FR2607391A1 - COMPOSITION PREVENTING DEVELOPMENT WITH ALCOHOL PATHOLOGICAL ACCUTATION - Google Patents

Abstract

PUBLIC HEALTH. COMPOSITIONS PREVENTING THE DEVELOPMENT OF PATHOLOGICAL ADDICTION TO ALCOHOL CONTAINING THE FOLLOWING INGREDIENTS, IN MGG: LEUCO-ANTHOCYANES 219-270 CATHECHINS 153-187 FLAVONOLS 81-99 LIGNIN 68-83 REDUCING SUGARS 216-264 PECTIN AMINES 18-22 FREE 27-33 ORGANIC ACIDS 36-44 STEROLS 4, 5-5, 5 METHYLSTEROLS 1, 35-1, 65 DIMETHYLSTEROLS 1, 98-2, 42 LIGNANES 13, 5-16, 5 GLUCOSIDES OF LIGNANES 9-11 ACIDS-PHENOLS 13, 5-16, 5 ALDEHYDES PHENOLS 4, 5-5, 5 ALCOYL FERULATES 4, 5-5, 5 FIGHT AGAINST ALCOHOLISM.

Description

The present invention relates to compositions preventing

  development of pathological addiction

to alcohol.

  The invention is applicable in the food industry as an additive to alcoholic beverages or alcohol-free, as a means of preventing alcoholism, and to improve the biological quality of food products (confectionery,

bread products).

  At present, pharmacological agents are widely used for the therapy of patients suffering from chronic alcoholism, raising the general resistance of the body (tonics, vitamin therapy), and developing in the patients negative reflexes towards alcohol. In addition, agents that reduce the toxicity of alcohol and its metabolites (detoxification therapy) and the drugs that cut abstinence syndrome are widely used. However, all of the aforementioned means of anti-alcoholic therapy have for objective, above all,

  treatment of overt clinical forms of alcoholism

  me or has the character of anti-recurrence therapy.

  All of the known pharmacological agents are not intended for widespread use in consumers of alcoholic products, which precludes the possibility of using these agents for the primary prevention of alcohol abuse and

chronic alcoholism.

  Synthetic products are known that neutralize the pathological action of alcohol on the human body by reducing the level of ethanol in the blood. A. As an active ingredient these products contain at least one substance belonging to the group of carbohydrates and polyhydric alcohols and / or at least one substance of the group of compounds comprising a cyclic tricarboxylic acid and / or compounds containing the radical d such an acid, and / or at least one compound encasing the gastric mucosa, and / or at least one choleretic compound. The various products act as protectors of the liver and detoxicants as a result of the consumption of alcohol, and, in addition, heal the pathological phenomena caused by the absorption

  alcohol (see French Patent No. 2340725).

  The above-mentioned effect is obtained by normalizing the ratio between the oxidized forms of the pyridine nucleotides and the reduced forms of nucleotides, which ensures the realization of the metabolism of carbohydrates by the tricarboxylic acid cycle. Another active component of said compositions is the substances which reduce the absorption of ethanol by the digestive tract and the blood ethanol content. It goes without saying that in this case the effect of the ethanol sought by the consumer (euphoria, relaxation) is significantly reduced. On the other hand, the known compositions are presented in the form of medicinal products whose use must either precede the ingestion of alcohol or be simultaneous with ingestion.

  alcohol, follow it. Nevertheless, the compositions

  mentioned are not food additives that may be added to alcoholic beverages,

  given that they significantly alter the organ-

leptics of the product.

  It has been proposed to develop a composition, comprising components, the combination of which provides an effective action against the negative effects of ethanol and toxic products of its oxidation in the body through the normalization of major metabolic pathways degradation of ethanol and its metabolites, without deteriorating the organoleptic characteristics of the alcoholic or non-alcoholic beverages in which the said

composition can be introduced.

  The composition according to the invention, preventing the development of pathological addiction to alcohol comprises the following ingredients, in mg / g: leuco-anthocyanins 219-270 catechins 153-187 flavonols 81-99 lignin 68-83 reducing sugars 216 -264 pectins 18-22 free amino acids 27-33 organic acids 36-44 sterols 4,5-5,5 methylserols 1,35-1,65 dimethylsterols 1,98-2,42 lignans 13,5-16,5 glucosides of lignans 911 phenol acids 13.5-16.5 aldehydes - phenols 4.5-5.5 ferulas of alkyls 4,5-5,5 The composition according to the invention is a

  association of products widely used in nature.

  The composition according to the invention has the property of acting clearly on the processes of the metabolism of ethanol, without engaging in the pathways unfavorable to the organism

  the use of ethanol, as well as to slow down the process

  education of the physical dependence of alcohol, to reduce the level of its consumption and, by

  to reduce alcoholic excesses. In addition, the composi-

  according to the invention is not toxic, even after prolonged use for many years, it has pleasant organoleptic characteristics and can be used as a food additive in the

  alcoholic and non-alcoholic beverages.

  Other features and advantages of the invention

  will be better understood by reading the detailed description

  composition, preventing the development of habituation

  alcohol, and examples of its realization.

  The proposed composition contains as leuco-

  anthocyanins: leucodelphinidin, leucocyanidin and / or leucopelargonidine. Catechins are represented by epigallocatechin (-), gallocatechin (+),

  epicatechin (-), catechin (+) and / or epicatechin-

  gallate (-). As flavonols the composition comprises: quercetin 3monoglucoside, kampferol 3-monoglucoside, miricetin 3monoglucoside, quercetin 3-glucoside and / or astragalin. The reducing sugars are represented by: D-glucose, D-fructose, sucrose, rafinose, arabinose and / or xylose. As free amino acids, the composition of the invention contains: lysine, histidine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, cystine, valine, methionine,

  isoleucine, leucine, tyrosine, and / or phenylalanine.

  The organic acids of the composition of the invention are represented by tartaric, malic, citric, ascorbic, α-ketoglutaric, fumaric, galacturonic, glyceric, glycolic, glycuronic, oxalic, succinic and / or shikimic acids. As sterols the composition of the invention comprises S-cytosterol, stigmasterol, camispolesterol. The composition of the invention contains as methyl sterols: obtusifoliol and / or citrostadienol. The dimethylsterols of the composition of the invention are: C-amirine, amirine, lupeol, taraxerol, tarasasterol, germanicol. As lignans, the composition of the invention contains: oxymatairsinol, matairésinol, pinoresinol, liovyl, isolariciresinol and / or olivile. As glycosides of lignans it contains: arabinoside of querinol and / or xyloside of querinol. Phenolic acids

  of the composition of the invention are para-oxy acids.

  benzo; that protocatechic, gallic, vanillic and / or syringic. Phenol-aldehydes are represented by vanillin, syringic aldehyde, sinaptic aldehyde and coniferol aldehyde. As alkyl ferulas the composition of

  the invention comprises the alkylated ethers of ferulic acid

  in which the alcoholic part is represented by octadecanol, eicosanol, docosanol, tetracosanol

and hexacosanol.

  The composition of the invention containing the compounds listed above can be obtained in the form of natural mixtures of biologically active substances of vegetable origin. The composition of the invention is soluble and / or

  dispersible in water, ethanol and hydro-

  alcoholics. The composition of the invention has a low toxicity, its LD50 being equal to 36.5 ml per 1000 g of mass

body of the rat.

  Pharmacological investigations of the action of

  the composition of the invention on the consumer processes

  ethanol and the formation of dependence

  physics were performed on animals and humans.

  Under conditions of chronic experimentation (during weeks), in mature male rats of Wistar line, the study of the level of consumption of ethanol under the conditions of free choice between water and a dilution at 15% ethanol. Previously, the rats were tested for ethanol resistance by the "lateral decubitus" method following the intraperitoneal injection of a 25% ethanol solution at a rate of 4.5 g / kg. body weight of the animal. Rats with the same high ethanol tolerance coefficient were used in the experiment. Animals

  were subsequently placed in cages with water

  graduated, and under free choice conditions between a 15% dilution of ethanol and water, the

  daily consumption of liquids.

  The control group (12 rats) included the animals

  consuming the 15% ethanol solution.

  The experimental batch (12 rats) was characterized by the fact that, in the drinking trough, the composition of the invention, at a rate of 1 ml, was added to the 15% ethanol solution.

  of said composition for 50 ml of 15% ethanol solution.

  At the end of 13 weeks of active alcohol, the animals were deprived of access to alcohol for a period of 10 days (deprivation period), after which

  again recorded the amount of liquids consumed.

  The results of this experiment are summarized in the

table 1.

  In the batch of control animals the period of deprivation was characterized by abstinence phenomena, resulting in a modification of the behavior of the animals, the appearance in some cases of tremor, rustling

  moderate hair. In the experimental batch, the demonstrations

  Abstinence was absent.

