RU2381800C1 - Hepatoprotective and antihepatotoxic pharmaceutical composition and method of treating hepatic diseases that involves introduction of said composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmacy and represents a hepatoprotective and antihepatotoxic pharmaceutical composition containing 200-400 mg of ademetionine and 100-200 mg of ursodeoxycholic acid and a pharmaceutically acceptable carrier, differing that it additionally contains 250-500 mg of taurine, 300-600 mg of thioctic acid, 140-300 mg of silimarin, 180-500 mg of L-arginine, 250-500 mg of L- carnitine, 250-2000 mg of L-tryptophane, 250-500 mg of L-glutathione or eltacine and 100-200 mg of artichoke extract.

EFFECT: invention provides extended range of products with high hepatoprotective and antihepatotoxic activity.

7 cl, 5 ex, 1 tbl

Description

The invention relates to the field of medicine and pharmacy, more specifically to the treatment and prevention of liver diseases, more particularly to the treatment of fatty liver disease, more specifically to a hepatoprotective pharmaceutical composition containing ademetionine, ursodeoxycholic acid and a carrier, characterized in that it further contains taurine and thioctic acid and to a method for treating a number of liver diseases, comprising administering to a patient in need of such a pharmaceutical composition.

Ademethionine (S-adenosyl-L-methionine) is a precursor of the amino acid methionine, takes part in the synthesis of some biologically active compounds (glutamine, taurine, cysteine), which play an important role in the detoxification of liver cells, therefore, against the background of its intake, detoxification function of the liver improves. Ademethionine increases the content of putrescine in the liver tissues, which is a stimulator of hepatocyte repair. In clinical practice, ademetionine is used in the complex treatment of various toxic liver damage, cirrhotic and precirrhotic conditions.

Ursodeoxycholic acid (hereinafter - UDCA) - bile acid, a component of human bile (approximately 5% of the amount of bile acids); possesses hepatoprotective, anticholestatic, litholytic, immunomodulating, antiapoptotic, antifibrotic effects.

It stabilizes the membranes of hepatocytes and cholangiocytes, has a direct cytoprotective effect, reduces the amount of potentially hydrophobic toxic acids by reducing the absorption of cholesterol in the intestine and hypocholesterolemic deuterium. UDCA inhibits cell death due to toxic bile acids.

In addition, UDCA, possessing high polar properties, forms non-toxic mixed micelles with apolar (toxic) bile acids, which reduces the ability of gastric reflux to damage cell membranes in biliary reflux gastritis and reflux esophagitis. UDCA also forms binary molecules capable of being incorporated into cell membranes, stabilizing them and making them immune to cytotoxic micelles. UDCA is able to reduce the saturation of bile with cholesterol by inhibiting its absorption in the intestine, inhibiting its synthesis in the liver and lowering secretion into bile. UDCA increases the solubility of cholesterol in bile, forming liquid crystals with it, reduces the lithogenic index of bile, dissolves cholesterol gallstones (in the initial stage), and prevents the formation of new stones. It induces choleresis rich in bicarbonates, which leads to an increase in the passage of bile and stimulates the excretion of toxic bile acids through the intestines.

Under the action of UDCA, the synthesis of IgM is reduced, the expression of HLA antigens on the membranes of hepatocytes and cholangiocytes is reduced, which prevents the immunologically mediated cytotoxicity of N-lymphocytes or autoantibodies against liver cells (mediated hepatoprotective effect). Also, under the action of UDCA, a decrease in the concentration of intracellular Ca ²⁺ occurs; as a result, the exit of cytochrome P450 from mitochondria is blocked, which prevents the activation of enzymes involved in the apoptosis reaction - caspases - and the development of apoptosis.

The antifibrotic effect of UDCA is shown.

