RU2318538C1 - Pharmaceutical composition based on hepatoprotector and prebiotic and method for producing and applying the composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves administering pharmaceutical composition for restoring liver functions, cholesterol metabolism and intestinal biocenosis.

EFFECT: enhanced effectiveness of treatment.

13 cl, 1 tbl

Description

The invention relates to medicine, in particular to hepatology and pharmacology, and can be used to obtain and use a pharmaceutical composition based on hepatoprotector and prebiotic for the treatment and prevention of liver diseases selected from the group: gallstone disease, fatty hepatosis and non-alcoholic steatohepatitis, primary biliary cirrhosis liver, gallbladder cholesterosis, drug and toxic liver damage.

The urgency of the problem is associated with an increase in the frequency and severity of liver diseases - the main organ of detoxification of exogenous poisons. The reasons for the increase in liver morbidity are environmental dysfunction in most parts of the world.

An additional and directly associated with the impact of environmental factors is a decrease in immunity in the population, leading to a significant increase in infectious lesions of the liver, and primarily viral hepatitis.

The source of infection with viral hepatitis is a sick person, the transmission route is either fecal-oral or parenteral, depending on the type of virus: A, B, C, D, G, E. The susceptibility of the population to this infection is high.

Regardless of the entry gate, the virus eventually enters the liver, where it has a direct toxic effect on the liver cells, which is combined with immune-mediated damage to their membranes.

With all forms of viral hepatitis, one of the frequent serious complications is a violation of the normal processes of formation and secretion of bile, the so-called cholestatic syndrome, accompanied by jaundice. Most often it manifests itself in viral hepatitis A (HAV) - “enteric” viral hepatitis and in viral hepatitis E, in which the frequency of icteric forms is 100%.

In severe forms of the course of acute viral hepatitis (OVH) and exacerbations of chronic hepatitis, a violation of the structure and functional activity of the biliary ducts is one of the reasons for the development of a severe complication - biliary cirrhosis.

In addition to viral hepatitis, a significant proportion of liver morbidity is associated with exposure to food toxicants (alcohol, other toxic substances, various medicines).

One of the earliest pathological complications of toxic liver damage is steatohepatitis - a consequence of a disturbance in the normal balance between the intake of fats in the body and their metabolism.

It should be emphasized that the violation of the normal processes of formation and biliary passage of bile is one of the common consequences of exposure to high doses of a number of drugs (antibiotics, sulfonamides, chlorpromazine, histamine receptor and estrogen blockers, as well as cytostatics).

In the last decade, the so-called autoimmune hepatitis is being diagnosed more and more often - a consequence of a deep violation in the cellular immunity system. Its most severe consequence is primary biliary cirrhosis.

Violation of the processes of bile formation and biliary excretion is most clearly expressed in the form of gallstone disease (cholelithiasis), in which there is an excessive accumulation (stagnation) of bile in the gallbladder with the subsequent formation of calculi (cholelitis or gallstones).

With all of the aforementioned liver diseases, one of the important etiological and pathogenetic factors is a violation of normal metabolic processes of bile acids (FA) - one of the most important factors in normal digestion.

FAs are formed in the liver from cholesterol (Hofmann AF. Bile acid secretion, bile flow and biliary lipid secretion in humans. Hepatologi. 1990; 12; 17S; Meier PJ. The bile salt secretory polarity of hepatocytes. J. Hepatol. 1989; 9: 124).

The main FAs found in human bile are cholic acid (CC) (3a, 7a, 12a-trioxy-5b-cholanic acid), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) (3a, 12a-dioxi-5b-cholanic acid). Stereoisomers of cholic and deoxycholic acids in the form of allocholic (ACA), ursodeoxycholic (UDCA) and lithocholic acid (LAC) (3a-manooxy-5b-cholanoic acid) were found in significantly smaller amounts in bile.

HC and CDA, the so-called primary FAs, are formed in the liver during the oxidation of cholesterol, and DCA and LCA are formed from primary FAs in the intestine under the influence of enzymes of microorganisms of the intestinal microflora.

The quantitative ratio of HC, CDC and DHA in bile is normally 1: 1: 0.6.

In cystic bile, FAs are present mainly in the form of paired compounds - conjugates. In the intestine, mainly in the ileum, FAs are absorbed into the blood, return to the liver with blood and again are secreted as part of bile - this is the so-called portal-biliary circulation of FAs, therefore 85-90% of the total amount of FAs contained in bile constitute FA absorbed in the intestine.

Portal-biliary circulation of FAs makes FA conjugates easily absorbed in the intestine, as they are water-soluble, while in the intestine 10-15% of the total number of FAs is cleaved by the enzymes of the microorganisms of the intestinal microflora, and the products of their degradation are excreted in the feces.

FA, emulsifying fats, thus ensure the absorption in the small intestine of insoluble fatty acids and cholesterol, as well as vitamins: B, K, E and calcium salts.

In addition, FAs have a strong choleretic effect, stimulate intestinal motility, and also have bacteriostatic and anti-inflammatory effects.

In view of the foregoing, a possible component of the method of treatment and prevention of many pathological conditions of the liver is the use of bile acid preparations, primarily UDCA.

UDCA is a tertiary bile acid, first discovered in the bile of a Chinese bear in 1902. UDCA has been used in medicine for several centuries: even in ancient China, dried bear bile was prescribed in the treatment of diseases of the stomach, intestines and liver. UDCA is formed by bacterial enzymes from 7-keto-lithocholic acid, which enters the liver from the small intestine.

The chemical formulas of UDCA and hydrophobic CDCA are identical (C ₂₄ H ₄ O ₄ ).

The use of UDCA for the treatment of, in particular, liver diseases leads to a dose-dependent change in the above ratio of bile acids: UDCA becomes the main component of bile, while the content of CDCA and other FAs decreases.

A lower accumulation of UDCA in bile is observed in patients with liver diseases, which may be associated with a decrease in absorption due to a decrease in the formation of endogenous micelles from bile acids in duodenal bile or with a decrease in secretion of bile acids themselves.

UDCA and LHC are found in human bile, as mentioned above, only in very small quantities (0.1% -5%).

Despite the good absorption of UDCA in the intestine, its plasma level remains relatively low due to the rapid hepatic clearance, because effective conjugation of UDCA with glycine, taurine, N-acetyglucosine, glucuronic acid and sulfate occurs in the liver.

The effect of UDCA on cholesterol in bile is complex. The absorption of cholesterol in the intestine, its synthesis in the liver and secretion in bile are reduced. However, the level of cholesterol in the blood under the influence of UDCA does not significantly decrease.

UDCA and its conjugates, which are not absorbed in the small intestine, are metabolized in the distal small intestine and colon by indigenous bacteria.

In the intestine, UDCA is cleaved and dehydroxylated to lithocholic acid (LCC). LHC, contained in very small amounts in human bile, is formed in the small intestine under the influence of microflora in the process of utilization of many fats; from the small intestine, LHC enters the colon and rectum, where it is partially absorbed and enters the liver.

In the liver, LHC binds to sulfate anions, then to glycine and taurine, and thus is secreted into bile. Its derivatives are little absorbed in the intestine and excreted through the stool. Such a process is an effective mechanism for eliminating toxic HLC from the body.

CDCA causes a decrease in the activity of 3-hydroxy-3-methylglutarylcoenzyme A reductase, an enzyme involved in the synthesis of cholesterol, and also helps to reduce cholesterol absorption in the intestine, which leads to a change in the ratio of bile acids and cholesterol towards the prevalence in the total pool of bile acids of CDCA.

The above mechanisms determine the use of HDCA in the dissolution of gallstones, consisting mainly of cholesterol.

