxic effect reduced the activity of the slices by 58%. After restoration of the initial composition (without the Antipohmelin preparation and without the “damaging effects”), after 30 minutes, a complete restoration of the activity of the hypocampal slices was not observed. When using the drugs in examples 2-6, the anoxic effect inhibited electrical activity by 10% and toxic activity by 15-20%, and 30 minutes after the end of the drug, the activity of the hypocampal sections was completely restored, which indicates the pronounced antiencephalopathic properties of the drugs according to the examples 2-6.

Tests on groups of volunteers to evaluate the proposed compositions for objective effectiveness

The tests were carried out under the following conditions:

As an alcoholic beverage, high-quality vodka “Gzhelka” of a single batch was used. When taking alcohol at home, it was allowed to take other alcoholic beverages according to individual preferences.

The assessment was carried out:

1) when taking 50 ml of vodka on an empty stomach (laboratory conditions),

2) when drinking at home without limiting the minimum or maximum dose,

3) when stopping a hangover the next morning after the maximum possible intake of alcohol at home.

All studies carried out objective monitoring of the condition of the subjects in terms of the dynamics of the rhythms of the electroencephalogram, electrocardiography, the volume of short-term and long-term memory, variational pulsometry and rhythmocardiography.

Additional biochemical studies were conducted to determine the state of carbohydrate metabolism, the degree of anaerobic activation of glycolysis, and the development of acidosis.

In the tests, Antipohmelin tablets (the closest analogue) and compositions in the form of marketable products were used according to the examples.

Test 4.

Under laboratory conditions, a group of volunteers of 12 people of both sexes (7 men and 5 women) who did not systematically drink alcohol, took 50 ml of vodka on an empty stomach. Two types of examination performed on an empty stomach:

a) with a preliminary intake in 60 minutes of each of the types of compositions in turn and without daily intake (2 tablets of “Antipohmelin”, 2 tablets or capsules according to examples, 3 g of “effervescent composition” in a glass of water) or 2 g per dry composition in juice;

b) with the reception similarly to the previous one directly with vodka or 30 minutes after taking vodka at will.

Each volunteer took vodka in laboratory conditions 7 times with an interval of a week: without drugs, from each of the compositions in turn before taking (a), from each of the compositions in turn during or after (b).

As can be seen from the data in table 3, the claimed tool significantly contributed to the improvement of objectively recorded parameters of brain activity, including the improvement of short-term and long-term memory, cardiovascular system, glucose homeostasis and ischemic changes, usually caused by alcohol. The detected positive changes characterize a significant decrease in the degree of intoxication when drinking alcohol on an empty stomach, despite the fact that the rate of utilization of ethanol increases sharply both with preliminary and subsequent administration of the proposed agent after 30 minutes.

Test 5.

When taking vodka at home (without limitation in dose), volunteers took the composition (4 tablets of “Antipohmelin”, 2 tablets, or capsules, or dragees, or 3 g of “effervescent composition” per glass of water, or 2 g of the composition in juice according to examples ) immediately before the feast or at the beginning of the feast. According to the agreement, each subject should drink at least 300 ml of vodka. The survey involved 12 practically healthy men aged 35-65 years who regularly drink alcohol (on average 1-3 times a week), but have no craving for alcohol and can lead a sober lifestyle for a long time.

The noted changes are shown in table 3.

Test 6.

The same group as in test 4, the same conditions for taking alcohol, but taking the compositions in the morning (6 tablets of “Antipohmelin”, 3 tablets, or 3 capsules, or 4 tablets, or 5 g of “effervescent composition” in a glass of water, or 3 g of the composition in juice according to examples).

The noted changes are shown in table 3.

For tests 4-6, it is typical that volunteers noted a faster, softer and more comfortable effect of the proposed compositions compared to Antipohmelin. It was also noted that the next day after taking alcohol, the reaction was more confident, especially when driving a car.

As can be seen from the examples, the compositions according to the invention most fully remove the harmful effects of alcohol. All compositions act objectively stronger than the composition “Antipohmelin”, adopted as the closest functional analogue, while possessing a pronounced hepatoprotective and antiencephalopathic effect.

Claims (16)

1. A tool with hepatoprotective and anti-encephalopathic properties, designed to reduce alcohol intoxication, prevent and relieve alcohol intoxication and a hangover syndrome, as well as prevent adverse effects on the liver, containing as active substance components based on succinic, fumaric and glutamic acids, characterized in which contains at least one B-group vitamin. 2. The tool according to claim 1, characterized in that it additionally contains up to 30.0 wt.% (In terms of dry extract) of at least one extract of medicinal plants selected from the extract of lemongrass, eleutheracoccus, melilot, rhodiola rosea, ginseng and / or a mixture thereof. 3. The tool according to claim 1 or 2, characterized in that it additionally contains up to 80 wt.% A substance selected from the group of L-carnitine, glycine, L-arginine, taurine and / or a mixture thereof. 4. The tool according to claim 3, characterized in that it additionally contains up to 80 wt.% A substance selected from the group of methylsulfonylmethane, dihydroquercytin, dimethyl sulfoxide or a mixture thereof. 5. The tool according to claim 1 or 2, characterized in that it further comprises nicotinamide, or nicotinic acid, or a mixture thereof. 6. The tool according to claim 3, characterized in that it further comprises nicotinamide or nicotinic acid, or a mixture thereof. 7. The tool according to claim 4, characterized in that it further comprises nicotinamide, or nicotinic acid, or a mixture thereof. 8. The tool according to claim 1 or 2, characterized in that it is a powder mixture, or granular mixture, or tablet, or capsule, or dragee, or drink. 9. The tool according to claim 4, or 6, or 7, characterized in that it is a powder mixture, or granular mixture, or tablet, or capsule, or dragee, or drink. 10. The tool according to claim 9, characterized in that it is an effervescent drink. 11. The tool of claim 10, characterized in that it contains a component selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, ammonium bicarbonate, ammonium carbonate, or a mixture thereof in an amount equimolar to the acid content. 12. The tool of claim 8, characterized in that it further contains up to 1000 wt.% Sweetener and energizer and / or filler selected from the group of sucrose, glucose, sorbose, sorbitol, fructose, saccharin, aspartame, xylitol, other sweeteners, aspartic acid, sodium aspartate, amino acids, sorbic acid, potato starch, corn starch and / or a mixture thereof. 13. The tool according to claim 9, characterized in that it additionally contains up to 1000 wt.% Sweetener and energizer and / or filler selected from the group of sucrose, glucose, sorbose, sorbitol, fructose, saccharin, aspartame, xylitol, other sweeteners, aspartic acid, sodium aspartate, amino acids, sorbic acid, potato starch, corn starch and / or a mixture thereof. 14. A method of protecting, reducing alcohol intoxication, preventing and removing alcohol intoxication and a hangover syndrome by administering a biologically active agent, characterized in that the agent according to any one of the preceding claims 1 to 13, suitable for use before, and / or during and / or after drinking alcohol. 15. The method according to 14, characterized in that the tool is administered through the mouth no later than an hour before drinking or while taking alcohol 25-5000 mg of powder, or granules, or 1-10 tablets, or dragees, or capsules , or one glass of bubbly. 16. The method according to 14, characterized in that the tool is administered through the mouth after taking alcohol, 50-10000 mg of powder, or granules, or 1-20 tablets, or dragees, or capsules, or 1-3 glasses of a drink or an effervescent drink .