UDCA is indicated for use in acute and chronic hepatitis, viral hepatitis A, B, C (possibly in combination with peginterferon and lamivudine or ribavirin), liver cirrhosis, alcoholic and toxic (including drug) liver disease, alcohol and toxic hepatitis, liver steatosis in diabetes mellitus, non-alcoholic steatohepatitis, in case of cholestatic liver diseases, primary biliary cirrhosis, primary sclerosing cholangitis, cholelithiasis, pregnant cholestasis, biliary reflux gastritis, reflux esophagus ite, cystic fibrosis of the liver, cystic fibrosis, biliary dyskinesia, biliary atresia, liver disease in the prophylaxis cytostatic agents, hormonal contraceptives et al. Drug.

Previously, the author of the present invention proposed (Kozhoka T.G. Medicines in parasitology and gastroenterology, problems of production and provision of the population. - M .: MIEMP, 2006, p. 99) hepatoprotective pharmaceutical composition (in the form of tablets or capsules) containing 200 -400 mg of ademetionine in combination with UDCA, with a preferred ratio of components from 1: 1 to 1: 3, respectively, proposed as a prototype of the present invention.

In the above work, the hepatoprotective effectiveness of this composition was not studied, and therefore the task arises of studying its hepatoprotective effect and its enhancement by including additional components in the composition of the composition.

Recently it was shown (Naruta E.E., Nikolaeva I.A., Kirko S.N., Lis R.E., Buko V.U. Therapy of non-alcoholic steatohepatitis caused by methionine-deficient diet. - Izv. National Academy of Sciences of Belarus. Ser.Med.Sci., 2008, No. 2, p. 65) on an experimental model of non-alcoholic steatohepatitis in rats caused by a methionine-choline-deficient diet, that the administration of the UDCA monopreparation or the combination of "UDCA + lipoic (thioctic) acid" normalized most of the parameters that underwent a change under the influence of methioninecholine diet, histopathology In addition, the activity of serum marker enzymes, liver triglycerides, as well as the content of serum TNFa, leptin and adiponectin.

In the framework of the present invention, it was unexpectedly found that the composition of ademetionine and UDCA, which also contains taurine and thioctic (lipoic) acid, has, in comparison with the prototype, unexpectedly higher hepatoprotective and antihepatotoxic activity, which constitutes an unexpected technical result of the present invention and provides useful the properties of the claimed composition in the treatment of a number of liver diseases, such as acute or chronic hepatitis, non-alcoholic steatohepatitis, fatty liver, cirrhosis liver, liver fibrosis and hepatic encephalopathy.

Taurine is a natural product of the exchange of sulfur-containing acids: cysteine, cysteamine, methionine. It is a white crystalline powder, soluble in water and practically insoluble in alcohol. Taurine has membrane-protective properties. It can regulate the release of GABA, has the properties of a inhibitory mediator.

Taurine improves metabolic processes in the liver and other organs and tissues, treatment with taurine in cardiovascular failure leads to a decrease in congestion in the small and large circles of blood circulation. The drug moderately reduces blood pressure in patients with arterial hypertension. With diabetes, taurine decreases blood sugar; a significant decrease in the concentration of triglycerides, to a lesser extent cholesterol, a decrease in the plasma lipid atherogenicity is observed.

Commercially available, taurine is available as Dibicor "(0.25 and 0.5 g tablets).

It was previously shown that taurine activates metabolic processes in the liver, increases its resistance to pathogenic effects, activates the restoration of its functions in various injuries (Yartsev E.I., Goldberg E.D., Komennikov Yu.A. Taurin (pharmacological and anti-radiation properties ). - M .: Medicine, 1975. - 158 p .; Pasantes-Morales H., Wright CE, 9 Gaul GE // Biochem. Pharmacol. - 1985. - V. 34, N12. - P.2205-2207) .

Thioctic (alpha-lipoic) acid (1,2-Dithiolan-3-pentanoic acid) has hepatoprotective, detoxification, hypocholesterolemic, hypolipidemic, antioxidant effects, is a coenzyme of oxidative decarboxylation of pyruvic acid and alpha-keto acids, normalizes lipid metabolism, normalizes energy and lipid metabolism regulates cholesterol metabolism. It improves liver function, reduces the damaging effect of endogenous and exogenous toxins on it.

