RU2391989C2 - Pharmaceutical hepatoprotective composition and treatment method - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention belongs to medicine and pharmaceutics, notably to pharmaceutical hepatoprotective composition for oxidative stress reduction and inhibiting of lipid peroxide oxidation reactions and designed for treatment and/or prevention of liver diseases chosen from group, including viral hepatitis A, B, C, D, E and alcoholic hepatitis, it contains therapeutic effective quantities of thioctic (alpha-lipoic) acid, flavonolignans, glycyrrhizic acid or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, featuring by additional therapeutically active quantity of flacoside, selenium or its pharmaceutically acceptable derivate and acridonacetic acid or its pharmaceutically acceptable salt, and to disease, chosen from group, including viral hepatitis A, B, C, D, E and alcoholic hepatitis , which includes of invented pharmaceutical composition 2-3 times a day.

EFFECT: oxidative stress reduction and inhiting of lipid peroxide oxidation reactions.

20 cl, 1 tbl, 6 ex, 4 dwg

Description

The present invention relates to the field of medicine and pharmacy, in particular to a pharmaceutical composition for treating and / or preventing hepatitis of viral and / or alcoholic etiology. More specifically, the invention relates to a pharmaceutical hepatoprotective composition for treating and / or preventing hepatitis of viral and / or alcoholic etiology, containing in a therapeutically effective amount of thioctic (alpha-lipoic) acid, flavanolignans, glycyrrhizic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, characterized in that it further comprises a therapeutically effective amount of flacoside, selenium or a pharmaceutically acceptable derivative thereof, and acridone susne acid or a pharmaceutically acceptable derivative thereof, and a method for treating viral hepatitis comprising orally administering said pharmaceutical composition.

Viral hepatitis is one of the leading groups of diseases in the structure of infectious pathology. The widespread, high morbidity, duration of the course with a tendency to severe forms, often leading to complications, the frequent formation of a protracted and chronic course, as well as the possibility of the outcome of the infection process in malignancy, necessitate an in-depth study of the pathogenesis, clinic and treatment of this group of diseases.

Of paramount importance in recent decades are viral hepatitis with parenteral transmission, the etiological structure of which is associated not least with the prevalence of drug addiction. The risk of contracting viral hepatitis among this contingent, according to WHO, ranges from 50 to 90%.

The pathological process in viral hepatitis and toxic lesions is accompanied by severe metabolic disturbances and multiple organ pathologies, often leading to the development of liver fibrosis and cirrhosis [1].

Another important pathology, also leading to chronic cirrhosis or liver fibrosis, is alcoholic hepatitis.

The term “alcoholic hepatitis” is used to refer to acute degenerative and inflammatory liver lesions caused by alcohol and capable of progressing to cirrhosis in a large number of cases. Alcoholic hepatitis is one of the main options for alcoholic liver disease, along with alcoholic fibrosis is considered a harbinger or initial stage of cirrhosis. This designation is devoid of indications of the time length of the process. Separate consideration of acute and chronic alcoholic hepatitis is advisable. When ingested, about 90% of the alcohol is metabolized in the liver with the formation of acetaldehyde, a substance that affects liver cells - hepatocytes. Alcohol and its metabolites trigger a cascade of chemical reactions in the body, leading to hepatocyte hypoxia and, ultimately, to liver cell necrosis.

Alcoholic hepatitis is a diffuse inflammatory process in the liver tissue, which is the result of toxic damage to the liver by alcohol and its decomposition products. This is usually a chronic disease that develops 5-7 years after the start of regular alcohol consumption.

The prior art [2] known biologically active additive with hepatoprotective properties based on components of plant origin, designed to reduce alcohol dependence and containing as components of plant origin Kuju root powder, Kuju extract, dandelion root, Canadian yellow root, aloe leaves, aloe leaves, Gotu Kola , silymarin, gentian root, additionally contains pantothenic acid or calcium pantothenate, alpha lipoic acid, N-acetylcysteine and L-glutathione. The specified additive is not a pharmaceutical composition, but a dietary supplement, and cannot be proposed as a prototype of the present invention; in addition, it does not follow from the description of the said patent that it can be used in the complex treatment of hepatitis, especially viral.