  The 15% ethanol consumption characteristics under the free choice conditions were different in the control batch and in the experimental batch which consumed the mixed 15% ethanol dilution of the composition of the invention. From the 8th week there was a clear tendency to reduce the consumption of ethanol in combination with the composition of the invention and, after deprivation, this difference was more than 100%. An important criterion for the formation of physical dependence in the control group was the 12% increase in ethanol consumption after 10 days of deprivation. In the experimental batch the consumption of ethanol in combination with the composition of the invention after the deprivation

remained at the same level.

Table 1.

  Effect of the composition of the invention on the quantity of ethanol diluted at 15% consumed daily (in mg per kg of body weight of an animal) under the conditions of free

choice of the drink.

  m, p Duration of consumption (weeks)

Statistic index

tick 1 2 3 4 5 6 7

1 2 3 4 5 6 7 8 9

  1. Quantity of ethanol M + 28.9 20.1 22.5 26.6 28.3 25.6 27.9 at 15% consumed (lot m 1.86 1.18 2.29 2.05 1, 86 1.97 2.32 control) 2, Amount of ethanol M + 33.8 32.2 37.0 34.0 25.9 26.6 29.8 at 15% + composition m 3, 88 4.09 2.93 3.13 2.53 2.26 1.3

of the invention, consume

  mea (experimental batch) p 0.05 0.05 0.01 0.2 0.1 - -

  N CD Table 1 (continued) Action of the composition of the invention on the amount of ethanol diluted to 15% consumed daily (in mg per kg body weight of an animal) under the conditions of free

choice of the drink.

  m, p Duration of consumption (weeks)

Statistic index

that 8 9 10 11 12 13 15

11 12 13 14 15 17

  1. Quantity 1% c M + 26.8 24.0 28.2 29.7 29.4 24.7 9 29.4 ethanol 15% con - o. -C summed (batch m 1.33 2.06 2.25 1.76 3.44 1.29 3.12 control) FF 2. Quantity M + 15.3 18.9 22.0 22.0 20.0 13.0 13.0% ethanol 15% + comostiond 15% + m 1.49 1.36 2.17 1.66 2.42 2.12 2.41 composition of m, the invention, with 0.01 0.001 0.001 0.2 0.1 0.05 0.00

summed up (lot

rimental) no o

Table 2.

  Effect of the composition of the invention on the distribution of rats (%) with respect to the consumption of ethanol at% (alcoholic stress) Group d.an u Time of alcoholizationX Group of animals 3 months 6 months 8 months - Small drinkers (from 20 to 60 ml per 1000 g of body weight) 26/45 73/76 67/79 - Drinkers (from 60 to 80 ml per 1000 g of body weight) 31/12 22/21 21 / 15 - Heavy drinkers (more than 80 ml per 1000 g body weight) 43/13 5/3 12/6

  x Note: to the numerator - ethanol consumption -

  at 15%, at the denominator - 15% ethanol consumption associated with the composition of

the invention.

  The introduction, in ethanol at 15% of the composition of the invention, under the conditions of alcoholization by stress (absence of water in the food ration) prolonged (38 months) brings an important modification of the distribution of the animals. by consumption groups of

alcohol (Table 2).

  The conditions of the above-mentioned experiment provided for the individual control of the consumption of liquids, tested in the different groups of animals, and it was established that among the rats consuming the alcohol with the composition of the invention, the amount of great animals

  drinkers was significantly larger.

  To exclude the possibility of organ-

  the leptic of the composition of the invention on the consumption rate of the alcohol under the conditions of free choice of the drink, parallel experiments were carried out, in which the composition was introduced,

  not in the tested drink, but through the intragastric

  than. Regardless of the route of administration of the

  composition of the invention, the results of the investigations

were identical.

  By gas-liquid phase chromatography we determined

  mined the ethanol level in the blood of animals in the control group and in that of the experimental batch of animals, which had consumed for 3 months the tested fluids. 90 minutes before sacrificing the animals, they were intraperitoneally injected with 25% ethanol (control group) and 25% ethanol in combination with the composition.

  of the invention in the ratio of 50: 1 (experimental batch).

  The results of the experiment (Table 3) show a significant increase in BAC (more than 4-fold) in previously received animals and

  prolonged the composition of the invention.

he

Table 3.

  Effect of the composition of the invention on the elimination of ethanol 90 minutes after the intraperitoneal injection (i.p.) of ethanol at 25% at a rate of 4.5 g / kg of body weight of the animal. Experience Statistical index Amount of ethanol in the blood (%)

1 2 3

  1. Pet care (injection of 25% ethanol) 7 M + m 0.72 + 0.14 2. Consumption during 3 months of ethanol at 15% (injection of ethanol at%) 14 M + m 1.0 + 0.14 p 0.2 i 2 3 3. Consumption during 3 months of ethanol at 15% in

association with the

  position of the invention (injection of ethanol at%) 11 M + m 2.52 + 0.57 p 0.01 4. Consumption during 3 months of ethanol at 15%

in association with

position following the invention

  (25% ethanol injection + composition M + m 4.26 + 0.78 in the ratio of 50: 1) 0.001 The rapidity of alcohol removal from blood depends, in the first place, of the activity of alcohol

  dehydrogenase (ADH), which was studied against a background of

  Acute and chronic alcoholic xication. Following a single intraperitoneal administration of 15% ethanol to the animals at a dose of 4.5 g / kg, the activity of ADH minutes after injection was 8.5 mM / min. 1; in relation to the intact lot; the addition of the composition of the invention inhibited the activity of the enzymes in the presence of ethanol, which became 5.86 mM / min / 1. In chronic experiments, following the administration of ethanol (passive alcoholization) during 1.5 months by daily administration of ethanol at 15% and ethanol in

  combination with the composition of the invention, at

  test of 1 g / kg we got data, confirming

  the results of the previous experiment (Table 4).

Table 4.

  Alcohol dehydrogenase activity in blood serum and liver following the ingestion of 15% ethanol in combination with the composition of the invention during

1.5 months.

  Activity Activity of ADH Ethanol in DHA in the blood serum ceded blood Bonichen according to the method of serum liver JM / ml Skureki mM / min / l mM / min / 1 mM / min / 1 1. Ethanol 15% 3.1 + 1.17 3.15 + 0.14 47, 02 + 1.91 16.21 + 1.14 2. Ethanol 15% + composition 2.63 + 0.49 2.86 + 0 , 05 37.4 + 1.61 21.87 + 2.5 3. Composition of the invention (1:50 aqueous solution) 2, 76 + 0.33 2.21 + 0.05 34.39 + 2 , 4.32 + 0.4

4. Physical solute

  logic 2.51 + 0.29 2.51 + 0.06 40.5 + 3.29 4.9 + 0.6 5. Control animals without any 2.6 + 0.33 2.46 + 0.09 40 , 51 + 1.3 4.14 + 0.3 treatment Under the conditions of free choice between 15% ethanol and water (batch of the controls) and between 15% ethanol with the composition of the invention, and water, at the expiry of 1.5 and 3 months of consumption, the activity of alcohol dehydrogenase was studied before deprivation and after deprivation. The results of this study appear in the

table 5.

Table 5.

  Activity of alcohol dehydrogenase under the conditions of free choice of tested drinks. Activity of DHA Consumption during 1.5 months Consumption during 3 months mM / min / l1 before deprivation after deprivation before deprivation after deprivation 1. Ethanol 15% 2.7 + 0.26 3, 61 + 0, 48 2.64 + 0.27 4.3 + 0.63 2. Ethanol 15% + composition according to the invention 1.87 + 0.22 3.35 + 0.44 3.95 + 0.66 2.63 +0.49 3. Controls 4.33 + 1.08 4.79 + 0.64 2.2 + 0.28 3.08 + 0.58% o Thus, the addition of the composition of the Inhibits the Oxidation Rate of Ethanol in the Liver

  by inhibiting the activity of alcohol dehydrogenase.

  Investigations into the metabolism of lipids and carbohydrates in animals following administration of the

  the invention on an alcoholic background for 3 and 6 months.

  For this purpose the rats received daily, during 3 and

  6 months, intragastrically, 2 mi of the solutions

  mentioned by 100 g body weight of animals. The batches of witnesses received the first batch - water

  distilled, the 2nd batch - 15% ethanol, the 3rd batch -

  15% ethanol containing 5% of the composition of the invention, and the 4th batch - of the aqueous solution of the

composition of the invention.

  The results obtained are represented in the

tables 6, 7, 8 and 9.

  Subsequently, pharmacological investigations were made of the composition of the invention as

  means of reinforcing the general resistance of the

  me. For this purpose, the action of the composition of the invention on the resistance of rats to overheating was studied. 1. Overheating of female rats without a specified lineage (60 animals) was performed by UHF field irradiation using the microwave therapy apparatus (2375 MHz - 17 mA) for 10 minutes once a day for 4 days. The composition of the invention was administered at a dose of 2.5 ml / kg (in all series of experiments by the intragastric route) for 5 days before the start of irradiation, and on the day of the experiment, one hour before irradiation with UHF. We recorded the

  number of rats dropped after 4 irradiations.