Deoxycholic acid (DCA) is a bile acid that is formed in humans in the intestines by the action of intestinal microflora enzymes, absorbed into the blood and secreted by the liver as part of bile.

It is believed that the hydrophobic salt of DHA can be a link between impaired intestinal motility and lithogenicity of bile. The main bile acids in humans are HC and HDCA, the primary bile acids synthesized in the liver from cholesterol. Secondary DHA is formed in the distal parts of the small intestine and in the colon under the influence of intestinal microflora enzymes, namely bacterial 7-alpha-dehydroxylase, from cholic acid. DCA is partially absorbed from the intestine and is involved in the recirculation of bile acids after conjugating it in the liver with taurine or glycine. An increased transit time through the intestines enhances the formation of DCA as a result of bacterial metabolism, and a decrease in transit time has the opposite effect.

As a result, the amount of DCA varies significantly: from 10 to 30% of the total pool of bile acids. Recently, it has been proved that in patients with cholelithiasis the number of gram-positive anaerobic bacteria is increased and their 7-alpha-dehydroxylase activity in the cecum is increased in comparison with healthy patients.

At the same time, a correlative relationship was established between delayed transit through the intestine, an increased proportion of DHA, a supersaturation of bile with cholesterol, and the formation of calculi. It is assumed that DCA promotes lithogenicity of bile and the formation of calculi by slowing the transit time through the intestines, which, in turn, increases the absorption of cholesterol and, through a positive feedback mechanism, promotes the formation of DCC itself.

In addition, DCA can enhance the secretion of cholesterol into bile by acting on the canalicular membrane of the hepatocyte, where cholesterol is in the sphingomyelin domains, and also enhance crystallization of cholesterol in bile, destabilizing vesicles with cholesterol.

In cystic bile, FAs are present mainly in the form of paired compounds - conjugates. As a result of conjugation of FAs with the amino acid glycine, glycocholic (GHK) or glycohenodeoxycholic (GHDKh) acids are formed. Conjugation of FAs with taurine (2-aminoethanesulfonic acid C ₂ H ₇ O ₃ N ₅ ), a product of the degradation of the cysteine amino acid, produces taurocholic (THC) or taurodeoxycholic acid (TDCA). Conjugation of FA includes the steps of forming CoA - FA esters and combining the FA molecule with glycine or taurine via an amide bond with the participation of the lysosomal acyltransferase enzyme. The ratio of glycine and taurine FA conjugates in bile, an average of 3: 1, can vary depending on the composition of food and the hormonal status of the body.

Thus, metabolic disorders of bile acids is one of the important pathogenetic factors in the development of a number of liver diseases.

A known method of treatment of the above liver diseases, which consists in the use in the form of mono - or complex therapy of drugs UDCA (RU 2002123352 A from 03/27/2004).

There is also a method of treating liver diseases by using HDCA in complex therapy (Russian Drug Register. Drug Encyclopedia. Editor-in-chief G.L. Vyshkovsky. M.: “RLS-2006”, 2005, pp. 895-896).

However, in these methods of treatment, the therapeutic effect develops only after a long time (from several to 6-12 months) of the use of drugs, and often requires, in essence, their lifelong administration.

This is largely due to the fact that the use of FA preparations as monotherapy cannot completely eliminate such an important pathogenetic factor as intestinal dysbiosis and complex systemic metabolic disorders caused by the latter.

As a medicine with hepatoprotective properties, other substances have been used for a long time in terms of the structure and mechanisms of action of the substance, the validity of which is referred to by many experts as true hepatoprotectors.

They often include, in particular, the class of so-called essential phospholipids.

Phospholipids, or phosphoglycerides, are highly specialized lipids and are important fundamental components of cell membranes and membranes of structural elements of cells, such as mitochondria, and can be called “essential” (essential) for the growth, development and proper functioning of all somatic cells. In addition to their role in the construction of cell membranes, phospholipids are important constituents of lipoproteins, "pulmonary surfactants" and bile. They take part in the work of the nervous system, in membrane enzymatic reactions, play an important role in metabolism and oxidative processes. Being part of lipoproteins, phospholipids affect the concentration of cholesterol in the blood.

Phospholipids located in platelets take part in the process of blood coagulation, which ultimately shows their effect on the protective function of blood and hemodynamics in the body of mammals and humans. The chemical structure of phospholipids, their biphilicity, the presence of charged groups determines the uniqueness of their physiological properties.

The main function of phospholipids is the formation of a double lipid layer in cell membranes. The structure and function of cell membranes is of extreme importance to human health. A feeling of general malaise, dysfunction and various diseases can in many cases be explained by damage to the membranes or their instability. By introducing phospholipids, it is possible to influence the membrane functions associated with membrane proteins and correct them, at least to some extent, and sometimes completely correct the impaired function.

Essential phospholipids mainly penetrate the liver cells, penetrate the hepatocyte membranes, normalize the liver functions, metabolize lipids and proteins, promote the activation and protection of phospholipid-dependent enzyme systems, improve the detoxification function of the liver, restore its cellular structure, improve regeneration and inhibit the formation of it connective tissue.

The drug reduces the level of energy consumption in the liver, converts neutral fats and cholesterol into easily metabolizable forms, stabilizes the physicochemical properties of bile.

Essential phospholipids normalize the digestion in the intestines of not only fats, but also solid foods indirectly by restoring the structure of liver cells, which leads to the normalization of bile formation and biliary excretion (Gurevich KG Essential phospholipids in the treatment of liver diseases. Qualitative clinical practice. 2002, No. 4 pg. 108-111).

Another representative of the group of substances with hepatoprotective properties is the extract from the plant of milk thistle as the main active ingredient in silymarin. Its action is hepatoprotective, regenerating, detoxifying.

It neutralizes free radicals in the liver, prevents the destruction of cellular structures. Specifically stimulates RNA polymerase and activates the synthesis of structural and functional proteins and phospholipids in damaged hepatocytes. It stabilizes cell membranes, prevents the release of intracellular components (transaminases) and accelerates the regeneration of liver cells. It inhibits the penetration of certain hepatotoxic substances into the cell (poisonous toadstool).

Clinical pharmacology: improves the general condition of patients with liver diseases, reduces subjective complaints: weakness, a feeling of heaviness in the right hypochondrium, loss of appetite, vomiting, skin itching, normalizes laboratory parameters: transaminase activity, gamma-glutamyl transferase, alkaline phosphatase, bilirubin level. With prolonged use increases the life expectancy of patients with cirrhosis.

Often, a number of amino acids or their derivatives are also referred to as hepatoprotective preparations.

The most famous of them is ademethionine (Russian Medicines Register. Encyclopedia of drugs. Editor-in-chief G.L. Vyshkovsky. M.: RLS-2006, 2005, p. 51).

This drug compensates for the deficiency of ademetionine and stimulates its production in the body, especially in the liver and brain. The S-adenosyl-L-methionine (ademethionine) molecule donates a methyl group in the methylation reactions of phospholipids of cell membranes of proteins, hormones, neurotransmitters, etc. (transmethylation). It is a precursor to physiological thiol compounds - cysteine, taurine, glutathione (provides the redox mechanism of cellular detoxification), CoA, and others in trans sulfation reactions. After decarboxylation, it participates in the aminopropylation processes as a precursor of polyamines - putrescine (a stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure.

It has an anticholestatic effect, is effective in the intralobular variant of cholestasis (impaired synthesis and bile flow). The anticholestatic effect is due to increased mobility and polarization of hepatocyte membranes, due to the stimulation of the synthesis of phosphatidylcholine in them. This improves the function of bile acid transport systems (BFAs) associated with hepatocyte membranes and promotes the passage of FAs into the biliary system. It stimulates the detoxification of FAs, increases the content of conjugated and sulfated FAs in hepatocytes. Conjugation with taurine increases the solubility of FAs and their removal from hepatocyte.