After oral administration, it is rapidly and completely absorbed, C _{max is} reached after 50 minutes. Bioavailability is about 30% (due to presystemic biotransformation). It oxidizes and conjugates in the liver. Excreted by the kidneys in the form of metabolites (80-90%) with T _1/2 20-50 min. The total plasma clearance is 10-15 ml / min.

Thus, in accordance with the present invention, two objects are claimed:

1) a hepatoprotective and antihepatotoxic pharmaceutical composition containing therapeutically effective amounts of ademetionine and ursodeoxycholic acid and a pharmaceutically acceptable carrier, characterized in that it further comprises therapeutically effective amounts of taurine and thioctic acid, and

2) a method for treating a liver disease selected from acute or chronic hepatitis, non-alcoholic steatohepatitis, fatty liver, liver cirrhosis, liver fibrosis and hepatic encephalopathy, comprising oral administration of a single dose of the pharmaceutical composition of the invention to a subject in need, 1-2 doses 2 -3 times a day.

Preferably, the ratio of therapeutically effective amounts of ademetionine and UDCA in the claimed composition is in the range from 3: 1 to 1: 3.

Preferred but not limiting claims in accordance with the present invention, therapeutically effective amounts of ademetionine and UDCA are 200-400 mg and 100-200 mg, respectively, the preferred therapeutically effective amount of thioctic acid is 300-600 mg, the preferred therapeutically effective amount of taurine is 250 -500 mg.

Additionally, the pharmaceutical composition of the invention may also contain silymarin, L-arginine, L-carnitine, L-glutathione (or its equivalent, the drug eltacin), L-tryptophan and artichoke extract.

Silymarin is the sum of flavonoids from the fruits of milk thistle, has a hepatoprotective effect. Inactivates free radicals in the liver, interrupts the process of lipid peroxidation and prevents the destruction of cellular structures. In damaged hepatocytes, it stimulates the synthesis of structural and functional proteins, stabilizes cell membranes, prevents the loss of transaminases, and accelerates the regeneration of liver cells. Fully and quickly absorbed from the digestive tract. The liver is metabolized by conjugation. It is excreted mainly by the intestines, where it enters with bile, to a small extent - with urine. Not cumulated.

Improves the condition of patients with liver diseases, normalizes laboratory parameters (activity of transaminases, gamma-glutamyltransferase, alkaline phosphatase, bilirubin level, etc.).

Silymarin is indicated for toxic liver damage, chronic hepatitis (non-viral etiology), cirrhosis of the liver (as part of complex therapy), the state after hepatitis, chronic intoxications (including professional), long-term medication, alcoholism.

A preferred amount of silymarin in the composition of the present invention is 140-300 mg per dose of the pharmaceutical composition.

L-arginine (L-2-amino-5-guanidine-valerianic acid, used in the form of aspartate) is an amino acid that is replaceable for a healthy adult, but practically not synthesized in the body of children and the elderly. L-arginine is a part of proteins, especially protamines (up to 85%) and histones. L-arginine helps accelerate the synthesis of growth hormone and other hormones. L-arginine (NH-C (NH ₂ ) NH (CH ₂ ) ₃ CH (NH ₂ ) -COOH) is an aliphatic amino acid. It is present in the body in its free form and as a part of proteins (a lot of arginine in protamines).

L-arginine is a donor and natural carrier of nitrogen. Arginine supplies nitrogen to the system of NO synthases synthesizing nitric oxide (NO) - nitroso group. The nitroso group is a mediator of muscle relaxation of vessels of the arterial bed (mainly arterioles), thus exerting a cardinal effect on vascular tone and, therefore, on the value of diastolic pressure. With a lack of L-arginine and insufficient activity of NO synthases, the diastolic pressure increases;

L-arginine is involved in the cycle of transamination and excretion of the final nitrogen from the body, that is, the breakdown product of waste proteins. From the power of the cycle (ornithine - citrulline - arginine) depends on the body's ability to create urea and cleanse from protein slags.

L-arginine serves as a carrier and donor of nitrogen necessary for the synthesis of muscle tissue. It helps to increase muscle mass and reduce fat with adequate physical activity.