  It was established that during the day following the last irradiation, in the control group, 22% of animals fell, whereas in the batch of animals that received the

  composition of the invention, 11% p <0.01.

  2. The overheating of the male rats of Wistar line was performed thermostatically at a temperature of +43 C. The composition according to the invention was administered at a rate of 2.5 ml / kg daily and as a preventive measure for 20 days. Rectal temperature was taken into account

and the lethality of animals.

  It was established that the mortality in the control group of the rats was 76% (28 animals out of 37), and in the experimental batch, where the animals had received the composition of the invention, it was equal to 56% (22). animals out of 39, p <0.001). The composition of the invention did not act

  on the rectal temperature of animals.

  3. In the same overheating conditions of the male rats of Wistar line, the composition of the invention was administered as a preventive measure for 48 days

at a rate of 1 ml / kg.

Table 6.

  Modification of the neutral lipid level in the liver of the rats, having consumed the liquids tested during 3 months

  (in% relative to total lipids, M + m).

LOTS OF ANIMALS

I II III IV V

  control distilled water ethanol aqueous solution 15% ethanol at 15% of the composition + composition of the invention of the invention Esters of II cholesterol 14.5 + 1.10 14.5 + 0.49 12.5 + 0.93 12.5 + 0.48) 15.0 + 1.21% of the control group 100 86 86 103 Triglycerides 13.6 + 0.55 17.2 + 1.112) 20.1 + 0, 843) 20.6+ 1.773) 20.1 + 1.033)% of the control group 127 148 151 148 Free fatty acids 12.8 + 1.60 12.8 + 0.48 12.3 + 0.50 11.5 + 0.53 10.6 +0.92 I)% of control group 100 96 90 83 Cholesterol 16.6 + 0.9 17.2 + 0.63 16.1 + 0.91 14.2 + 0.67I) 15.3 + 1, 22% of the control group 104 97 86 92 Residual fraction 32.5 + 1.05 38.3 + 0.97 39.0 + 1.02 41.2 + 1.30 39.0 + 1.00 I) p 0 , 05; 2) p <0.02; 3) p <0.01 p - significance level% w no

TABLE 7.

  Modification of the neutral lipid level in the liver of the rats, having consumed the fluids tested for 6 months (in% relative to the total lipids M + m)

LOTS OF ANIMALS

  Neutral lipids I II III IV Distilled water ethanol ethanol 15% + compo- Aqueous solution

  % sition of the invention of the composition

tion of

vention

Esters of choles-

  terrol 16.96 + 0.69 16.52 + 0.70 16.62 + 0.35 16.74 + 0.27 15.81 + 0.14% of the control group 99 100 100 95 Triglycerides 15.16 + 0 , 13.88 + 0.12 18.19 + 0.26I) 14, 18 + 0.22I) 13.64 + 0.42I) CD% of the control group 92 120 94 90 Free fatty acids 16.67 + 0 , 48 17.21 + 0.11 14.0 + 0.39) 17.30 + 0.37 18.66 + 0.88% of the control group 103 84 104 112 Cholesterol 17.28 + 0.26 17.07 +0.16 16.61 + 0.69 16.72 + 0.89 17.06 + 0.19% of the control group 99 96 97 99 Residual fraction 33.93 + 0.40 35.38 + 0.74 34 58 + 0.47 35.06 + 0.52 34.83 + 0.61 I) p <0.05; 2) p <0.02 ro o W

TABLE 8.

  Modification of the activity of lysosomal hydrolases in the liver of rats following the consumption of ethanol and of the composition according to the invention during 3 and 6 months (nanomole / ml / min, M + m) 3 months 6 months LOTS OF ANIMALS p-glucosidase -galactosidase 6-glucosidase Pgalactosidase

  at................................................. .... at __________________......________________...---

  Controls 0.47 + 0.04 0.33 + 0.01 0.49 + 0.05 0.35 + 0.01 1. Distilled water 0.43 + 0.01 0.35 + 0.01 0.54 +0.08 0.43 + 0.02% of the control group 91 106 110 78 2. Ethanol 15% 0.58 + 0.08) 0.37 + 0.04 0.87 + 0.092 0.86 + 0.063 )% of the control group 123 112 178 247 C 3. Ethanol 15% + Composition 0.50 + 0.05 0.35 + 0.06 0.66 + 0.081) 0.26 + 0.01% of the control group 106 4. Aqueous solution of the composition 0.40 + 0.02 0.31 + 0.03 0.38 + 0.05 0.25 + 0.011)% of the control group 85 94 78 70 1) p (0 , 05; 2) p <0.01; 3) p <0.01 a

- TABLE 9 -

  Modification of the liver content of rats in biological polymers containing carbohydrates after the consumption of ethanol and the composition of the invention, for 3 or 6 months (mg%, M + m) 3 months 6 months Lots of animals Hexose Hexosamines Hexose Hexasamines 1. Controls 26.68 + 1, 54 32.53 + 2.37 26.26 + 1.43 49.00 + 1.76 rM 2. Distilled water 18.67 + 1.121) 29, 60+ 2.52 20.45 + 1.72 68.53 + 6.972)% of the control group 70 91 78 140 3. Composition of the invention 33.35 + 2.731) 36.02 + 1.47 28.91 + 1, 34 102.43 + 7, 633)% of the control group 125 Ili 110 209 4. Ethanol 15% + composition 18, 43 + 271) 28.10 + 2.65 19.71 + 1.101) 84.72 + 4.213% the invention, 69 86 75 173% of the control group 5. Ethanol 15% 16.67 + 221) 25.84 + 1.771) 16.32 + 1.002) 30.22 + 5.412)% of the control group 62 79 62 62 1) p. 0.05 2) p 4 0.01 3) p <0.001 o I4 In the control group the mortality was 54% (30 animals out of 55), while in the batch of animals which had been overheated after administration prolonged of the composition of the invention, it was equal to 42% (24 rats out of 57, p <0.001). 4) Overheating male rats of Wistar lineage under conditions already exposed. The composition of the invention was administered at the dose of 1 ml / kg 50 minutes before the installation of the animals in the thermostat. Duration of the overheating session 40 minutes or 2 hours. The animals were sacrificed by decapitation. The activity of hexokinase and glucose-6-phosphate dehydrogenase (here and in the cases

  following the formation of nicotinamide-di-

nucleatide-phosphoric - ANDPxH).

  It was established that after the rats have been overheated for 40 minutes, the composition of the invention precludes the reduction of glycogen level and the activity of the

  glucose-6-phosphate dehydrogenase in the liver (Table 10).

  After overheating for two hours, said composition no longer has any action on the level of

parameters studied.

  Cooling (hypothermia) of Wistar male rats was caused by placing the animals in a refrigerator at +5c for one to two hours. The composition of the invention was administered at a rate of 1 ml / kg, 60 minutes before

the recooling.

- TABLE 10 -

  Effect of the composition of the invention on the modification of glycogen (mg%), hexokinase (micromole NADPxH / min / g of tissue), glucose-6-phosphate dehydrogenase (micromole NADPxH / min / g of tissue) to following overheating (+45 C)

  Hexokinase Glucose-6 Glucose Groups

of phosphate

  Hydrogenase Overheating: 40 minutes 1. Control 3226 + 148 0.42 + 0.025 1, 80 + 0.61

2. Overheating-

  only 2387 + 209 0.34 + 0.19 1.57 + 0.095 p <0.005 p 0.020 p 4 0.050

3. Overheating

ment +

  2968 + 121 0.40 + 0.18 1.71 + 0.077 p 0.030 p 0.030 p <0.30 Overheating: 2 hours 1. Control 4628 + 207 0.50 + 0.019 1.56 + 0.058

2. Overheating-

  only 2175 + 271 0.31 + 0.027 1.17 + 0.095 p <0.0001 p 0.0001 p <0.003

3. Overheating

ment +

  2869 + 219 0.29 + 0.020 1.04 + 0.081 p4 0.060

  p - for the comparison of groups 1 - 2 and 2 - 3.

  It was found that during the first hour of cooling the rats there was a reduction in glycogen stores in the liver and a reduction in

  the activity of hexokinase and glucose-6-phosphate-

  Hepatic dehydrogenase. Prior administration of the composition of the invention prevented the decrease of these parameters (Table 11). In the case of cooling for two hours, the composition of the invention

no protective effect.

- TABLE 11 -

  Action of the composition of the invention, on the modification of glycogen (mg%) and the activity of hexokinase (micromole

  NADPxH / min / g tissue) and glucose-6-phosphate-deshydrate

  drugase (micromole NADPxH / min / g tissue) in the liver

  rats following cooling (+5 C).