Sulfation provides the possibility of elimination by the kidneys, facilitates the passage through the membrane of hepatocytes and excretion with bile. In addition, sulfated FAs protect liver cell membranes from the toxic effects of non-sulfated FAs (present in high concentrations in hepatocytes with intrahepatic cholestasis).

In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, it reduces the severity of pruritus and changes in biochemical parameters, including direct bilirubin, alkaline phosphatase activity, aminotransferases, etc. The therapy was accompanied by the disappearance of asthenic syndrome in 54% of patients and a decrease its intensity in 46% of patients. Antiasthenic, anticholestatic and hepatoprotective effects persisted for 3 months after discontinuation of treatment. It has been shown to be effective in hepatopathies caused by hepatotoxic drugs (paracetamol, etc.). As a result of treatment of patients with opioid addiction, accompanied by liver damage, there was a regression of the clinical manifestations of withdrawal symptoms, an improvement in the functional state of the liver and microsomal oxidation processes, and an antidepressant effect.

Application: intrahepatic cholestasis, liver damage: toxic, including alcoholic, viral, medicinal (antibiotics, antitumor, antituberculosis, antiviral drugs, tricyclic antidepressants, oral contraceptives); cirrhotic and precirrotic conditions; encephalopathy, including associated with liver failure (alcohol, etc.); depressive and withdrawal syndrome.

In addition to directly affecting liver tissue, ademetionine has a number of additional pharmacological effects, such as an antidepressant effect (develops in the first week and stabilizes during the second week of treatment). Also, this drug is empirically used for osteoarthritis, which is accompanied by a decrease in pain and stimulation of proteoglycan synthesis and partial regeneration of cartilage tissue.

However, the use of essential phospholipids in the treatment of liver diseases, as for other hepatoprotectors, usually does not provide a complete cure, and when drugs are withdrawn, relapses or exacerbations of liver diseases often occur, including due to a persistent violation of the intestinal biocenosis, which is persistent in many diseases of the gastrointestinal tract and liver.

In recent years, in gastroenterology, the concept of the unity of all processes occurring in the pathology of the gastrointestinal tract has begun to gain increasing recognition. In the framework of this concept, one of the most important components of this normal state is the normalization of the microflora of the large intestine.

The microflora of the gastrointestinal tract (GIT) and the liver inextricably interact in the processes of detoxification of the body. The microbiota in the composition of the biofilm first comes into contact and subsequent metabolic reactions with all substances entering the body with food, water or atmospheric air. Microbiota transforms chemicals into non-toxic end products or into intermediates that are easily destroyed in the liver and then removed from the body.

The body has two main detoxifying organs - the liver, which protects the body through oxidative reactions, and the microflora of the digestive tract, which uses hydrolytic reduction processes for these purposes. Violation of the interaction of these systems leads to mutual functional and structural changes in themselves and the body as a whole. Therefore, the enterohepatic circulation of various organic and inorganic compounds can, without exaggeration, be considered cardinal homeostatic mechanisms. A decrease in the detoxification function of the gastrointestinal microflora in case of dysbiosis due to various pathogens (drugs, food, stress, etc.) increases the load on the enzymatic systems of the liver and, under certain conditions, contributes to the occurrence of metabolic and structural changes in it.

With an imbalance in the microecology of the digestive tract, an increase in the proportion of potentially pathogenic gram-negative bacteria leads to a significant accumulation of endotoxins in the intestinal lumen. The latter, penetrating through the intestinal mucosa into the local circulatory system, and then through the portal vein into the liver, cause damage to hepatocytes or potentiate the adverse effects of other toxicants. 90% of all endotoxins are released optionally by anaerobic gram-negative bacteria. Endotoxins damage cell membranes, disrupt ion transport, cause fragmentation of nucleic acids, induce the formation of free radical oxidation products, initiate apoptosis, etc. (Gracheva N.M. et al. Hilak-forte in the complex treatment of patients with acute intestinal infections and chronic diseases of the gastrointestinal tract with dysbacteriosis. Consilium medicum. 2004. No. 1. P.31-34).

Consequently, one of the possible ways to restore violations in the complex relationship of microbiota and the liver is to combat intestinal dysbiosis.

Thus, there is a method for normalizing intestinal microflora by introducing into (per os) probiotics - living bacteria, species and genera that normally colonize the large intestine of humans and other mammals (V.F. Demin et al. Experience in the use of biofitocorrection in children with dysbiosis. Questions modern pediatrics. 2003, No. 3, vol. 2, pp. 33-36).

However, the use of probiotics in the form of monotherapy does not give sustainable effects due to the "foreignness" of bacterial strains introduced from outside, as well as their rather rapid elimination (3-5 days) after stopping the drug (LS).

Other drugs used to correct intestinal microbiota disorders - prebiotics - are deprived of this drawback.

Prebiotics include, in particular, many oligosaccharides that are not utilized by the human body due to the absence in the intestines of their own enzymes that break down such sugars.

Indigestible oligosaccharides include, in particular: fructooligosaccharides (FOS), maltooligosaccharides, galactooligosaccharides, inulin, lactulose, and some other oligosaccharides that can be used as prebiotics (Sheveleva S.A. Probiotics, Prebiotics and Probiotic Issues. Nutrition, 1999, No. 2, pp. 33-39; Shoaf K et al. Prebiotic galactooligosaccharides reduce adherence of Enteropathogenic Escherichia coli to tissue culture cells. Infect Immun. 2006 Sept. 18. Abstr.).

FOS in terms of chemical structure are oligofructosaccharides in which β-, D-fructofuranose residues are interconnected by β-2, 1-glycosidic bonds and have an α-glucose residue at one end of the chain connected to the fructose bond α-1, 2. Their can be considered as derivatives of sucrose, to the fructose part of which 1 to 3 fructofuranose residues are attached by β-2, 1 bonds. The main components of FOS are 1-kestose (GF ₂ ), nystosis (GF ₃ ) and 1F-fructofuranosylnose (GF ₄ ) .

FOS have a pronounced prebiotic effect, are not absorbed in the upper gastrointestinal tract, inhibit the growth of putrefactive microflora, contribute to the normalization of blood pressure and lipids in the blood, improve the adsorption of calcium and magnesium, increase immunity, have a beneficial effect in constipation and purulent processes; prevent colon cancer.

FOS, like all prebiotics, are not hydrolyzed by the digestive tract enzymes, are not absorbed in the small intestine, and, unchanged in the colon, are a selective substrate for the growth of normal microflora.

Lactulose is a disaccharide consisting of galactose and fructose (4-0-D-galactopyranosyl-D-fructose). In vivo, a small amount of lactulose can form when milk is heated to temperatures above 100 ° C. Lactulose is highly soluble in water and about 1.5-2 times sweeter than lactose.

The prebiotic effect of latulose is manifested by an increase in the volume of the contents of the colon, a decrease in pH, as well as a decrease in the ammonia content in the colon and an increase in the content of short-chain fatty acids, in particular propionic acid (ZDUNCZYK Z et al. Physiological effects of lactulose and inulin in the caecum of rats. Arch Anim Nutr. - 2004 .-- Vol. 58 (1). - P.89-98).

The effect of lactulose on the intestinal microflora due to an increase in the number of bifidobacteria with an increase in the activity of microbial β-galactosidases is also known (BOUCHNIC Y et al. Prospective, randomized? Parallel group trial to evaluate the effects of lactulose and polyethylene glycol-4000 on colonic flora in chronic idiopathic constipation. Aliment. Pharmacol. Ther. - 2004. - Vol.19 (8). - P.889-899).