Previously in the prior art [3] it was shown that the combination of alpha-lipoic (thioctic) acid, silymarin and selenium can be successfully used in the treatment of hepatitis C.

Thioctic (alpha-lipoic) acid (1,2-Dithiolan-3-pentanoic acid) has hepatoprotective, detoxification, hypocholesterolemic, hypolipidemic, antioxidant effects. It is a coenzyme of oxidative decarboxylation of pyruvic acid and alpha-keto acids, normalizes energy, carbohydrate and lipid metabolism, and 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.

The effectiveness of the use of alpha-lipoic acid in alcoholic liver damage is indicated in [4].

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. Does not cumulate.

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

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

Selenium is an essential trace element necessary for the normal functioning of cells. It takes part in cellular respiration, nucleic acid synthesis, supports the action of antioxidants. Selenium is a structural component of important enzymes - antioxidant and hormone synthesizing. In particular, glutathione peroxidase, a powerful “trap” of free radicals. Selenium (in the form of selenmethionine) potentiates the antioxidant activity of vitamin E, activates glutathione and, together with vitamin E, protects cell membranes, mitochondria, microsomes and lysosomes from lipid peroxidation. In the framework of the present invention, selenium is preferably used in the form of selenium methionine or selenium oxide.

The possibility of creating a pharmaceutical composition for the treatment of viral hepatitis in the form of tablets or capsules containing thioctic acid, silymarin and a pharmaceutically acceptable derivative of selenium (for example, selenium methionine) in a ratio of 0.9: 1.6: 0.0004, is also indicated in the author’s work of the present invention [5]. However, the source [5] does not provide any data on the effectiveness of this composition in the treatment of hepatitis.

In addition, it would be useful to increase the effectiveness of this drug due to the inclusion of other components with antiviral, hepatoprotective, antitoxic and antioxidant activity, such as glycyrrhizic acid contained in licorice root extract (Glycyrrhiza glabra, Glycyrrhiza uralensis), and flacoside.

It was previously shown that glycyrrhizic acid or its pharmaceutically acceptable derivatives can be successfully used even in cases of interferon-resistant viral hepatitis [6], [7], [8]. It was shown that glycyrrhizic acid has an antiviral and anti-inflammatory effect, inhibits the reproduction of viruses in the liver and other organs by stimulating the production of interferons, increasing phagocytosis, and increasing the activity of natural killer cells. It has a hepatoprotective effect due to antioxidant and membrane stabilizing activity, in connection with which, based on a combination of glycyrrhizic acid and essential phospholipids, the domestic drug Phosphogliv was previously developed and registered. Glycyrrhizic acid potentiates the action of endogenous glucocorticosteroids, providing anti-inflammatory and anti-allergic effects in non-infectious liver lesions.

Flacoside is an antiviral, antioxidant and antihypoxic, hepatoprotective drug of plant origin created by the domestic company Vilar (from Amur velvet leaves, Phellodendron amurensis Rupr., And Laval velvet leaves, Phellodendron amurensis var. Lavalleiae Sprague.

The chemical structure is 7b D-glucopyranoside-8 (3-methylbut-2-enyl) -4 ', 5, 7-trioxy flavanone. It has an antiviral, hepatoprotective, antioxidant effect. Stabilizes cell membranes, induces the production of interferon; It is known [9] that flacoside has antiviral activity against herpes simplex viruses and viral hepatitis A and B. Flacoside is also indicated for chronic diffuse liver lesions.