  Groups of animals Glycogen Hexokinase Glucose-6-phosphate dehydrogenase at 1 hour of cooling 1. Controls 4109 + 195 0.51 + 0.017 1.62 + 0.078 2. Cooled 2794 + 207 0.41 + 0.022 1.20+ 0.101 p <0.0001 p 40.003 p To 0.004 3. Having undergone cooling with consumption of the composition 3493 + 172 0.48 + 0.013 1.39 + 0.089 p At 0.020 p <0.020 2 hours of cooling 1. Indicators 3078 + 189 0.63 + 0.017 1.57 + 0.075

2. Having undergone the refii-

  loss 1754 + 237 0.47 + 0.028 1.27 + 0.103 pOO p 0.001l p 0.0000.037

3. Having undergone the cooling

  with the consumption of 1908 + 226 0.44 + 0.022 1.41 + 0.091 mation of the composition p - for the composition of groups 1-2 and 2-3 The study of the action of the composition was carried out according to the the invention, on the resistance of animals to muscular fatigue: 1) the experiments were carried out on male mice without precise lineage, with a mass of 28 to 33 g. The composition of the invention was administered enterally by means of a three-animal probe at three different doses: 0.1; 0.15 and 0.22 ml per 20 g of weight

  one hour before the beginning of the muscular work.

  The control animals received a corresponding volume of physiological saline. The studies were carried out on the apparatus "endless rope". We recorded the duration of the race of the mice on the vertical rope moving

  downward, until the animals are completely exhausted.

  By graphic constructions, the dose of the composition of the invention was found which would increase the running time of the mice by 33%. The activity of the composition of the invention was expressed in conventional units

of action stimulation (UA33).

  It was established that the capacity to work muscular

  the number of mice increases proportionally with

  dose they had received from the invention. The adminis-

  Composition of the composition at the maximum dose (0.22 ml / kg) increases the working capacity by 41% compared to controls (Table 12);

- TABLE 12 -

  Stimulation action of the composition of the invention over the duration of the muscle working capacity of the mice

  on the device of "endless rope".

  Run time of mice Groups of animals min% p (13) Saline solution 27.0 + 2.1 100 Composition of the invention: 0.1 ml / 20 g (10) 30.0 + 1.8 111 0.5 0.15 ml / 20 g (11) 32.0 + 2.8 118 0.5 0.22 ml / 20 g (15) 38.0 ± 2.7 141 0.001

  Note: in brackets the number of animals in each batch.

  2) It was used as an experimental action model

  swimming in rats (here, as in other cases, male rats of the Wistar line) for a water temperature of +30 C. The composition of the invention was administered to rats at a dose of 10 ml / kg one hour before the start of swimming. We took into account the duration of the

  swim until a complete exhaustion of the animals.

  It was established that in the controls the swimming time was 392.6 ± 29.0 min, whereas in the animals that received the composition of the invention it was 519.4 ± 40.0 min. ie after swimming was 32%

longer (p = 0.023).

  3) The composition of the invention was administered one hour before the start of swimming at a rate of 1 ml / kg, then

  the animals swam for 15 minutes or two hours.

  The condition of the animals was evaluated according to glycogen content

  and the activity of hexokinase and glucose-6-phosphate-

dehydrogenase in the liver.

  It was found that swimming in these two times resulted in a reduction in liver glycogen content and a reduction in the activity of hexokinase and glucose-6-phosphate dehydrogenase. The prior administration of the composition of the invention prevented the decrease of the parameters studied for a swimming duration of two hours, but did not bring about a change in their level compared to the controls for a swim.

minutes (Table 13).

- TABLE 13 -

  Effect of the composition of the invention on the glycogen level (mg 1100 9), the activity of hexokinase (micromole

  NADPxH / min / g tissue) and glucose-6-phosphate-

  dehydrogenase (micromole NADPxH / min / ç; tissue) in the liver of animals during swimming (temperature

water 30-32 C.

* Glucose-6

  Groups of animals Glycogen Hexokinase phosphate-

  dehydrogenase Swimming 15 minutes 1. Control 4216 + 216 0.50 + 0.019 1.44 + 0.068 2. Animals swimming 2993 + 278 0.31 + 0.029 1.01 + 0.094 p <0.002 p 40.0001 p <0.010 3. Animals having donated Composition of 2902 + 202 0, 35 + 0.015 0.98 + 0.101 Swimming 60 minutes 1. Control 3511 + 201 0.54 + 0.025 1.51 + 0, 075 2. Animals having swum 2633 +163 0.37 + 0.024 1.13 + 0.095 p 4 0.004 p 4 0.0001 p <.0.008 3. Animals having swum after absorption of the composition 3089 + 133 0.44 + 0.021 1.39 + 0.071 p <0.040 p <0.040 p 40.040

  p - for the comparison of groups 1-2 and 2-3.

  4) The composition of the invention was administered one hour before a swimming session of 15 minutes. Cyclic adenosinemonophosphate levels in the adrenal glands, cyclic guanosine monophosphate in the adrenals and liver were determined using the radioimmunoassay method (Ammerscham). Part of the control group and experimental group rats rested after swimming for one hour, then determined

again the same settings.

  The swimming of the rats caused the rise of the level

  cyclic adenosine monophosphate and guanosine

  cyclic monophosphate in the adrenals, as well as the reduction of cyclic guanosine monophosphate in the liver (acute stress during energy supply by glycolysis). After one hour of rest, the level of cyclic adenosine monophosphate and the

  Cyclic guanosine monophosphate normalized. The composition

  sition of the invention had no influence on the level of cyclic adenosine monophosphate and cyclic guanosine monophosphate in the adrenal glands,

  but normalized the biosynthesis of guanosine-monophosphate

  cyclical phate in the liver one hour after swimming

(Table 14).

- TABLE 14 -

  Effect of the Composition of the Invention on the Cyclic Adenosinemonophosphate Content of the Adrenal and Cyclic Guanisine Monophosphate of the Adrenal and Liver Rats After Overload Testing of Muscle Effort

and rest.

  Adenosine-MPC, Guanidine-MPC, Groups of animals pmol pmol adrenal adrenal adrenal

1 2 3 4

  1. Controls 8.5 + 0.55 (7) 0.09 + 0.01 (7) 0.22 + 0.67 (7) 2. Swimming 15 minutes 17.9+ 1.8 (7) 0, 30 + 0.04 (7) 0.14 + 0.035 (7) p 4 0.05 p L 0.001 3. Swimming 15 minutes + rest 1 hours 8.1 + 0.63 (6) 0.18 + 0.02 (7) 0.059 + 0.045 (6) pt 0.05 p 4 0.001 p <0.001 4. Swimming 15 minutes + injection of the composition 17.3 + 1.87 (7) 0.25 + 0.06 (6) 0 , 25 + 0.06 (6) 5. Swimming 15 minutes + ingestion of the composition and rest 1 h 9.0 + 0.65 (6) 0.14 + 0.01 (7) 0.136 + 0.009 (7) p The effect of the composition of the invention on the resistance of rats to hypokinesia caused by maintaining the animals in individual cages with a sliding lid for two days was also investigated. The composition of the invention was administered throughout the period of hypokinesia, at a rate of I ml / kg twice

per day.

  At the end of hypokinesia there was a reduction in hepatic glycogen stores, a decrease in cholesterol levels in the adrenal glands, and in the activity of alcohol dehydrogenase (evaluated according to the method of Schlesinger et al., 1966). In animals, having received the composition of the invention, the reduction of the parameters studied as a result of hypokinesia was less pronounced.

(Table 15).

- TABLE 15 -

  Effect of the composition of the invention on the content of adrenal cholesterol (mg / g), glycogen mg / 100 g and on the activity of alcooldéhydrogénase (micromole NADPxH / min / g of tissue) in the liver of rats in hypokinesia

for 2 days.

alcohol-dehydrogen

  Animal Groups Cholesterol Glycogen Genase Gasease 1. Controls 44 + 1.6 3975 + 222 5.04 + 0.234 2. Hypokinesis 96 + 2.4 2862 + 251 5.90 + 0.250 p <0.010 p <0.004 p <0.020 3. Hypokinesia + ingestion of composition 43 + 1.9 3577+ 203 4.94 + 0.258 p (0.030 p <0.040 p 0.010 p - for comparison of groups 1-2 and 2-3) The effect of the composition of the invention on the resistance of animals to

chemical aggressions.

  2) As a model of the lesion action was used sodium hexobarbital narcosis. The composition of the invention is administered at doses of 2.5, 0 and 10 ml / kg, and then, two hours later, hexobarbital sodium is injected into the peritoneal sac at a rate of 19.8 mg. 100 g body weight We recorded the

  lateral decubitus duration of the animals.

  It was established that in the control animals the duration of the narcosis was 90.6 ± 3.9 min, in the animals which received the composition of the invention, at the

  dose of 2.5 ml / kg at 85.5 + 5.4 min at a dose of 5.0 ml / kg

  75.7 + 3.1 min (83.6%, p = 0.009), at a dose of 10 ml / kg -

  at 72.9 + 3.7 min (80.5%, p = 0.005), which is to say that the composition of the invention acts on the awakening according to

the dose received.