Being a prebiotic, lactulose, at the same time, is still used in therapy, mainly or even exclusively, as a mild and effective laxative. The laxative effect of lactulose is directly related to the prebiotic effect and is due to an increase in the volume of the contents of the colon (by about 30%) due to an increase in the number of bacterial populations.

For example, there is a method for normalizing disorders of the intestinal microflora, including the use of prebiotics, in particular the indigestible oligosaccharide (lactulose, FOS, etc.) (JP 2003-155242 from 05.27.2003).

There is very little information in the literature about attempts to use prebiotics to treat liver diseases.

According to published data (Nikitin I.G. et al. Dufalac (lactulose) in the treatment of intestinal dysbiosis in non-alcoholic steatohepatitis. Clinical perspectives of gastroenterology, hepatology, coloproctology, 2002, No. 1, pp. 24-29; Savelyev BC Lipid distress syndrome in Surgery.Vestnik of the Russian Military Medical Academy. 1999, No. 1, pp. 36-39) their use as single drugs in itself is ineffective in attempts to treat liver diseases, since in this case cell damage and, accordingly, functions are not completely eliminated. since zhennoy liver tissue.

The therapeutic effect of the use of prebiotics only occurs after a sufficiently long period of time and in this case the complete restoration of impaired lipid, in particular cholesterol metabolism is not achieved. Moreover, in the above studies, lactulose was used in high doses (about 30 ml of concentrated syrup per person), which are known not only as prebiotic, but as laxatives. At such high doses, lactulose is usually used in hepatology mainly to alleviate the symptoms of hepatic encephalopathy, that is, in palliative symptomatic relief of the condition in patients with almost incurable conditions (late stage cirrhosis). In these situations, the normalization of intestinal microflora is not able to give any long-term effect.

Therefore, in the treatment regimens of various diseases, the schemes of the integrated use of drugs of various groups, for example, immunomodulators and antibiotics, choleretic drugs, etc., are increasingly used.

In this regard, in particular, there is a known method for the treatment of chronic non-calculous cholecystitis with manifestations of dysbiosis through the use of a combination of hepatoprotector (glutargin) and eubiotics (bifiform) (UA 70018 of September 15, 2004).

However, the therapeutic result of this combination is short-lived due to the above limitations associated with the use of probiotics.

There is also known a method of treating liver diseases with cholestatic syndrome by using a combination of hepatoprotector of plant origin (extract obtained from Silibum marianum) with the probiotic strain Lactobacillus bulgarinii and some other substances (BG 108250U from 04.30.2005).

However, in this case, the positive therapeutic effect is relatively short-lived.

There is a method of correction of Savelyev’s lipid distress syndrome by means of complex therapy, including hepatoprotector of plant origin - hepatene, and metabolite probiotic hilak-forte (V. Petukhov. Liver dysfunction and dysbiosis with lipid distress syndrome. Breast cancer, 2002, No. 10, t .4, pp. 158-160).

However, neither the treatment regimen with the indicated agents, nor their dose or ratio are defined in this analogue, and the interaction of the drugs used is not shown.

It is also known that the use of a combined preparation for the treatment of liver diseases containing alkaline sphingomyelinase as the main active principle, and various substances, including from the class of probiotics (Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus, as an additional active ingredient) catenaforme), prebiotics and UDCA (EA 5166 dated 12/30/2004).

In the above analogue, the leading role is played by sphingomyelinase (lysosomal enzyme), which is used to prevent and / or treat various diseases selected from the group: impaired activity of the small intestine, malignant tumors, disorders in the immune system, inflammation and desquamation of the mucous membrane of the small intestine, condition associated with impaired cholesterol synthesis, impaired absorption of the small intestine, allergic diseases of the small intestine.

Moreover, as auxiliary substances, the indicated pharmaceutical composition includes: probiotics (Lactobacillus acidophilus, Lactobacillus brevis, Lactobacilus casei, etc.), a bile acid derivative - ursodeoxycholic acid and prebiotic - lactulose.

But the patent description does not disclose the role of these auxiliary substances in the treatment of liver diseases, and there is no scientific justification for their inclusion in this composition.

The use of this pharmaceutical composition for the treatment of these diseases is not without its main drawback - the short duration of action due to an exogenous probiotic strain. Moreover, the prebiotic components present in the composition are largely utilized by the exogenous strain introduced above.

In addition, the inclusion of a very large number of components with a different nature of action in the preparation does not allow not only to assess their role and therapeutic effect, but also does not exclude the mutual antagonism of such effects, which increases the likelihood of individual variations in the reaction to the introduction of such a large number of drugs.

The closest analogue of the claimed invention is a liver function improving agent or component that functions as a methyl group donor and includes a digestible oligosaccharide containing galactose, used as a functional food product (JP 2003-155242 from 05.27.2003).

In this case, the methyl group donor is selected from the group of amino acids, including S-adenosylmethionine, and the galactose-containing oligosaccharide is selected from the group including, lactulose or galactooligosaccharide.

However, in the aforementioned patent, the authors do not consider the prebiotic effects of the composition at all, and in the proposed agent the role of the oligosaccharides of the component (and only presumably) is reduced by the authors to the elimination of ammonia-induced hepatoencephalopathic intoxication.

Thus, the authors of the closest analogue do not associate the normalizing lipid metabolism effect of compounds - donors of metal groups with the normalization of the intestinal microbiocenosis, and this condition is not stated at all in the examples cited.

The lack of understanding of the inextricable relationship between the state of intestinal microbiocenosis and lipid metabolism reactions, the participation of representatives of normal microflora in the rupture of the vicious circle of enteropathogenic bile acid recycling, does not allow one to choose correctly not only the component composition of the compositions depending on the degree of disturbance of these most important components of the metabolic process, but also to the necessary degree monitor the adequacy and effectiveness of the therapy of liver diseases.

Reducing the role of the first component of the composition only to the function of a donor of a metal group, the authors unjustifiably disregard other mechanisms of lipid metabolism disturbance, in particular cholesterol metabolism, which play an important role in the development of many liver diseases.

The difference of the claimed method from the closest analogue is as follows:

- clearly defined liver disease, different from the closest analogue, for the treatment of which the present pharmaceutical composition has been developed;

- a pharmaceutical composition was developed, including hepatoprotector and prebiotic, selected strictly from a limited number of representatives of these groups of drugs;

- the feasibility of introducing a hepatoprotector and a prebiotic simultaneously in one pharmaceutical composition is shown in view of their synergistic effect on each other;

- developed the ratio of hepatoprotector and prebiotic in the claimed pharmaceutical composition.

The aim of the present invention is to achieve significant positive effects in the form of accelerating the normalization of health and reducing the severity of symptoms of the disease in the complex treatment of certain liver diseases.

Achieving this goal is achieved by using a combined (complex) drug in the treatment of liver diseases containing a mixture of hepatoprotector and prebiotic substance, in particular, oligosaccharides that are not digested in the intestine.

The technical result to which the present invention is directed is to restore liver function in the shortest possible time and prevent relapse of the disease due to the restoration of cholesterol metabolism and intestinal biocenosis due to the synergistic interaction of hepatoprector and prebiotic, which also leads to the prevention of side effects of the hepatoprotector.

As a hepatoprotector in the present invention, bile acids / bile salts selected from the group: GCC, GHDC, THC, TDCA, UDCA, CDCA and essential phospholipids were used.

The presence in the claimed pharmaceutical composition of a hepatoprotector and a prebiotic provides a pronounced and lasting therapeutic effect due to the synergistic action of the hepatoprotector and prebiotic.