L-arginine has a pronounced psychotropic effect. Causing an increase to the upper normal borders of somatotropic hormone (STH) (or it is also called growth hormone), L-arginine helps to improve mood, makes a person more active, proactive and hardy, improves sexual function.

L-arginine is used in a number of hepatoprotectors, immunomodulators, cardiac drugs, drugs for burn patients, HIV / AIDS patients, as well as in formulations for parenteral nutrition in the postoperative period. Recently, drugs with arginine have been used in gerontology and oncology.

In the composition of the present invention, a preferred amount of L-arginine is 180-500 mg per dose of the pharmaceutical composition.

L-carnitine is a natural substance related to group B vitamins. It participates in metabolic processes as a carrier of long chain fatty acids (palmitic and others) from the cytoplasm to mitochondria, where these acids undergo an oxidation process with the formation of adenosine triphosphoric acid and acetyl-CoA. It improves protein and fat metabolism, increases the secretion and enzymatic activity of gastric and intestinal juices, improves the absorption of food, reduces excess body weight and reduces muscle fat content. Increases resistance to physical stress, inhibits the formation of keto acids and anaerobic glycolysis, reduces the degree of lactic acidosis, contributes to the economical use of glycogen and increases its reserves in the liver and muscles. It has an anabolic and lipolytic effect, normalizes increased basic metabolism in hyperthyroidism, being a partial thyroxine antagonist.

It is well absorbed in the intestine, the concentration in blood plasma reaches a maximum after 3 hours and remains in the therapeutic range for 9 hours. It easily penetrates the liver, myocardium, and more slowly into the muscles. It is excreted by the kidneys, mainly in the form of acyl ethers.

Indications for use: cardiovascular disease, hypertension, myocarditis; prevention of atherosclerosis and its complications, heart attack, stroke; weight loss programs; programs of body cleansing, detoxification, rejuvenation; heavy physical exertion; sports medicine; fatty degeneration of the liver; alcoholism; chronic fatigue syndrome, asthenic syndrome.

The preferred amount of L-carnitine in the composition of the present invention is 250-500 mg per dose of the pharmaceutical composition.

L-glutathione (L-gamma-glutamyl-L-cysteinylglycine) is one of the most important endogenous antioxidants and cofactors of the enzymes glutathione peroxidase, glutathione transferase, glutathione reductase, which together with NADPH form the glutathione antioxidant system of the body.

L-glutathione has the ability to bind free radicals, reduce the processes of peroxidation, increase the efficiency of oxygen use. L-glutathione is a metabolic regulator; when used sublingually, it increases the intracellular level of glutathione and glutathione-dependent enzymes, the activity of redox enzymes, ATP synthesis, the use of oxygen in tissues, reduces the processes of peroxidation, and promotes the rational use of oxygen.

In connection with the known important role of free radical reactions in the etiopathogenesis of liver diseases, L-glutathione is also shown in the complex treatment of liver diseases.

A preferred amount of L-glutathione in the composition of the invention is 250-500 mg per dose of the pharmaceutical composition.

In the framework of the present invention, in the composition of the claimed pharmaceutical composition, L-glutathione can be replaced by a similar (250-500 mg) amount of a commercially available drug eltacin, which is a mixture of interchangeable amino acids - glycine, L-glutamic acid and L-cysteine.

L-tryptophan is an essential amino acid that is not synthesized in the body. Tryptophan is involved in maintaining nitrogen balance in metabolic processes, acts of excitation and inhibition, as well as the transformation of one type of energy into another. Nicotinic acid formed from tryptophan is an important component in energy metabolism. Participates in the synthesis of proteins, as well as in the synthesis of a number of biologically active substances: vitamin B ₃ (nicotinic acid), serotonin, melatonin, etc.

Tryptophan consumption causes the pituitary gland to produce more growth hormone. L-tryptophan regulates the function of the endocrine apparatus that prevents anemia, regulates blood pressure, and is responsible for the synthesis of hemoglobin.