  2) In the mouse experiments, narcosis was caused by sodium thiopental sodium

  doses: 62.5; 75.0 and 100 mg / kg, intraperitoneally

  tonéale. The composition of the invention was administered at a rate of 10 ml / kg two hours before injection of the

  thiopental sodium. The following were assessed: the speed of

  lateral decubitus, duration and lethality of animals. It was found that among the mice that received the thiopental at the dose of 62.5 mg / kg, after administration of the composition of the invention, 22% of animals had taken the position of lateral decubitus, while in the control group (thiopental) the proportion being 100% of animals (p 40,001). The duration of the lateral decubitus in the controls was equal to 53.5 min and in the animals of the experimental batch

- 120 min (p 4 0.05).

  In the batch of mice that received thiopental sodium at a dose of 75 mg / kg, the mortality was 28%, whereas in the batch of rats that had previously received the composition of the invention it was only 12%. , 5% (p <0.001). In controls, the duration of lateral decubitus

  was equal to 30.0 min and, with administration of the composi-

  of the invention at 15.0 min (p <0.05).

  For the highest dose of thiopental sodium (100 mg / kg), the duration of the lateral decubitus was equal to 269 + 0.2 min, and with prior administration of the composition of the invention, to 260 min (p <0, 05). In the

  two lots the animal mortality was the same.

  The action of the composition of

  the invention on certain aspects of carbohydrate metabolism.

  For this purpose the following experiments were carried out.

  1) In experiments on ordinary animals

  without special preparation under conditions of

  the composition of the invention was administered.

  twice a day for 5 days. In this series

  of experiences, as well as in the following series, on -

  determined the blood glucose concentration according to the anthronic method, and the liver glycogen level

according to Zeifter's method.

  It was established that the administration for 5 days of the composition of the invention to ordinary animals caused some increase in the glucose level in the body.

  blood and glycogen in the liver (Table 16).

  2) The study of carbohydrate metabolism was carried out in fasted rats for 18 or 48 hours. The composition of the invention was administered at the dose of 1 ml / kg one hour before the sacrifice of the animals. The following were studied: the blood sugar level, the insulin level in the blood serum, the latter being established according to the radioimmunoassay method. It was established that fasting 18 hours causes rats to reduce blood sugar. The composition of the invention prevented the decrease in blood sugar

  (Table 16). Fasting animals for 48 hours produces

  know a statistically significant reduction in blood sugar and liver glycogen levels. This

  phenomenon was accompanied by the reduction of the concentration

  insulin in the blood serum.

  Following the preliminary administration to the animals,

  during 5 days, of the composition of the invention, one will not observe

  only a tendency to maintain the initial blood sugar and hepatic glycogen content. The serum concentration of insulin was in this case significantly

  greater than animals in the control group (Table 16).

  3) The action of the composition of the invention was studied

  the metabolism of carbohydrates in rats receiving

  an overabundant diet. The composition of the invention

  was administered at a dose of 1 ml / kg

before the sacrifice of the animals.

  In the conditions of superabundant feeding of the rats, the compound of the invention had no action

  blood sugar content, while raising the

  the hepatic glycogen content and lowering the concentration of insulin in peripheral blood

(Table 16).

  We have studied the antioxidant properties of the composition of the invention. For this purpose, in order to obtain lipid activation by peroxides,

  in rats of the Wistar lineage (40 animals)

  put a stress on them by the skin of the neck during 24 hours. The animals in the experimental batch once received the composition of the invention at a dose of 1 ml / kg before "hanging". The accumulation of lipids in the liver was judged by the content of this organ in

malonic dialdehyde.

  It has been established that the composition of the invention does not produce a change in the malonic dialdehyde content of the liver of ternary rats. In the rats subjected to the aforementioned stress the malonic dialdehyde content increases by 6 times, so in the case of stress after

  administration of the composition of the invention, the accumu-

  malonic dialdehyde is much lower (norm - 86.5 + 29.0, stress - 452 + 20, stress plus composition

  of the invention - 296 + 15) (p = 0.001).

  Therefore, the composition according to the invention

  has antioxidant properties.

Table 16.

  Action of the composition of the invention on some parameters of

  carbohydrate metabolism in rats.

  Groups of animals Blood sugar Glycogen Insulin in blood mg% hepatic micro One / ml Usual diet of rats Reference 91 + 2.7 (9) 4966 + 406 (9) Administration

composing

tion of the invention

  100.5 + 1.78 * (13) 6071 + 250 * (10) -

  after an 18-hour fast

ordinary (10) 106.8 + 3.7 -

fasting (8) 83.8 + 2.0 * -

Young + Administration

composing

  i ml / kg 30 min before sacrifice (10) 106.0 + 4.2 * after a 48-hour fast Regular feeding (10) 116.5 + 5.0 5059 + 452 17.56 + 1.12 fasting (10) 86.0 + 5.0 * 495 + 257 * 9.56 + 0.69 *

Fasting + adminis-

of the Com

  position 91.0 + 5.0 593 + 151 14.5 + 1.0 * overfeeding of rats

Without adminis-

  composition (10) 119.0 + 4.3 4966 + 406 22.8 + 2.3

With administrative

  The composition is administered intragastrically at a rate of 1 ml / kg twice daily. during 5 days. In parentheses

  the number of animals interested in each group.

  We also studied the biological parameters

  of men's blood, having received the composition of

  the invention on an alcoholic background.

  In clinical conditions, we examined the action of the composition of the invention on the rate of ethanol elimination from blood and on the activity of alcohol-dehydrogenase blood, as well as the indices of the activity of lysosomal hydrolases, the level of protein-linked hexosoamines and the fraction of neutral lipids. The first group of individuals participating in the study was hospitalized patients with chronic alcoholism; the second group was constituted

  by people of Mongoloid race, genetically intoxicated

  alcohol, and the third group was repre-

  felt by europoides practically healthy and not abusive

no alcohol.

  In the double-blind study conditions, the individuals participating in the study drank alcohol with the composition of the invention (1:50) or the aqueous solution of this composition the invention. The volume of liquid consumed was equal to 200 ml per 70 kg of body weight. The intervals between the ingestions were 4 days. Before ingestion of the liquid, then at the expiration of 1.2 and 4 hours after ingestion

  venous blood for biochemical investigations.

  The results of the investigations appear in

  Tables 17, 18, 19, 20, 21 and 22.

Table 17.

  Activity of b-galactosidase in the blood serum of volunteers (nanomole ml / min, M + m) GROUPS Ethanol 40% start after 1h after 2h after 4h

1 2 3 4 5

  - - - - - - - - - - --________- - - - - - - - - ------------ 37- - - - - - - - - - - - - - -

  1. Healthy Europoids 5.95 + 0.62 6.66 + 0.21 19.94 '+2.2 35.57 + 1.63% of departure rate 112 335 598 2. Mongoloids 5.77 + 0, 94 5.92 + 0.68 12.153) +0.87 12.613) +0.98% of starting rate 103 211 219 3. Suffering patients 3) 1) Alcoholism 8.79 + 0.67 21.92 + 0.94 7.98 + 0.20 10.46 +0.91% of starting rate 249 91 122 1) p (0.05 2) p 4 0.01 3) p <0.001 Co osj LY TABLE 17 ( continued) Activity of β-galactosidase in the blood serum of volunteers (nanomole ml / min, M + m)

  __________________________________________________________________________ ____________________________________

  Aqueous composition of the composition

  __________________________________________________________________________ _________

  departure after lh after 2h after 4h

  __________________________________________________________________________ ____________________________________

6 7 8 9

  1) 1 1. Healthy Europoids 5,72 + 0,19 5,09 + 0,27 4,06 1) +0,44 6,85 1 + 0,48% of starting rate 89 71 120 2. Mongoloids 6 , 89 + 0.47 6.30 + 0.33 6.87 + 0.57 7, 50 + 0.44% starting rate 91 99 109 3. Patients suffering from 3) alcoholism 11.72 + 0, 72 11,95 + 0,83 13,94 + 0,85 24,26 + 1.58% departure rate 102 119 207

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

  TABLE 17. (continued) Activity of (-galactosidase in the blood serum of the volunteers (nanomole ml / min, M + m) Ethanol 40% + composition

  __________________________________________________________________________ _______

  departure after lh after 2h after 4h

  __________________________________________________________________________ ______________________________________

11 12 13

  1. Healthy Europoids 5.90 + 0.42 5.78 + 0.54 6.55 + 0.42 18.03) +1.6% of starting rate 98 111 305 2. Mongoloids 6.33 + 0, 44 9.39 + 0.71 9.23 + 0.84 16.4 + 1.5 c. w% of starting rate 148 146 259 3. Patients suffering 2 2) 2) of alcoholism 10.45 + 0.39 15.15 2 + 0.72 14.002) +0.86 12.82) +0.9 % of departure rate 145 134 122

  __________________________________________________________________________ _____________________________________

os -J oM

Table 18

  Modification of the hexose-amine content of human blood serum (mg in 100 ml, M + m) Voluntary groups I. Healthy Europoids Departure After 1 h After 2 h After 4 h