The prior art [10] discloses a pharmaceutical composition proposed as a prototype of the present invention for the treatment of chronic liver disease (including liver cirrhosis and liver fibrosis), viral hepatitis, non-alcoholic steatohepatitis, liver cirrhosis and liver fibrosis, containing therapeutically effective amounts of glycyrrhizin (or its pharmaceutically acceptable derivative, including pharmaceutically acceptable salt), schizandra extract, ascorbic acid, L-glutathione, silymarin, alpha lipoic (thioctic) acid and d-a fa-tocopherol, and a method of treating these diseases comprising parenteral or oral administration of said composition in a therapeutically effective amount to a patient in need thereof. Preferably, said composition contains from 1000 to 1500 mg of glycyrrhizin or a pharmaceutically acceptable derivative thereof, from 1500 to 3000 mg of schizandra extract, from 500 to 10000 mg of ascorbic acid, from 50 to 1000 mg of L-glutathione, from 80 to 1000 mg of silymarin, 150 to 1200 mg of alpha lipoic acid, 200 to 1600 μg of d-alpha tocopherol. The composition in accordance with the prototype can be performed both in the form of a solution for parenteral administration, and in the form of an oral dosage form.

Nevertheless, the important task remains the creation of new combined drugs for the treatment of hepatitis alcohol and viral etiology, affecting a wider range of etiopathogenetic links of the disease.

It is known that one of the most important areas in the treatment of viral hepatitis is the use of immunocorrectors, in particular inducers of endogenous interferon, in particular such as cycloferon.

Cycloferon (acridonoacetic acid in the form of N-methylglucamine salt), developed by the domestic company Polisan, is a low molecular weight inducer of early α-, β- and γ-interferons by immunocompetent macrophage cells and T- and B-lymphocytes. In peripheral blood leukocytes induces the synthesis of 2500 IU / ml of interferon. In tissues and organs containing lymphoid elements, cycloferon induces high levels of interferon, which has an antiviral, antiprotozoal, antibacterial, antitumor effect. Cycloferon contributes to the correction of the immune system both in the case of immunodeficiencies and in autoimmune conditions. Cycloferon is highly effective in rheumatic and systemic diseases of the connective tissue, suppressing autoimmune reactions and exerting anti-inflammatory and analgesic effects.

Cycloferon does not have pyrogenicity. In experimental studies, no mutagenic, teragenic, embryotoxic, carcinogenic effect of the drug was revealed. It goes well with traditional therapeutic agents (antibiotics, immunotropic drugs, etc.).

Cycloferon is indicated for use in adults for the prevention and treatment of herpetic and cytomegalovirus and acute respiratory viral infections, for the complex treatment of HIV infection (AIDS, stage IIA – IIIB), and for viral hepatitis (A, B, C, D) [11], [12], [13], with neuroviral infectious diseases (serous tick-borne meningitis, multiple sclerosis, etc.), with chlamydial infections (urogenital chlamydia, chlamydial reactive arthritis, venereal lymphogranuloma); with secondary immunodeficiencies of various etiologies (chronic bacterial and fungal infections, the postoperative period, burns, etc.), with systemic diseases of the connective tissue (rheumatoid arthritis and other autoimmune diseases), with degenerative joint diseases (deforming osteoarthritis and spondylosis); in children - with viral hepatitis A, B, C, delta, GP and HIV infection, with herpes infection (herpes simplex, cytomegalovirus infection, infectious mononucleosis, etc.).

It was unexpectedly found within the framework of the present invention that a pharmaceutical composition comprising thioctic (alpha-lipoic) acid, flavanolignans, glycyrrhizic acid or a pharmaceutically acceptable salt thereof, as well as flacoside, selenium or its pharmaceutically acceptable derivative and acridonoacetic acid (cycloferon), has more excellent, in comparison with the prototype, hepatoprotective activity, which is an unexpected technical result, in accordance with the present invention, and is especially useful Second in the treatment of hepatitis alcoholic and viral etiology.