The synergistic effect of the hepatoprotector, for example, UDCA, and the prebiotic is due to the fact that UDCA normalizes the digestion of not only fats in the intestines, but also solid foods by increasing the synthesis of bile acids and UDCA itself in the liver, which contributes to the normalization of intestinal microflora, and the prebiotic itself helps to normalize microflora by stimulating the growth of resident strains, which entails the manifestation of immunostimulating effects and other effects of normoflora, and as a result, improvement of digestion processes, better s detoxification of exogenous toxins own microflora, which also reduces the metabolic burden on the liver, promotes the normalization of metabolism of fatty acids and cholesterol, it appears, in turn, a stabilizing effect on all the body's cells, including hepatocytes.

Thus, the combination of bile acids or salts of bile acids in one pharmaceutical composition with non-digestible oligosaccharides in the small intestine selected from the group: lactulose or FOS, maltooligosaccharides, galactooligosaccharides, inulin, allows you to restore the functioning of hepatocytes and the liver as a whole due to the normalization of intestinal biocenosis, which , in turn, provides stabilization of the achieved therapeutic result for a long time.

As is known in diseases of the liver, and gallstone disease with mainly cholesterol stones, the patient’s blood contains an increased content of toxic products coming from the colon to the blood, especially ammonia, a nitro compound that is formed during bacterial decomposition of protein in the colon by proteolytic microflora, which increases the toxic load on the liver.

Thus, the restoration of microflora in the intestine indirectly contributes to an increase in the reduction of the toxic load on the liver and an increase in UDCA in the liver, which, in turn, helps to restore the composition of bile, in particular, to increase bile acids by reducing the synthesis of cholesterol by the liver, and this, in turn, prevents relapse of the disease, in particular gallstone disease with predominantly cholesterol stones.

In view of the foregoing, the active components in the presented pharmaceutical composition mutually enhance the available therapeutic properties of each of them.

The claimed pharmaceutical composition may include, as an active principle, various substances with hepatoprotective properties, in particular, a hepatoprotector selected from the groups: amino acids or their derivatives, active hepatoprotective substances from extracts of the milk thistle plant (silymarin, silibinin), or essential phospholipids or bile acids / salts of bile acids selected from the group: HCA, HDCA, DHA, UDCA, GDCA, TUDC, THC, GCC in a single dose of 50 mg to 500 mg and a prebiotic selected from the group of indigestible f rmentami human intestinal oligosaccharides such as lactulose or fructooligosaccharide (FOS), galacto-oligosaccharides or maltooligosaccharides or inulin or taken in prebiotic effective therapeutic dose of each, galactooligosaccharides, xylo-oligosaccharides or maltooligosaccharides, at a ratio of prebiotic to hepatoprotector from 1: 2 to 1: 250.

The claimed pharmaceutical composition may be in the form of tablets (coated or uncoated) or granules or globules or powders or capsules or suspensions or emulsions or gels.

Moreover, the claimed pharmaceutical composition may additionally contain excipients generally accepted in the pharmaceutical industry, such as microcrystalline cellulose or lactose, or corn starch, or potato starch, or hydroxypropyl methylcellulose, or carboxymethyl cellulose, or hydroxypropylmethyl cellulose, or hydroxypropylmethyl cellulose, or hydroxypropylmethyl cellulose, or calcium stearate or magnesium stearate or polysorbate or polyvinylpyrrolidone or polyethylene glycol or Falk, or titanium dioxide, or silica.

The claimed composition is prepared by mixing its constituent components, both active (hepatoprotector selected from the group: essential phospholipids or bile acids / bile salts and prebiotic), and auxiliary selected from the group: microcrystalline cellulose or lactose, or corn starch, or potato starch, or hydroxypropyl methyl cellulose, or carboxymethyl cellulose, or hydroxypropyl methyl cellulose, or hydroxypropyl cellulose, or their pharmaceutically acceptable salts, or ludipress, or calcium stearate, Whether magnesium stearate or polysorbate, or polyvinylpyrrolidone, or polyethylene glycol, or talc, or titanium dioxide, or silica.

The claimed pharmaceutical composition is administered orally with a large amount of water over a period of time from 1.5 to 3 months.

The claimed pharmaceutical composition can be used to treat patients with liver diseases selected from the group: gallstone disease with predominantly cholesterol stones, alcoholic and nonalcoholic steatohepatitis, primary biliary cirrhosis of the liver, gall bladder cholesterosis, drug and toxic liver damage and allows for a relatively short time ( from 6 to 12 weeks) achieve long-term remission of the disease.

Moreover, therapeutic efficacy is from 89% to 95%.

The claimed pharmaceutical composition has no contraindications and can be used to treat patients with liver diseases mentioned above, including against the background of severe concomitant diseases (with the exception of late stages of liver cirrhosis, malignant neoplasms of the gastrointestinal tract or other organs), regardless of age the patient.

The claimed composition does not have significant side effects, because the active components that make up the pharmaceutical composition are used in small and medium single therapeutic doses and for a fairly short period of time.

The proposed composition options are low cost and, therefore, available for all categories of patients.

Patients are treated on an outpatient basis and do not require, however, compliance with a bed or half-bed regime, which allows patients to lead a normal lifestyle.

The proposed pharmaceutical composition can be successfully used not only for treatment, but also for the prevention of exacerbations of liver diseases selected from the group: cholelithiasis mainly with cholesterol stones, alcoholic and nonalcoholic steatohepatitis, primary biliary cirrhosis, gallbladder cholesterosis, drug and toxic damage liver due to the restoration of the structure and function of both hepatocytes and liver function in general, due to the normalization of intestinal microflora.

The impact on the body of the proposed pharmaceutical composition in a certain dose provides for a gradual and increasing strengthening of the therapeutic effect and the inclusion of new levels of homeostasis regulation: subcellular, intracellular, tissue, organ, systemic and organismic, due to restoration of lipid metabolism, in particular cholesterol, due to normalization of intestinal microbiocenosis.

During treatment, which is carried out on an outpatient basis, the patient is recommended to observe a regimen of at least three meals a day throughout the duration of treatment; do not recommend taking alcohol, fatty and spicy foods, other drugs; prohibit fasting and hard physical work.

The final diagnosis is made on the basis of additional types of examinations (liver ultrasound or biliary tract R-graphy) and laboratory blood tests (biochemistry: cholesterol and its fractions, bilirubin and its fractions, alkaline phosphatase, ALT, ACT, ESR, etc.).

We examined 60 patients, while all patients showed clinical symptoms of liver damage of one degree or another: yellowness of the skin and sclera, itching of the skin, discomfort or heaviness in the right hypochondrium, dyspeptic symptoms: nausea, decreased appetite, vomiting, weakness, lethargy, discoloration of urine (darker) and stool (relief or diarrhea).

All patients were previously treated both on an outpatient and inpatient basis, using various drugs.

Most patients (37 out of 60) had concomitant diseases: chronic gastroduodenitis, diseases of the cardiovascular system (CVS): hypertension (GB), coronary heart disease (CHD); lung diseases: pneumosclerosis, bronchial asthma (BA), etc. In addition, in 85% of patients, concomitant disorders of the state of large intestine microbiocenosis were revealed. All patients of the experimental groups (50) were treated with the claimed pharmaceutical composition in the developed mode of administration: 3 times a day with meals for 1.5-3.0 months.

By the end of the 2nd week, in all 50 patients, despite the nature of liver damage, detoxification and synthetic functions of the liver were restored, against the background of restoration of intestinal biocenosis.

All patients noted a subsidence of discomfort in the right hypochondrium and an improvement in overall well-being by 5 days already. At the beginning of the 2nd week, all patients subjectively noted the disappearance of dyspeptic disorders, restoration of appetite, normalization of urine and stool, the disappearance of itching of the skin and the initial restoration of skin color against a background of a significant improvement in general condition and mood; at the same time, the subsidence or disappearance of symptoms of concomitant pathology was noted.