  __________________________________________________________________________ _____________

1 2 3 4 5 6

  1. Ethanol 40% 72.57 + 3.55 66.93 + 4.10 66.00 + 2.51 61.20 + 2.62% starting rate 92 91 85 2. Ethanol 40% + composition 53 , 33 + 2.39 50.40 + 3.85 42, 532) +1.79 50.53 + 3.27% of the starting rate 95 80 95 3. Composition 72.16 + 4, 01 94.13) +3 , 92 93.44 3) +0.04 87.52 2) +1.90% of the starting rate 131 130 122

  __________________________________________________________________________ _____________

  1) eg 0.05 2) p 0.01 3) p <0.001 Co C) -IL> o (continued Table 18) Modification of hexose-amine content of human blood serum (mg in 100 ml, M + m) Voluntary groups II Healthy Mongoloids Departure After 1 h After 2 After 4 h

7 8 9 10

  1. Ethanol 40% 48.93 + 3.31 46.40 + 1.72 48.64 + 2.93 53.20 + 3.75% of the starting rate 95 99 109 2. Ethanol 40% + Composition 84 , 60 + 3.70 63.203) +1.21 100.642) + 3j, 70 93.33 + 4.22% of the starting rate 75 119 110 3. Composition 36.68 + 3.71 45.211) +3.00 53.201 ) +1.52 53,203) + 2.74% of the starting rate 127 149 149 1) or 0.05 2) p <0.01 3) p <0.001 ro -'j Lo (continued Table 18) Change in hexose-amine content of human blood serum (mg in 100 ml, M + m) Voluntary groups III. Alcoholism Departure After 1 h After 2 h After 4 h

11 12 13 14

E 4% 1 61) -)

  1. Ethanol 40% 68.30 + 2.76 56.06 + 2.81 54.64 +3.43 57.371) +3.32 N% of the starting rate 82 80 84 2. Ethanol 40% + Composition 75 , 94 + 4,41 73,71+ 3,10 66,97 + 5,37 70,42 + 4,16% of the starting rate 97 88 93 3. Composition 60, 11 + 4,81 62,27 + 3 , 15 69.94 1) + 3.00 60.23 + 3.30% of the starting rate 103 116 100 1) p <0.05 2) eg 0.01 3) p <0.001 Lo o

Table 19

  Modification of the content of different serum lipid fractions of the individuals who took ethanol at 40% (in% relative to the total lipids, M + m) Fraction Group I - Healthy Europoids Departure After 1 h After 2 h After 4 h

1 2 3 4 5 6

  __________________________________________________________________________ _______________

  1. Cholesterol Esters 21.72 + 1.81 27.031) +1.32 23.06 + 1.15 23.95 + 0.90% of the starting rate 125 106 110 2. Triglycerides 17.40 + 0.72 16,53 + 0,97 19, 11 + 0,75 19,08 + 0,78% of the starting rate 95 110 110 3. Free fatty acids 17,06 + 0,65 16,88 + 0,50 15, 87 + 0.42 17.24 + 0.95% of the starting rate 99 93 101 4. Cholesterol 19.64 + 0.86 18.25 + 0.87 19.04 + 0.24 19.08 + 0, 48% of the starting rate 93 97 97 5. Total residual fraction 24.18 + 0.52 24.29 + 1.85 22.92 + 0.73 20.65 + 0.70 1) p <0.05; 2) p <0.01 (continued Table 19) Modification of the content of different serum lipid fractions of individuals who took 40% ethanol (in% relative to total lipids, M + m) Fraction Group II - Healthy Mongoloids Departure After 1 h After 2 h After 4 h

  __________________________________________________________________________ _______________-

7 8 9 10

1. Esters of choles-

  terol 26.66 + 1.19 27.89 + 1.33 21.22 + 0.54 29.62 + 1.44% of the starting rate 105 80 11 2. Triglycerides 17.45 + 0.76 16.63 +0.86 16.48 + 0.71 19.02 + 0.22% of the starting rate 95 94 110 3. Free fatty acids 15.10 + 0.47 16.57 + 1.08 18, 452) + 0.57 13.87 + 1.15% of the starting rate 110 122 92 4. Cholesterol 18.54+ 0.50 17.79 + 0.26 20.04 + 0.66 17.03 + 0.71% starting rate 96 108 92 5. Total residual fraction 22,25 + 0,31 21,12 + 0,64 23,75 + 0,97 20,46 + 0,93 1) p 0,05; 2) p <0.01 (continued Table 19) Modification of the content of different fractions of the serum of the individuals having taken 40% ethanol (in% relative to the total lipids, M + m) Fraction Group III - patients suffering from alcoholism Departure After 1 h After 2 h After 4 h

11 12 13 14

1. Esters of choles-

  terol 25.90 + 2.14 26.47 + 2.16 22.66 + 1.05 25.37 + 2.48% of the starting rate 102 88 98 2. Triglycerides 15.28 + 1.05 15.40 +0.76 16.37 + 0.69 15.99 + 1.24% of the starting rate 101 107 105 3. Free fatty acids 15.29 + 1.35 18.641) +1.47 19.292) +0.47 16.69 + 1.99% of the starting rate 122 126 109 4. Cholesterol 17, 94 + 0.99 18.71 + 1.74 21.65 + 1.96 19.82 + 0.71% of the rate of leaving 104 121 111 5. Total residual fraction 25.60 + 1.68 20.78 + 0.81 20.03 + 1.16 22.13 + 1.29 1) p 0.05; 2) p 0.01 o LQ

Table 20

  Modification of the level of the different fractions of the lipids in the blood serum of the individuals after ingesting the aqueous solution of the composition of the invention (in% relative to the total lipids, M + m) Fraction Group I - Healthy Europoids Departure After 1 hr After 2 hrs After 4 hrs

1 2 3 4 5 6

  1. Cholesterol esters 23.07 + 1.47 22.74 + 2.10 23.44 0.54 23.10 + 089% of the starting rate 99 102 101 2. Triglycerides 17.24 + 0.82 16, 75 + 0.67 20.49 + 1, 29 17.63 + 0.75% of the starting rate 97 119 102 3. Free fatty acids 16,14+ 1,20 17,17 + 0,39 16,85t0, 42 17.90 + 0.63% of the starting rate 110 104 111 4. Cholesterol 17.43 + 1.57 18.69 + 1.93 19.97 + 0.54 17.89 + 0.93% of the rate 107 115 103 5. Total residual fraction 26.12 + 2.30 24.05 + 1.70 19, 25 + 0.74 23.48 + 0.71

  __________________________________________________________________________ ________________

  Lq no (continued Table 20) Modification of the level of the different fractions of the lipids in the blood serum of the individuals after ingestion of aqueous solution of the composition of the invention (in% relative to the total lipids, M + m) Fraction Group II - Healthy Mongoloids

  ____________________________________________________________

  Departure After lh After 2h After 4h

7 8 9 10

  1. Cholesterol esters 23,12 + 1,32 21,34 + 1,38 23,59 + 0,54 23,17 + 0.46% of the starting rate 92 102 100 2. Triglycerides 16,79 + 2, 02 18.99 + 0.47 17.73 + 0, 33 18.08 + 0.56% of the starting rate 113 106 108 3. Free fatty acids 17.77+ 1.03 18.05 + 0.48 16 , 41 + 0.67 17.38 + 0.56% of the starting rate 102 92 98 4. Cholesterol 18.09 + 0.60 20.33 + 0.37 20.51 + 0.55 20.88 + 0 , 44% of the starting rate 112 113 115 5. Total residual fraction 24.23 + 1.60 21.29 + 0.92 21, 76 + 0.46 20.49 + 0.52

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - - - - - - - - - - - - - - -

  (continued Table 20) Modification of the level of the different fractions of the lipids in the blood serum of the individuals after ingestion of aqueous solution of the composition of the invention (in% relative to the total lipids, M + n) Fraction Group III - Sufferers suffering of alcoholism Departure After lh After 2h After 4h

11 12 13 14

  1. Cholesterol esters 22.49 + 0.44 24.87 + 0.54 24.43 + 0.86 24.05 + 0.62 OD% of the starting rate 111 109 107 2. Triglycerides 19.36 + 1 , 0 17.16 + 0.48 17.29 ± 0.39 17.58 0.84% of the starting rate 89 89 91 3. Free fatty acids 17, 77 0.65 17.77 + 0.55 17, 76 0.36 15.05 + 0.99% of the starting rate 100 100 85 4. Cholesterol 19.37 + 0.35 19.39 + 0.43 18.46 + 0.79 17.34 0.49% starting rate 100 95 90 5. Total residual fraction 21.01 0.61 20.81 0.82 23.06 l, 10 25.96 + 1.13 Q ______________----------- -------------------------------------------------- ------------ bones

Table 21

  Modification of the lipid fraction rate in the blood serum of individuals after ingestion of 40% ethanol (in% relative to total lipids, M + m)

  with administration of the composition of the invention. Fraction Group I - Healthy Europoids Departure After lh After 2h After 4h

1 2 3 4 5 6

  1. Cholesteryl esters 24.35 2.04 23.91 + 0.67 22.04 + 0.41 21.43 + 0.68% of the starting rate 98 91 88 2. Triglycerides 16.41 + 0.71 18.14 + 0.30 18.48 + 1.24 19.511) +0.69% of the starting rate 111 113 119 3. Free fatty acids 15.96 + 0.76 16.19 + 0.57 16.30 +0.26 15.90 + 0.24% of the starting rate 101 102 106 4. Cholesterol 19.21 + 0.86 18.87 + 0.38 18.06 + 0.84 20.06 + 1.58 % of departure rate 98 94 104 5. Total residual fraction 24.07 + 1.93 22.89 + 0.55 24, 52 + 1.61 22.94 + 1.17 ud o

  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - IJ

  (continued Table 21) Change in blood serum lipid fractions of individuals after ingestion of 40% ethanol (as% of total lipids, M + m)

  with administration of the composition of the invention.