Thus, in accordance with the present invention, the following are claimed:

- A pharmaceutical hepatoprotective composition for the treatment and / or prevention of hepatitis of viral and / or alcoholic etiology, containing in a therapeutically effective amount of thioctic (alpha-lipoic) acid, flavanolignans, glycyrrhizic acid or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, characterized in that it further contains a therapeutically effective amount of flacoside, selenium or a pharmaceutically acceptable derivative thereof and acridonoacetic acid or a pharmaceutically acceptable acceptable salt, and

- A method for the treatment of hepatitis of viral and / or alcoholic etiology, including oral administration of the pharmaceutical composition according to any one of claims 1 to 15 for 1-2 doses 2-3 times a day.

The term "hepatitis of viral etiology" hereinafter means hepatitis caused by viruses A, B, C, delta, F and G.

The composition, in accordance with the present invention, is used as part of complex therapy for the treatment of alcoholic and viral hepatitis in an amount of 1-2 doses 3 times a day.

Preferably, the individual doses of the pharmaceutical composition in accordance with the present invention may be in the form suitable for oral administration, preferably in the form of tablets, gelatine capsules (hard or soft), solution or suspension for internal use. Preferably, tablets or capsules in accordance with the present invention are made using carriers and auxiliary components conventional in the art. The pharmaceutical composition in accordance with the present invention can be made in the form of other dosage forms, for example suppositories, using auxiliary components customary for these dosage forms.

In accordance with the present invention, but without limiting the scope of the claimed claims, preferably the pharmaceutically acceptable salt of glycyrrhizic acid is sodium glycyrrhizinate;

preferably the pharmaceutically acceptable derivative of selenium is selenium methionine or selenium oxide, the pharmaceutically acceptable salt of acridonoacetic acid is the N-methylglucamine salt of acridonoacetic acid; preferably flavanolignans are silymarin.

The most preferred therapeutically effective amount of thioctic acid in a single dose of the pharmaceutical composition in accordance with the present invention is from 300 to 600 mg, the most preferred therapeutically effective amount of flavanolignans (silymarin) is from 150 to 300 mg, the most preferred therapeutically effective amount of flacoside is from 50 to 100 mg, the most preferred therapeutically effective amount of acridonoacetic acid is from 150 to 300 mg, most preferred An effective therapeutically effective amount of glycyrrhizic acid or sodium glycyrrhizinate is from 75 to 150 mg, and a most preferred therapeutically effective amount of selenium methionine or selenium oxide is from 50 to 150 μg.

The following examples are presented solely to illustrate the present invention, but not to limit the scope of the claims.

Example 1. Obtaining soft gelatin capsules

The mixer is filled with the ingredients of the drug in the following proportions, in g:

Thioctic acid - 300 g,

Silymarin - 150 g,

Flacoside - 50 g,

Sodium glycyrrhizinate - 75 g,

Selena methionine - 0.068 mg,

Cycloferon (acridonoacetic acid) - 150 g.

Mix thoroughly; soft gelatin capsules (1000 pcs.) are filled in with the resulting composition in accordance with procedures traditional for the art.

Example 2. Obtaining tablets

The mixer is filled with the ingredients of the drug in the following proportions, in g:

Thioctic acid - 600 g,

Silymarin - 300 g,

Flacoside - 100 g,

Sodium glycyrrhizinate - 150 g,

Selenium oxide - 0.135 mg,

Cycloferon (acridonoacetic acid) - 300 g.

Mix thoroughly; adjuvants necessary for the manufacture of tablets, which are traditional in the art, are added to the obtained composition in the required amount, thoroughly mixed and compressed into tablets (1000 pcs) on a tablet press, in accordance with procedures traditional in the art.

Example 3. Obtaining a suspension for oral administration

One portion of an aqueous suspension for oral administration contains: silymarin - 150 mg; thioctic acid - 300 mg; selenmethionine or selenium oxide (in terms of selenium content) - 50 μg; sodium glycyrrhizinate - 75 mg; flacoside - 70 mg; cycloferon (salt of acridonoacetic acid with N-methylglucamine) - 150 mg; filler (lactose) - 2400 mg; mannitol - 800 mg; sodium saccharinate -2 mg; flavors and flavorings - 30 mg.