According to biochemical blood tests, by the end of the 3rd week normalization of all biochemical parameters characterizing the functioning of the liver and lipid metabolism was noted.

Examples of the method:

1. Patient I., 46 years old.

Upon receipt of a complaint of aching pain in the right hypochondrium, radiating to the right shoulder, occurring 3-4 hours after eating fatty foods or after heavy meals, or after physical exertion, general weakness, decreased appetite, nausea, periodically vomiting, bitterness during mouth, loose stools, sometimes diarrhea, itchy skin, discoloration of urine (darker) and stool (lighter).

From the anamnesis: gallstone disease for 10 years. Not operated. It is treated on an outpatient basis, without any particular effect. Worse after exercise.

Objectively: increased nutrition, weight 75 kg, height 167 cm, skin is pale, with traces of scratching on the back and stomach. Icterus sclera.

The abdomen is soft, painful at the point of Kerr. Symptoms: Kerra, Mussey and Murphy are positive. Liver on the edge of the costal arch.

In the lungs, vesicular breathing. NPV 18 in 1 min.

Borders of the heart within the age norm. The tones are moderately muffled, the rhythm is correct, heart rate 78 in 1 min, blood pressure 140/85 mm Hg.

Pasternatsky’s symptom is negative on both sides.

Preliminary diagnosis: Chronic calculous cholecystitis in the acute phase. Examination:

Complete blood count: Hb 123 g / l; erythrocytes (Er) 4.11 · 10 ¹² / l; color indicator (CVP) 0.89; white blood cells 4.0 · 10 ⁹ / l; stab (W) leukocytes (L) 2%; segmented white blood cells (C) 46%; eosinophils (E) 5%; lymphocytes (L) 45%; monocytes (M) 2%; ESR 40 mm / hour.

General analysis of urine: relative density 1016; protein and glucose not detected; white blood cells 0-1-3 in s / z .; erythrocytes 0 in s / sp .; urine amylase 16.2 mg / l.

Coprogram: muscle fibers without striation a little; fatty acids are moderate; vegetable fiber undigested - a lot; starch; single cells.

Feces for dysbiosis: a decrease in the number of bifidobacteria and lactobacilli, respectively: 10 ⁵ / g, 10 ⁶ / g, due to an increase in fungi of the genus Candida.

Blood biochemistry:

- bilirubin and its fractions: total bilirubin (OB) - 22.8 μmol / L (N 3.4-20.5 μmol / L); direct bilirubin (PB) - 3.8 μmol / L (N - 0.85-3.4 μmol / L), indirect bilirubin (NB) - 11.7 μmol / L (N - 2.56-10.3 μmol / l);

- thymol sample (TP) - 12.1 DB (N - 4 PIECES), ACT - 79 PIECES (N - 60 PIECES), ALT - 72 PIECES (N - 50 PIECES), thymol sample (TP), 1.7 PIECES (N - 4 PIECES), alkaline phosphatase (ALP) - 362 PIECES (N - up to 295 PIECES), ChKh 15.3; sugar 3.5 mmol / L, (N - 4.4-6.6 mmol / L);

- cholesterol and its fractions: total cholesterol (OX) - 5.5 mmol / L (N - 3.65-5.2 mmol / L), high density lipoprotein cholesterol (HPSLP) - 0.8 mmol / L (N - 0.9-1.9 mmol / L), low-density lipoprotein cholesterol (HLDPL) - 3.2 mmol / L (N - 1.91-2.6 mmol / L), cholesterol atherogenic coefficient (CKA) 3.5 cu (N - up to 3 c.u.), ХХК 15.3 (N - up to 12).

- protein fractions: total protein 67 g / l (N 65-85 g / l), albumin 34 g / l (N - 36-50 g / l);

- antinuclear antibodies: AMA titer 1:10;

- coagulogram: PTI 24 s - 79%; thrombin time 35 s; free heparin - 12 s; fibrinogen 2.2 g / l; fibrinolytic activity> 240 min.

Coprogram: dysbiosis due to a decrease in lactobacilli and bifidobacteria: lactobacilli (10 ⁵ ) (N> = 10 ⁷ / g), bifidobacteria (10 ⁷ ) (N> = 10 ⁹ ).

R-graphy of the liver and biliary tract are indirect signs of calculous cholecystitis, stones do not contrast. Recommended by ultrasound of the liver and gall bladder.

Ultrasound of the liver - chronic cholecystitis, cholesterol stones: 0.9, 1.2, 1.5, 1.3 mm, the edges are even.

ECG - sinus rhythm, signs of moderate left ventricular hypertrophy. HELL 150/85 mm Hg; Heart rate 74 in 1 min.

The diagnosis is final: lipid metabolism disorder, hypercholesterolemia. Chronic calculous cholecystitis (cholesterol stones), in the acute phase.

Treatment: use of the claimed composition, the active principles of which are hepatoprotector - UDCA and lactulose in a ratio of 1: 2 (a single dose of UDCA is 325 mg), by mouth 3 times a day with meals for 1.5 months against a diet of No. 5.

Re-examination after 1.5 months:

On ultrasound, single stones with sizes of 1 and 2 mm.

According to a laboratory examination, no pathology was detected.

Recommended: continue therapy for up to 3 months.

After 3 months - ultrasound signs of chronic cholecystitis, no calculi.

Conclusion: chronic cholecystitis in remission.

2. Patient B., 45 years old.

Upon receipt of a complaint about a decrease in appetite, weakness, nausea, periodically vomiting, aching pain in the right hypochondrium after heavy or fatty foods.

A history of chronic alcoholism. Primary biliary cirrhosis. It is treated irregularly.

Objectively: low power. The skin is dry, hot to the touch. The skin is pale yellow, icteric sclera.

Above the lungs are a pulmonary sound with a boxy tint. Breathing is weakened, scattered dry rales over the entire surface of the lungs. NPV 20 in 1 min.

The borders of the heart are extended to the left by 1.0 cm. The tones are muffled. The rhythm is correct, accent II tone over the aorta.

The abdomen is soft, the right edge of the liver protrudes 2.0 cm from the edge of the costal arch, the edge is dense. The spleen is not enlarged.

Pasternatsky’s symptom is doubtful. Preliminary diagnosis: primary biliary cirrhosis? Examination:

Complete blood count: Hb 117 g / l; erythrocytes (Er) 3.5 · 10 ¹² / l; color indicator (CVP) 0.9; white blood cells 4.0 · 10 ⁹ / l; stab (P) - 17%, white blood cells (L) 6%; segmented white blood cells (C) 36%; eosinophils (E) 5%; lymphocytes (L) 35%; monocytes (M) 1%; ESR 40 mm / hour.

Urinalysis: relative density 1012; protein and glucose not detected; white blood cells 0-2-3 in n / a; erythrocytes 0-2 in s / sp .; urine amylase 14.7 mg / l.

Coprogram: muscle fibers without striation a little; fatty acids are moderate; vegetable fiber undigested - a lot; starch; single cells.