  Fraction Group II - Healthy Mongoloids Departure After lh After 2h After 4h

7 8 9 10

  1. Cholesterol esters 22.30 + 1.01 24.32 + 0.55 23.15 + 1.45 22.89 + 0.70% of the starting rate 109 104 103 C 2. Triglycerides 19.95 + 1 , 71 18.15 + 0.55 18.87 + 2.11 19.47-0.28% of the starting rate 91 95 98 3. Free fatty acids 16,12+ 0,46 16,17 + 1,10 15.83 + 0.58 19.95 084% of the starting rate 100 98 105 4. Cholesterol 17.84 + 0.28 18.02 + 0.93 17.66 + 0.89 19.22 + 0.45 % of departure rate 101 99 108 5. Total residual fraction 23.79 + 2.03 23.34 + 0.60 24, 46 + 1.45 21.47 + 1.33

  _-- - - - - - - - - - - - - - - - - - - - - - - -_-- - - - - - - - - - - - - - - - - - - - - - _-- - _-- - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

  (continued Table 21) Change in blood serum lipid fractions of individuals after ingestion of 40% ethanol (as% of total lipids, M + m)

  with administration of the composition of the invention.

  Fraction Group III - Patients with alcoholism Departure After lh After 2h After 4h

11 12 13 14

  1. Cholesterol esters 24.60 + 0.59 24.05 + 0.62 24.26 + 0.34 22.94 + 0.90% of the starting rate 100 101 95 2. Triglycerides 17.05 + 0, 52 16.50 + 0.56 17.43 + 0, 49 18.77 + 0.66% of the starting rate 97 102 110 3. Free fatty acids 15.95 + 0.53 16.63 + 0.41 17 , 00 + 0.50 17.01 + 0.52% of the starting rate 104 107 107 4. Cholesterol 18.37 + 0.73 17.85 + 0.44 19.07 + 0.42 19.89 + 0 , 49% of the starting rate 97 104 108 5. Total residual fraction 24.03 + 0.79 24.97 + 1.08 22, 24 + 1.20 21.39 + 0.51 bone. o -4 No

Table 22.

  Alcohol-dehydrogenase / ethanol system in individuals, having absorbed the ethanol solution with

  administration of the composition of the invention.

  __________________________________________________________________________ ______________________________________

Ethanol 40%

  __________________________________________________________________________ ______________________________________

  departure after lh after 2h after 4h

1 2 3 4 5 6

1. alcohol-

  dehydrogenase 0.46 + 0.16 1.24 + 0.56 1.83 + 0.58 2.39 + 0.66 2. ethanol 0 0.27 + 0.11 0.198 + 0.023 0.113 + 0.014 3. alcohol I dehydrogenase 2.81 + 0.97 3.15 + 0.67 3.17 + 0.87 3.15 + 0.89 Crm o C H 4 E ethanol 0.012 + 0.007 0.174 + 0.033 0, 188 + 0.024 0, 64 + 0.028

5. alcohol

  dehydrogenase 2.90 + 0.58 1.73 + 0.29 3.04 + 0.42 0.52 + 0.28 6. O ethanol 0.023 + 0.002 0.263 + 0.028 0.124 + 0.013 0.035 + 0 , 000035 M rM

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ____ _ '__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

  . TABLE 22 (continued) Alcohol-dehydrogenase ethanol system in individuals, having absorbed the ethanol solution with

  administration of the composition of the invention.

  Ethanol 40% + composition starting after lh after 2h after 4h

  __________________________________________________________________________ ______________________________________

7 8 9 10

  __________________________________________________________________________ ______________________________________

  1. O alcohol dehydrogenase 2.28 + 0.68 3.56 + 0.66 1.85 + 0.39 0.70 + 0.25 2. ethanol 0.138 + 0.032 0.182 + 0.054 0.203 + 0.022 E 3. O Alcohol-dehydrogenase 1.74 + 0.32 1.69 + 0.31 2.34 + 0.87 1.57 + 0.31

3a O ....-

  4. C, ethanol 0.206 + 0.023 0.105 + 0.029 0.103 + 0.033 Ex 5 .. alcooldéhydrogénase 2.56 + 0.23 1.78 + 0.68 2.35 + 0.57 0.69 + 0.34

H- H -

  6. O i ethanol 0.049 + 0.0004 0.174 + 0.025 0.174 + 0.016 0.86 + 0.01

DO --- - -

DEC

  o km W TABLE 22 (continued) Alcohol-dehydrogenase ethanol system in individuals, having absorbed the ethanol solution with

  administration of the composition of the invention.

  __________________________________________________________________________ _____________________________________

  _ _ _ _ _ _ _ _ _ _ _ _ __Components _ _ _ _ _ _ _ _ _ start after 1h after 2h after 4h ___......._ b ... ..._ b ...... ______________________________________________ it 12 13 14 1 .. alcooldéhydrogénase 1,06 + 0,46 0,79 + 0,27 1,79 + 0,35 1,67 + 0,47 2., ethanol 0.04 + 0.012 0.14 + 0.014 0.076 + 0.024 0.082 + 0.018 "i E 3., alcohol dehydrogenase 2.48 + 0.64 1.59 + 0.58 1.69 + 0.47 2 , 37 + 0.76 on, 4. ethanol 0 0 0 0 E 1 Vn 5., alcohol dehydrogenase 1.00 + 0.37 1.64 + 0.40 1.37 + 0.47 1.27 + 0 , 36 6. 0 ethanol 0.006 + 0.000008 0.042 + 0.032 0.076 + 0.035 0.015 + 0.00004 roos C.> 0o% O

  In addition, we realized during a period

  period of 10 months clinical trials of the composition of the invention, in 8 thousand men. To this end, we have used alcoholic beverages containing the composition of the invention. During the entire period of the test,

  volunteers did not use other alcoholic beverages.

  Total reduction in alcohol consumption

  The 10-month trial was 28.01%.

  During the 10-month clinical trial, the number of alcoholic psychoses in the aforementioned group of individuals was reduced to 4 cases compared with 12.5 cases on average for 6 periods.

previous analogs.

  The evolution of alcoholic intoxications is changing.

  fia: lighter form of abstinence syndrome, reduced need to take alcohol to overcome abstinence, appearance of somatic complaints preventing dipsomania in

people abusing alcohol.

  Among the individuals tested, we did not find any cases of demographic or social phenomena

excessive.

  Thus, at the end of the experiments and research

  realized we can conclude that the effect, summary, of

  the composition of the invention against the negative consequences

  Alcohol consumption consists of the action of the ingredients of the said composition on the main biological manifestations of ethanol: the membrane action of ethanol is reduced by the normalization of the stability of the membrane at costs of regulating cholesterol synthesis, its

  esterification and its inclusion in the structure of the

  brane. In addition, there is a normalization of the activity of membrane-bound enzymes and other

  parameters of permeability in the vitamin P-active system

quick;

* - Oxidation of ethanol is essential

  in the liver, this process being accompanied by

  the oxidized form of the nicotinamide dinucleotide

  NAD +. The other oxidation processes, taking place with the participation of NAD, are inhibited. The ingredients of the composition, of the invention, act as acceptors

  of the Hydrogen ion and contribute to the reduction of

NADH / NAD;

  during the oxidation of ethanol in the

  the most toxic metabolite - the acne

  taldéhyde, whose presence in the tissues subsequently ensures the constitution of the toxicological and narcotic characteristics of ethanol. The rate of oxidation of ethanol and acetaldehyde depends first and foremost on

  the activity of alcohol dehydrogenase and acetaldehyde

  dehydrogenase. The ingredients of the composition of the in-

  vention have the capacity to reduce the activity of alcooldéhhydrogènase, thereby slowing the oxidation of ethanol, and, moreover, to compete

  with ethanol as a substrate for alcohyde

  genesis. In this case is carried out thanks to the presence of alcooldéhydrogenase, oxidation first, not ethanol, but the competing substrate of the composition of the invention; - the caloric effect of ethanol, thanks to which it successfully enters into competition with other sources

  by surpassing them by its criterion of accessibility

  causes the narrowing of the main metal beam

  bowl of transformation of different food

  at the expense of the competitive isolation of dehydrogen

  specific nases and their prosthetic groups. The com

  position, according to the invention, contributes to the preservation, and even, as a result of prolonged consumption of alcohol, the restitution of other energy pathways, in particular,

  through gluconeogenesis.