Example 4. Obtaining suppositories

Samples of alpha-lipoic (thioctic) acid (300 g), silymarin (150 g), selenmethionine (100 mg), sodium glycyrrhizinate (100 g), flacoside (75 g), cycloferon (N-methylglucamine salt of acridonoacetic acid) (150 g ) are mixed, observing the rules of mixing powders (State Pharmacopoeia XI, issue 2, p. 150). The resulting mixture is triturated with a small amount of molten base, introduced into the remainder of the molten base in fractional portions and mixed until a homogeneous mass. The resulting suppository mass is filtered and fed to a machine for the manufacture of suppositories. The mass is poured into cells (1000 pcs.) From a film of polyvinyl chloride at + 32-34 ° С and cooled at a temperature of + 5-10 ° С, obtaining 1000 pcs. suppositories containing the composition in accordance with the invention.

The following Examples 5-6 demonstrate the therapeutic effect of the claimed pharmaceutical composition and confirm its unexpected advantages in comparison with the prototype.

Example 5

Patient S., 35 years old, was admitted 30.05.08 with a diagnosis of chronic active hepatitis of moderate degree of alcoholic origin. Anamnestically - sick 10 years, abuse alcohol. Previously, hepatoprotectors have not been treated. The last worsening is about a week after another alcohol abuse.

Subjectively, at the time of admission, marked weakness, nausea, periodic pain in the right hypochondrium, sweating, loss of appetite were noted. Objectively expressed are asthenisation, subictericity of sclera and skin integument, hepatomegaly with compaction, moderately sensitive by the edge of the liver upon palpation (Kurlov’s liver size is 12.5 × 10 × 10).

In biochemical analyzes, a cytolytic syndrome was expressed (ALT - 1.6 μmol / LH, AST - 1.2 μmol / LH, total bilirubin - 29.4 μmol / L, direct - 5.4 μmol / L. The total protein content was normal - 70 g / l, but dysproteinemia was noted: albumin accounted for 52%, gamma globulin - 23%). Activation of LPO processes was manifested in an increase in the content of the MDA level to 6.9 μmol / L. Serological markers of viral liver damage have not been derived. Dynamic hepatobyl scintigraphy showed an increase in liver in size, a moderate violation of the absorption and a pronounced violation of the excretory function of the liver. Morphological examination of the biopsy specimen shows severe liver dystrophy, sparse lymphocytic infiltration of portal fields with moderate expansion due to fibrosis. Small patches of hepatitis necrosis and diffuse intralobular lymphocytic infiltration were found in the border plate.

After treatment with the hepatoprotective pharmaceutical composition of the invention (in the form of gelatin capsules) containing 300 mg of thioctic acid, 150 mg of silibinin, 50 mg of flacoside, 75 mg of sodium glycyrrhizinate, 67.5 μg of selenium oxide, and mg of acridonoacetic acid in the form of N-methylglutamine salt taken 2 r / day before meals, the disappearance of nausea, pain in the right hypochondrium, a significant decrease in weakness, improved appetite. Kurlov’s liver size was 11x9x9 cm. Positive dynamics was also observed in the functional state of the liver in the form of normalization of the following biochemical parameters: decrease in AST activity to 0.2 μmol / lch, ALT to 0.6 μmol / lch, total bilirubin to 8.4 μmol / l, the absence of direct bilirubin, the disappearance of dysproteinemia - albumin accounted for 64%, gamma globulins - 14%. LPO activity also decreased: the MDA level decreased to 4.7 μmol / L. A dynamic puncture biopsy of the liver showed a significant decrease in lymphocytic infiltration of the portal tracts and inside the lobules, as well as the disappearance of necrosis in the border plate.

Example 6

We examined 24 patients (18 men, 6 women, average age 33 ± 5.0 years) with a diagnosis of chronic viral hepatitis C. All patients had antibodies to HCV in their blood and the presence of viral RNA.