It is believed that this amino acid stimulates the secretion of insulin, which in turn activates the synthesis of fatty acids in the liver. This amino acid is of particular importance in pharmacology, where it and its derivatives are used as ingredients in many drugs. In severe diseases such as cancer, tuberculosis, diabetes tryptophan contributes to the normal functioning of various body systems. Its deficiency in humans and animals leads to the development of pellagra, tooth damage, clouding of the cornea, cataract.

Tryptophan as a precursor to serotonin has an antidepressant effect, helps relieve anxiety before menstruation, hyperactivity, obsessive states, fibromyalgia and chronic fatigue syndrome, and contributes to good sleep and normal sleep.

Used in the treatment of depression, insomnia, migraine; reduces anxiety, controls hyperactivity in children, is good for the heart, and can help in some cases of alcoholism. It stores niacin, which prevents pellagra and mental inferiority. L-tryptophan is used by the body to create muscle proteins, antibody proteins of the immune system, is a building material for the production of the neurotransmitter serotonin, and is involved in the synthesis of melatonin and carnitine. Constant intake of tryptophan reduces the feeling of hunger, maintains mental balance (calm, good sleep).

Tryptophan increases the biological value of casein, soy proteins and, above all, collagen proteins.

L-tryptophan is an essential amino acid that is used by the brain along with vitamin B ₆ , niacin (or niacinamide) and magnesium to produce serotonin, a neurotransmitter that carries signals between the brain and one of the biochemical mechanisms of sleep in the body.

Helps cause natural sleep. Reduces pain sensitivity. Acts as a non-drug antidepressant. Helps reduce anxiety and stress. Reduces some symptoms of biochemical disorders in the body associated with the intake of alcohol, and also interferes with alcoholism. Contained in large quantities in cottage cheese, milk, meat, fish, turkey, bananas, dried dates, peanuts.

The hepatoprotective properties of tryptophan have been shown in the literature.

Tryptophan is available in tablets from 250 to 2000 mg. When used for relaxation, you need to take it during the day between meals and drink it with juice or water, but not with milk or other products containing protein.

A preferred amount of L-glutathione in the composition of the invention is 250-2000 mg per dose of the pharmaceutical composition.

Artichoke extract is a hepatoprotective, choleretic, diuretic, lipid-lowering agent of plant origin. The ascorbic acid, carotene, vitamin B ₁ and vitamin B ₂ , inulin contained in the artichoke contribute to the normalization of metabolism in the body.

Artichoke extract is recommended for the prevention and treatment of many diseases of the liver and gastrointestinal tract. Due to its versatile effect on the body, artichoke extract is also indicated as a health-improving and prophylactic agent.

Artichoke extract is a powerful hepatoprotector, i.e. the active substances contained in it protect liver cells from the action of toxins (including nitro compounds, alkaloids, salts of heavy metals, alcohol). Artichoke extract increases the production of coenzymes by hepatocytes and affects the metabolism of lipids, cholesterol and ketone bodies, improves the antitoxic function of the liver. It has a detoxifying effect on the liver or kidney parenchyma during antibiotic therapy.

Artichoke extract has a choleretic effect mainly due to the choleretic effect. It increases the volume of secreted bile and the secretion of bile salts. It promotes digestion, prevents the development of cholecystitis, reduces gas formation and normalizes intestinal activity.

Artichoke extract has a diuretic effect, reduces the level of nitrogen-containing substances in the blood.

Artichoke extract lowers blood cholesterol. It is used for the treatment and prevention of atherosclerosis. It is indicated for dyspeptic symptoms, biliary dyskinesia and gall bladder hypokinetic type, impaired bile outflow, cholecystitis, chronic and acute (in the phase of convalescence) hepatitis, cirrhosis, liver encephalopathy, drug, food, alcohol intoxication (other intoxication (other) intoxication (other). including hepatotoxic substances, nitro compounds, alkaloids, salts of heavy metals), chronic nephritis, chronic renal failure, acetonemia, oliguria in heart failure and liver cirrhosis, atherosclerosis (as part of complex therapy), obesity (as part of complex therapy).

A preferred amount of artichoke extract in the composition of the present invention is 100-200 mg per dose of the pharmaceutical composition.