Blood biochemistry:

- bilirubin and its fractions: total bilirubin (OB) - 28.4 μmol / L (N 3.4-20.5 μmol / L), direct bilirubin (PB) - 4.8 μmol / L (N - 0.85 -3.4 μmol / L), indirect bilirubin (NB) - 15.0 μmol / L (N - 2.56-10.3 μmol / L);

- thymol test (TP) - 16.1 PIECES (N - 4 PIECES), ACT - 90 PIECES (N - 60 PIECES), ALT - 74 PIECES (N - 50 PIECES), alkaline phosphatase (ALP) - 700 PIECES (N - up to 295 PIECES), sugar 6.6 mmol / L, (N - 4.4-6.6 mmol / L);

- cholesterol and its fractions: total cholesterol (OX) - 5.9 mmol / L (N - 3.65-5.2 mmol / L), high density lipoprotein cholesterol (HPSLP) - 10.8 mmol / L (N - 0.9-1.9 mmol / L), low-density lipoprotein cholesterol (HLDPL) - 3.6 mmol / L (N - 1.91-2.6 mmol / L), cholesterol atherogenic coefficient (CCA) 3.9 cu (N - up to 3 c.u.), ХХК 16.3 (N - up to 12); (norm up to 50);

- protein fractions: total protein 63 g / l (N 65-85 g / l), albumin 34 g / l (N - 36-50 g / l);

- antibodies: AMA in the titer of 1:45;

- coagulogram: PTI 24 s - 79%, thrombin time 31 s; free heparin 11 s; fibrinogen 2.0 g / l, fibrinolytic activity> 221 min.

Feces for dysbiosis: reduction of lactobacilli and bifidobacteria: lactobacilli (10 ⁴ ), bifidobacteria (10 ⁶ ).

R-graphy of the liver and biliary tract - an increase in the size of the liver due to the right lobe by 2.5 cm, the edges are clear, indirect signs of biliary cirrhosis. Recommended by ultrasound of the liver and gall bladder.

Ultrasound of the liver - signs of minor fatty liver and gallbladder cholesterosis. The pancreas is not enlarged. Intra- and extrahepatic bile ducts are not dilated. No evidence of portal hypertension was found.

Liver biopsy: Enhanced portal tracts are infiltrated by lymphocytes, plasma cells, macrophages and eosinophilic white blood cells. Among the cells of the portal tract infiltrates, formed lymphoid follicles are found. Infiltrates are found in the walls of some intralobular bile ducts. In some places, the integrity of the bile duct basement membrane is impaired. Near the affected bile ducts there are granulomas built from epithelioid and giant multinucleated cells. Conclusion: biliary cirrhosis.

ECG - sinus rhythm, signs of moderate left ventricular hypertrophy. HELL 150/85 mm Hg; Heart rate 76 in 1 min.

The diagnosis is final: lipid metabolism disorder, hypercholesterolemia. Primary biliary cirrhosis.

Treatment: the use of the claimed composition, the active principles of which are hepatoprotector - HDCA and FOS in a ratio of 1: 250 (a single dose of HDCA is 250 mg) orally 3 times a day with meals for 1.5 months on a diet No. 5.

Re-examination after 1.5 months.

Ultrasound positive dynamics: a decrease in fatty liver.

In blood tests: reduction of hypercholesterolemia OX - 4.6 mmol / L, HPSLPV - 1.2 mmol / L, CHC 13.2, OB - 21.5 μmol / L, AMA 1:30, total protein - 72 g / L , albumin - 34%, blood sugar 5.3 mmol / L, alkaline phosphatase - 301 PIECES, ACT - 70 PIECES, ALT - 62 PIECES, TP - 8.1 PIECES.

In the analysis of feces for dysbiosis: lactobacilli 10 ⁶ , bifidobacteria -10 ⁷ .

Recommended: continue therapy for up to 3 months.

After 3 months - AMA 1:15, bifidobacteria 10 ⁹ / g, lactobacilli 10 ⁷ g.

Conclusion: primary biliary cirrhosis of the liver 1 tbsp (significant positive dynamics).

3. Patient F., 50 l.

Upon receipt of a complaint of severe general weakness, a feeling of heaviness, and aching pains in the upper right abdomen that occur for no apparent reason, decreased appetite, nausea, periodically vomiting, bitterness in the mouth, loose stools, sometimes diarrhea, itchy skin, and discoloration of urine ( dark) and stool (lighter).

From the anamnesis: suffers from type II diabetes for 15 years, takes the sugar-lowering drug bukarban. It is under dispensary observation by an endocrinologist and a local therapist. Inpatient treatment is regularly carried out in the endocrinology department, but without any particular effect. The latter deterioration is associated with a viral infection (protracted course, complication: acute bronchitis, took antibacterial drugs - cephalosporins).

Objectively: increased nutrition: obesity 3 degrees, body mass index (BMI) 34, the skin is pale with traces of scratching on the abdomen and inner thighs. Icterus sclera.

The abdomen is significantly enlarged, soft, painful at the point of Kerr. The liver protrudes from under the edge of the costal arch by 2.5 cm, the edge is dense. The spleen is not enlarged.

In the lungs, vesicular weakened breathing (due to fatty tissue). NPV 22 in 1 min.

The borders of the heart are expanded: to the right by 1.0 cm, to the left by 1.5 cm. The tones are muffled, the rhythm is correct, soft systolic murmur above the apex of the heart. Heart rate 76 in 1 min, blood pressure 160/85 mm Hg

The symptom of Pasternatsky is doubtful on both sides.

Preliminary diagnosis: fatty hepatosis (?) Type II diabetes mellitus, obesity 3 tbsp.

Examination:

Complete blood count: Hb 121 g / l, red blood cells (Er) - 4.15 · 10 ¹² / l; color indicator (CVP) - 0.89, leukocytes - 3.8 · 10 ⁹ / l, stab (W) leukocytes (L) - 7%, segmented leukocytes (C) - 40%, eosinophils (E) - 5%, lymphocytes (L) 45%, monocytes (M) 3%, ESR 39 mm / hour. Blood glucose - 6.8 mmol / L.

Urinalysis: relative density 1016, protein traces; leukocytes 3-5 in s / sp., red blood cells 0 in s / sp., urine amylase 16.2 mg / l.

Coprogram: muscle fibers without striation a little; fatty acids are moderate; vegetable fiber undigested - a lot; starch; single cells.

Feces for dysbiosis: a decrease in the number of bifidobacteria and lactobacilli, 10 ⁵ / g, 10 ⁶ / g (respectively) due to an increase in fungi of the genus Candida.

Blood biochemistry:

- bilirubin and its fractions: total bilirubin (OB) - 27.0 μmol / L (N 3.4-20.5 μmol / L); direct bilirubin (PB) - 3.6 μmol / L (N - 0.85-3.4 μmol / L); indirect bilirubin (NB) - 11.2 μmol / L (N - 2.56 - 10.3 μmol / L);

- thymol sample (TP) - 8.0 units (N - 4 units), ACT - 69 units (N - 60 units), ALT - 76 units (N - 50 units), thymol sample (TP) 1.7 units ( N - 4 PIECES), alkaline phosphatase (alkaline phosphatase) - 346 PIECES (N - up to 295 PIECES), ChKh 15.3; sugar 6.9 mmol / L, (N - 4.4-6.6 mmol / L);

- cholesterol and its fractions: total cholesterol (OX) - 5.9 mmol / L (N - 3.65-5.2 mmol / L), high density lipoprotein cholesterol (HPSLP) - 0.8 mmol / L (N - 0.9-1.9 mmol / L), low-density lipoprotein cholesterol (ChLPLP) - 3.6 mmol / L (N - 1.91-2.6 mmol / L), cholesterol atherogenic coefficient (CCA) 3.8 cu (N - up to 3 c.u.), ХХК 16.3 (N - up to 12);

- triglycerides: 1.94 mmol / L (N - 0.45-1.82 mmol / L);

- protein fractions: total protein 67 g / l (N 65-85 g / l); albumin 38 g / l (N - 36-50 g / l);

- coagulogram: PTI 24 s - 79%; thrombin time 35 s; free heparin 12 s; fibrinogen 2.2 g / l; fibrinolytic activity> 240 min.