  Studies of the composition of the invention,

  experiments in animals and during the therapeutic trials of volunteers, established that the said composition has the property of ensuring

  rational ways of high resistance and restitution

  of the body. In all cases of application of extreme overloads on animals (physical, chemical

  and biological) there has been a clear protective effect.

  Moreover, the composition of the present invention

  also specific biological properties, inhibition of

  constitution of the subject's physical dependence

  alcohol and reduce the negative effects of metabolism.

  Toxic lites of ethyl alcohol.

  The wide range of biological action of the compound

  The invention is explained by the fact that it contains a batch of substances, ensuring optimal metabolic variants, aimed at conserving energy reserves.

  of the body by synthesis of carbohydrates from

  Non-carbohydrate bolites by way of glucogenesis.

Example 1

Composition comprising, in mg / g:

  leucodelphinidine 120; leucocyanidin 80; leucopélargo-

  nidine 45; (-) Epigallocatechin - 42; (+) Gallocatechin - 31; (-) epicatechin - 29; (+) catechin 60; (-) epicatechingallate 18; kampferol-3-monoglucoside 17;

  Quercetin 3-monoglucoside 22; 3-monoglucoside half

  Ricetin - 14; Quercetin-24 glycoside; astragaline 13; lignin 75; D-glucose - 83.6; D-fructose - 64; sucrose -33.5; rafinose 24; arabinose - 25; xylose - 31.6; pectin -20; lysine 3,4, histidine -0,2; arginine - 0.4; aspargic acid - 4.3; threonine - 1,1; serine -2.0; glumatic acid - 3.0; proline - 3.3; glycine - 2.2; alanine - 3.8; cystine - -0.3; valine - 1.8; methionine - 0.4; isoleucine - 0.8; leucine - 2.8; tyrosine - 0.5; phenylalanine - 0.3; tartaric acid -4.2;

  malic acid - 3.8; citric acid - 4.0; ascorbic acid

  bique - 4.0; ketoglutaric acid - 1.9; fumed acid

  - 2.1; galacturonic acid -2.2; glyceric acid - 1.8; glycolic acid - 1.7; glyco-uronic acid -3.0;

  oxalic acid - 2,3; succinic acid - 5.0; shiki- acid

  mic - 3.0; C-amine-0.4; -amarine - 0.4; lupeol - 0.3; taraxasterol - - 0.4; taraxerol - 0.4; germanicol - 0.3; obtusifoliol 0.8; citrostadienol - 0.7; -citrosterole - 3.2; stigmasterol - 1.0; campesterol - 0.8; oxymatairsinol - - 2.9; matairésinol - 2,3; pinoresinol - 2.5; L-vinyl - 2.7; isolariciresinol - 2.7; olivile - 1.9; arabinoside querinol - 6.2; xyloside of querinol - 3.8; 1,2-paraoxybenzoic acid; acid

  protocatechic - 3.5; gallic acid -1.9; vanilla acid

  lique - 4.3; syringic acid - 4.1; vanillin - 1.5; syringic aldehyde - 1.3; sinapic aldehyde - 0.9; coniferol aldehyde - 1.3; octadecanololferulate - 1.5;

  eicosanol-ferulate - 1.4; docosanol-ferulate - 1.1; tetra-

  cosanol-ferulate - 0.5; hexacosanol-ferulate - 0.5.

  This composition is dissolved at the rate of 5 g in

  ml of a 40% aqueous solution of ethanol.

  The hydro-alcoholic solution obtained has a red-brown color, a weak characteristic odor and a sweet-bitter taste. The solution has low toxicity, its

  LD50 represents 36.5 ml / 1000 of body weight of the rat.

  This solution has the power to ensure the rational ways of resistance and restitution of the body, it inhibits

  the constitution of the subject's physical dependence on

  cool and reduces the negative effects of toxic metabolites

ethanol.

Example 2

  The composition has the same ingredients as those listed in Example 1 but in the amounts

  following, in mg / g: leuco-anthocyanins -

  - 197.1; catechins - 137.7; flavanols - 72.9; lignin -

  - 61.2; reducing sugars - 410,76; pectin - 16.2; free amino acids 24,3; organic acids - 32.4; sterinols - 4.05; methyl sterols - 1.21; dimethylsterols

  - 1.78; lignans - 12.1; glucosides of lignans -

  - 8.1; phenolic acids - 12.1; aldehyde-phenols -

4.05; Ferulants of alkyls - 4.05.

  Dissolve the composition at a rate of 5 g in 100 ml of a 4% aqueous solution of alcohol. The solution obtained has a red-brown color, a weak characteristic odor and a weak sweet taste. The solution has a weak

  toxicity, its LD50 represents 41.2 ml / 1000 g of body weight.

porel of the rat.

  This solution has the power to ensure the

  As a result of the resistance and restitution of the body, it weakly inhibits the constitution of the subject's physical dependence on alcohol and reduces to a certain extent the negative effects of the toxic metabolites of ethanol. The biological activity of this composition is mediocre, and in some biological tests this

  activity can not be saved.

Example 3

  The composition has the same ingredients as those mentioned in Example 1, but in the following amounts, in mg / g: leucoanthocyanins - - 219; catechins - 153; flavanols - 81; lignin - 68; editors' sugars - 345, 17; pectin - 18; free amino acids - 27; organic acids - 36; sterinols - 4.5; méthylstérinols

  - 1.35; dimethylsterinols - 1.98; lignan-13.5; glue-

  cosides of lignans - 9; phenol-acids - - 13.5; al

  dehydrogen phenols - 4.5; ferulas of alkyls - 4,5.

  Dissolve the composition at a rate of 5 g in ml of a 40% aqueous solution of alcohol. The solution

  has a red-brownish color, a slight odor

tick and a bitter sweet taste.

  The solution has a low toxicity, its LD50

  represents 36.5 ml / 1000 g of weight weight for the rat.

  The solution has the power to ensure the

  of resistance and restitution of the body inhibits the constitution of the subject's physical dependence on alcohol and reduces to a certain extent the effects

  toxic metabolites of alcohol.

Example 4

  The composition has the same ingredients as

  those mentioned in Example 1, but taken from

  in mg / g: leuco-anthocyanins -

  - 270; catechins - 187; flavanols - 99; lignin - 83; reducing sugars 197.5; pectin - 22; free amino acids - 33; organic acids - 44; sterols - 5.5;

  methyl sterols - 1.65; dimethylsterols - 2.42; ligna-

  nes - 16.5; Lignan glucosides - 11; phenol acids - 16.5; aldehyde phenols - 5.5; ferulas of alkyls

- 5.5.

  Dissolve the composition at a rate of 5 g in 100 ml of a 40% aqueous solution of alcohol. The solution obtained

  has a red-brown color, a slight odor

  tick and a bitter sweet taste. The solution has a low toxicity, its LD50 representing 36.5 ml / 1000 g of weight

weight for the rat.

  The solution has the power to ensure the rational

  of resistance and restitution of the body, inhibits the constitution of the subject's physical dependence on alcohol and reduces the negative effects of its metabolites.

toxic.

Example 5

  The composition has the same ingredients as those mentioned in Example 1, but in the following amounts, in mg / g: leucoanthocyananes - - 297; catechins - 205; flavonols - 109; lignin - 91; reducing sugars - 120.6; pectin - 24; free amino acids - 36; organic acids - 48; sterols - 6; methyl sterols - 1.8; 2,6-dimethylsterols; lignans - - 18; Lignan glucosides - 12; acid-phenols - 18; aldehyde-phenols -6;

Ferulas of alkyl-6.

  Dissolve the composition at a rate of 5 g in 100 ml of a 40% aqueous solution of alcohol. The solution obtained

  has a brownish-red color, a distinct odor

  tick and a bitter taste. The solution has a low toxicity

  cited, its LD50 representing for the rat 33.3 m / 10/1000 g of

weight weight.

  The solution has the power to ensure the rational

  of resistance and restitution of the organism, it inhibits the constitution of the subject's physical dependence.

  alcohol and reduces the negative effects of its metabolism.

toxic substances.

R EV E N D I C A T I 0 N

  Composition, preventing the development to the accou-

  pathological tumors with alcohol, characterized in that it contains the following ingredients: in mg / g: leuco-anthocyanins - 219-270 catechins 153-187 flavanols - 89-99 lignin - 68-83 reducing sugars - 216-264 pectin - 18-22 free amino acids - 27-33 organic acids - 36-44 sterols - 4 5-5,5 methylsteiols - 1,35-1,65 dimethylsterols - 1,98-2,42 lignans - 13,5- 16.5 glucosides of liganes - 9,11 acids-phenols - 13,516,5 aldehydes-phenols - 4,5-5,5

ferulants of alkyls - 4,5-5,5.