The individual doses of the pharmaceutical composition in accordance with the invention can be in the form of solid dosage forms suitable for oral administration, preferably in the form of tablets (including modified release tablets, sustained release tablets, etc.), or gelatin capsules (including hard and soft gelatin capsules), or granules for the manufacture of an aqueous suspension. All appropriate dosage forms within the framework of this invention are prepared using traditional for these forms of auxiliary components and techniques.

The following examples serve only to illustrate the claimed invention, and not to limit the scope of claims.

Example 1

Preparation of soft gelatin capsules

The mixer is filled with carefully ground ingredients of the claimed pharmaceutical composition in the following proportions, g:

Ademethionine - 200 g;

Ursodeoxycholic acid - 200 g;

Silymarin - 200 g;

Thioctic acid - 300 g;

Taurine - 250 g;

L-arginine - 200 g;

L-carnitine - 500 g;

Artichoke Extract - 200 g

Example 2

Preparation of hard gelatine capsules

Weighed portions of ademetionine (200 g), ursodeoxycholic acid (100 g), silymarin (140 g), thioctic acid (300 g), taurine (250 g), milk sugar (500 g) are crushed and sieved through a No. 0.5 sieve, weighed polyvinylpyrrolidone (150 g) and calcium stearate (10 g) - through a sieve number 32.

The crushed powders are mixed in the mixer for 70 minutes, then the finished mixture is sieved on a vibrating screen with a hole diameter of 1 mm.

Hard gelatin capsules are filled with the capsule mixture thus obtained, on a capsule filling machine, and packaged in yellow glass jars, in a blister or other packaging.

Example 3

Preparation of pills

The mixer is filled with carefully ground ingredients of the claimed pharmaceutical composition in the following proportions, g:

Ademethionine - 400 g;

Ursodeoxycholic acid - 100 g;

Silymarin - 140 g;

Thioctic acid - 600 g;

Taurine - 500 g;

Artichoke extract - 100 g;

L-arginine - 200 g;

L-tryptophan - 250 g;

L-Glutathione or Eltacin - 250 g.

Thoroughly mix, to the resulting composition add the required excipients necessary for the manufacture of tablets, traditional in the art, mix thoroughly and press on a tablet press into tablets (1000 pcs.) In accordance with traditional procedures in the art.

Example 4

Granulate for the manufacture of an aqueous suspension

One portion (sachet) of granulate for the manufacture of an aqueous suspension contains: ademethionine - 200 mg; ursodeoxycholic acid - 200 mg; silymarin - 200 mg; thioctic acid - 300 mg; taurine - 250 mg; L-arginine - 200 mg; L-carnitine - 500 mg; artichoke extract - 200 mg; filler (lactose) - 2000 mg; mannitol - 750 mg; ammonium glycyrrhizinate - 12 mg; sodium saccharinate - 2.5 mg; flavors and flavorings - 30 mg.

Example 5

Antihepatotoxic effect of the claimed composition in vivo

60 rats taken for the study were divided into the following groups (12 animals each): a) “healthy” control (animals that did not receive a toxic agent); b) a control group that received once (at the beginning of the study) per os carbon tetrachloride as a hepatotoxic agent (20% solution in mineral oil, 3 ml / kg body weight); c) a group that received carbon tetrachloride once (20% solution in mineral oil, 3 ml / kg body weight) as a hepatotoxic agent, received for 2 weeks. before exposure to a toxic agent and within 2 weeks. after exposure to a toxic agent, daily per os the composition in accordance with the prototype (200 mg of ademethionine and 200 mg of UDCA); d) a group that received carbon tetrachloride once (20% solution in mineral oil, 3 ml / kg body weight), received for 2 weeks. before exposure to a toxic agent and within 2 weeks. after exposure to the toxic agent, per os daily, a capsule composition of the invention containing 200 mg of ademethionine, 200 mg of UDCA, 250 mg of taurine and 300 mg of thioctic acid; e) a group that received carbon tetrachloride once (20% solution in mineral oil, 3 ml / kg body weight), received for 2 weeks. before exposure to a toxic agent and within 2 weeks. after exposure to a toxic agent, per os daily, a capsule-containing composition containing 200 mg of ademethionine, 200 mg of UDCA, 250 mg of taurine, 300 mg of thioctic acid, 100 mg of artichoke extract, 180 mg of L-arginine, 250 mg of L-carnitine , 250 mg of L-tryptophan, 250 mg of L-glutathione or eltacin.