Coprogram: dysbiosis due to a decrease in lactobacilli and bifidobacteria: lactobacilli (10 ⁴ ) (N> = 10 ⁷ / g), bifidobacteria (10 ⁶ ) (N> = 10 ⁹ / g);

R-graphy of the liver and biliary tract - a uniform increase in the liver, no calculi. Recommended by ultrasound of the liver and biliary tract;

Ultrasound of the liver - hepatomegaly 2 tbsp. The pancreas is not enlarged. Intra- and extrahepatic bile ducts are not dilated. Signs of portal hypertension.

Esophagogastroduodenoscopy: expansion of the veins of the esophagus in / 3.

ECG - sinus rhythm, signs of moderate left ventricular hypertrophy, incomplete blockade of the right leg of the bundle, blood pressure 160/85 mm Hg; Heart rate 74 in 1 min;

The diagnosis is final: lipid metabolism disorder, triglyceridemia. Fatty hepatosis. Type II diabetes mellitus. Obesity 3 tbsp.

Treatment: the use of the claimed composition, the active principles of which are hepatoprotector - essential phospholipids and FOS in a ratio of 1:50 (a single dose of essential phospholipids is 50 mg), by mouth 3 times a day with meals for 1.5 months against a background of diet No. 5 .

Re-examination after 1.5 months.

The patient notes a decrease in itching of the skin, increased activity, itching does not bother, notes weight loss of 5 kg.

Ultrasound: there is a decrease in liver size. Conclusion: fatty hepatosis, hepatomegaly 1 tbsp.

According to laboratory tests: the content of triglycerides decreased - 1.82 mmol / L and total cholesterol - 5.0 mmol / L, blood sugar normalized - 4.9 mmol / L.

In stool analyzes, there was a significant increase in lactobacilli and bifidobacteria - 10 ⁶ / g and 10 ⁸ / g (respectively), no fungi of the type Candida were found.

Recommended: continue therapy for up to 3 months.

After 3 months, ultrasound signs of moderate hepatomegaly.

In blood tests without features. The intestinal microflora was restored: lactobacilli 10 ⁷ / g, bifidobacteria 10 ⁹ / g.

Conclusion: fatty hepatosis, signs of moderate hepatomegaly. Diabetes mellitus II tbsp., Compensation. Obesity 3 tbsp.

Verification of acute toxicity of the compositions.

The composition of UDCA and lactulose in a ratio of 1: 2 (group 1), UDCA and FOS in a ratio of 1:50 (group 2), essential phospholipids (lecithin) and galactoligosaccharides in a ratio of 1:30 (group 3), ademethionine and lactulose in a ratio of 1 : 50 (group 4) was administered to outbred white mice weighing 15-20 g through the mouth. The control group (group 6) was injected with an equal amount of a suspension of starch. The animals were observed for 4 days and the general condition was recorded (appearance, mobility (activity), regularity of food and water intake, type and nature of excrement).

Mixture (group) The maximum amount of the drug administered (g) Survival (living / dead) Appearance Food Mobility The type and nature of excrement one 2 6/0 N N N N 2 2 6/0 N N N N 3 2 6/0 N N N N four 2 6/0 N N N N 5 2 6/0 N N N N 6 2 6/0 N N N N

According to the results of the study, the acute toxicity of each composition does not occur under experimental conditions; all mixtures belong to the class of low toxic substances (LD ₅₀ values exceed 100 g / kg body weight).

Thus, the claimed pharmaceutical composition comprising hepatoprotector and a prebiotic selected from oligosaccharides not digested in the intestine as active principles can be recommended for use in clinical conditions for the treatment and prevention of liver diseases selected from the group: gallstone disease, fatty hepatosis and non-alcoholic steatohepatitis, primary biliary cirrhosis, gallbladder cholesterosis, drug and toxic liver damage.

Claims (13)

1. A pharmaceutical composition intended for the treatment and prevention of relapse of liver diseases caused by impaired lipid-cholesterol metabolism, selected from the group: cholelithiasis mainly with cholesterol stones, alcoholic and non-alcoholic steatohepatitis, primary biliary cirrhosis, gallbladder cholesterosis, drug and toxic liver damage, including hepatoprotector and prebiotic taken in effective doses as active principles, used for oral administration. 2. The pharmaceutical composition according to claim 1, used for oral administration as a biologically active food supplement. 3. The pharmaceutical composition according to claim 1, comprising as an active principle a hepatoprotector selected from the group: bile acids, salts of bile acids, essential phospholipids, amino acids, active components of plant extracts of milk thistle. 4. The pharmaceutical composition according to claim 1 or 3, comprising as a hepatoprotector bile acid or a salt of bile acid selected from the group: cholic acid (CC), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), ursodeoxycholic acid (UDCA), lithocholic acid (LCA), taurourosodeoxycholic acid (TUDC), hyodeoxycholic acid (GDC), taurocholic acid (TCA), glycocholic acid (GCC). 5. The pharmaceutical composition according to claim 1 or 3, comprising as a hepatoprotector bile acid or a salt of bile acid and a prebiotic in a ratio of 1: 2 to 1: 250 by weight of pure substances. 6. The pharmaceutical composition according to claim 3, including as a hepatoprotector essential phospholipids selected from the group: phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol. 7. The pharmaceutical composition according to claim 1 or 6, comprising as a hepatoprotector essential phospholipids and a prebiotic in a ratio of from 1: 0.1 to 1: 100 by weight of pure substances. 8. The pharmaceutical composition according to claim 3, comprising as a hepatoprotector the active components of plant extracts of Milk Thistle, selected from their group: silymarin or silybin. 9. The pharmaceutical composition according to claim 1 or 8, comprising, as a hepatoprotector, the active components of plant extracts of milk thistle and prebiotic in a ratio of 1: 0.1 to 1: 100. 10. The pharmaceutical composition according to claim 1, comprising as an active principle a prebiotic selected from the group: fructooligosaccharides (FOS), galactooligosaccharides (GOS), lactulose, maltooligosaccharides (MOS), xyloooligosaccharides (CBS). 11. The pharmaceutical composition according to claim 1, further comprising microcrystalline cellulose, or lactose, or corn starch, or potato starch, or hydroxypropyl methyl cellulose, or carboxymethyl cellulose, or hydroxypropyl methyl cellulose, or hydroxypropyl cellulose, or their pharmaceutically acceptable salts, or calcium or magnesium stearate, or polysorbate, or polyvinylpyrrolidone, or polyethylene glycol, or talc, or titanium dioxide, or silicon dioxide. 12. The pharmaceutical composition according to claim 1, made in the form of tablets, or granules, or globules, or powders, or capsules, or suspensions, or pastes, or syrups, or emulsions, or gels intended for oral administration in doses corresponding to known doses of hepatoprotector and prebiotic, 2-3 times a day. 13. Obtaining the pharmaceutical composition according to claim 1 for the treatment of liver diseases selected from the group: cholelithiasis mainly with cholesterol stones, alcoholic and nonalcoholic steatohepatitis, primary biliary cirrhosis of the liver, gallbladder cholesterosis, drug and toxic liver damage, by mixing active components: hepatoprotector and prebiotic, taken in effective doses, with microcrystalline cellulose, or lactose, or corn starch, or potato starch, or hydroxypropi methyl methyl cellulose, or carboxymethyl cellulose, or hydroxypropyl methyl cellulose, or hydroxypropyl cellulose, or with their pharmaceutically acceptable salts, or ludipress, or calcium stearate, or magnesium stearate, or polysorbate, or polyvinyl pyrrolidone, or polyethylene glycol, di-silicon, or trimethylene glycol, or trimethylene glycol, or trimethylene glycol.