At the end of the study, a blood sample from the tail vein was taken from each animal for biochemical analysis, during which the level of serum enzymes - glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GAT) was determined.

After that, all animals were slaughtered, the liver was extracted from each animal, its weight was determined. The results of the study are shown in table 1.

The data presented indicate that the composition of ademetionine, ursodeoxycholic acid, taurine and thioctic acid in accordance with the present invention has an unexpectedly high, compared with the composition in accordance with the prototype, hepatoprotective and antihepatotoxic activity and, therefore, can be successfully used in the treatment of a number liver diseases such as acute or chronic hepatitis, non-alcoholic steatohepatitis, fatty liver disease, cirrhosis, liver fibrosis and liver ence phalopathy.

Table 1 Group The weight of the liver, g GPT, mcg / L GAT, μg / L Healthy Control 5.43 ± 0.22 *** 28.49 ± 3.75 *** 101.20 ± 7.00 *** Control group 7.92 ± 0.18 ** 195.22 ± 8.32 ** 301.31 ± 14.20 ** Ademethionine, 200 mg + UDCA, 200 mg 6.55 ± 0.15 *** 134.84 ± 11.3 *** 210.06 ± 11.32 *** Ademethionine, 200 mg + UDCA, 200 mg + Taurine, 250 mg + Thioctic acid, 300 mg 5.91 ± 0.14 ** 101.34 ± 5.71 ** 130.54 ± 8.40 ** Ademethionine, 200 mg + UDCA, 200 mg + Taurine, 250 mg +
Thioctic acid, 300 mg +
artichoke extract, 300 mg +
L-arginine, 180 mg +
L-carnitine, 250 mg +
L-tryptophan, 250 mg +
L-Glutathione or Eltacin, 250 mg 5.72 ± 0.15 ** 75.42 ± 5.45 ** 120.67 ± 9.35 ** Legend:
** - p <0.01
*** - p <0.001

Claims (7)

1. Hepatoprotective and antihepatotoxic pharmaceutical composition containing 200-400 mg of ademetionine and 100-200 mg of ursodeoxycholic acid and a pharmaceutically acceptable carrier, characterized in that it additionally contains 250-500 mg of taurine, 300-600 mg of thioctic acid, 140-300 mg of silymarin , 180-500 mg L-arginine, 250-500 mg L-carnitine, 250-2000 mg L-tryptophan, 250-500 mg L-glutathione or eltacin and 100-200 mg artichoke extract. 2. Hepatoprotective and antihepatotoxic pharmaceutical composition according to claim 1, characterized in that the ratio of the amounts of ademetionine and ursodeoxycholic acid is in the range from 3: 1 to 1: 3. 3. Hepatoprotective and antihepatotoxic pharmaceutical composition according to any one of claims 1 and 2, characterized in that it is made in the form of a tablet. 4. Hepatoprotective and antihepatotoxic pharmaceutical composition according to any one of claims 1 and 2, characterized in that it is made in the form of a hard gelatin capsule. 5. Hepatoprotective and antihepatotoxic pharmaceutical composition according to any one of claims 1 and 2, characterized in that it is made in the form of a soft gelatin capsule. 6. Hepatoprotective and antihepatotoxic pharmaceutical composition according to any one of claims 1 and 2, characterized in that it is made in the form of granules for the manufacture of an aqueous suspension. 7. A method of treating a liver disease selected from acute or chronic hepatitis, non-alcoholic steatohepatitis, fatty liver, liver cirrhosis, liver fibrosis and hepatic encephalopathy, comprising oral administration to a subject in need of this individual of a pharmaceutical composition according to any one of claims 1 to 6, 1-2 doses 2-3 times a day.