At random, patients were divided into two groups of 12 people.

During the 20 weeks of treatment, patients of group I received 3 times a day a pharmaceutical composition in accordance with the prototype (in the form of gelatin capsules) containing: 500 mg of glycyrrhizic acid, 500 mg of schizandra extract, 2 g of ascorbic acid, 150 mg of L-glutathione, 250 mg of silymarin, 150 mg of thioctic acid and 800 μg of d-alpha tocopherol.

Patients of group II for 20 weeks of treatment received 3 times a day the pharmaceutical composition in accordance with the present invention (in the form of gelatin capsules), containing: 300 mg of thioctic acid, 250 mg of silymarin, 150 mg of sodium glycyrrhizinate, 100 mg of flacoside, 100 μg of selenium methionine and 150 mg of N-methylglucamine salt of acridonoacetic acid (cycloferon).

Every 2 weeks, a biochemical blood test of each of the 24 patients was performed, including the determination of liver enzymes (aspartate aminotransferase, AST, alanine aminotransferase, ALT). The dynamics of changes in each of the indicated biochemical parameters in both groups by week is shown in the table and in Figs. 1-4 (along the abscissa axis is the week of the study, along the ordinate axis is the number of patients with a given value of the biochemical indicator).

No. of weeks research AST, U / L ALT, UNIT / L Group 1 0 > 80 - 8 people 120-100 - 9 people 60-80 - 3 people 100-80 - 3 people <60 - 1 pers. 80-60 - 0 people <60 - 0 people 2 > 80 - 8 people 120-100 - 8 people 60-80 - 2 people 100-80 - 4 people <60 - 2 people 80-60 - 0 people <60 - 0 people four > 80 - 6 people 120-100 - 7 people 60-80 - 4 people 100-80 - 5 people <60 - 2 people 80-60 - 0 people <60 - 0 people 6 > 80 - 6 people 120-100 - 6 people 60-80 - 3 people 100-80 - 3 people <60 - 3 people 80-60 - 3 people <60 - 0 people 8 > 80 - 5 people 120-100 - 3 people 60-80 - 4 people 100-80 - 3 people <60 - 3 people 80-60 - 3 people <60 - 3 people 10 > 80 - 5 people 120-100 - 2 people 60-80 - 4 people 100-80 - 5 people <60 - 3 people 80-60 - 2 people <60 - 3 people 12 > 80 - 3 people 120-100 - 0 people 60-80 - 6 people 100-80 - 4 people <60 - 3 people 80-60 - 6 people <60 - 2 people fourteen > 80 - 3 people 120-100 - 0 people 60-80 - 5 people 100-80 - 4 people <60 - 4 people 80-60 - 2 people <60 - 6 people 16 > 80 - 2 people 120-100 - 0 people 60-80 - 6 people 100-80 - 3 people <60 - 4 people 80-60 - 2 people <60 - 7 people eighteen > 80 - 3 people 120-100 - 0 people 60-80 - 5 people 100-80 - 1 person <60 - 4 people 80-60 - 3 people <60 - 8 people twenty > 80 - 1 pers., 120-100 - 0 people 60-80 - 8 people 100-80 - 1 person <60 - 3 people 80-60 - 3 people <60 - 8 people Group 2 0 > 80 - 11 people 120-100 - 8 people 60-80 - 1 person 100-80 - 3 people <60 - 0 people 80-60 - 1 people <60 - 0 people 2 > 80-10 people 120-100 - 7 people 60-80 - 1 pers., 100-80 - 3 people <60 - 1 pers. 80-60 - 2 people <60 - 0 people four > 80 - 9 people 120-100 - 7 people 60-80 - 2 people 100-80 - 2 people <60 - 1 pers. 80-60 - 3 people <60 - 0 people 6 > 80 - 7 people 120-100 - 4 people 60-80 - 5 people 100-80 - 5 people <60 - 0 people 80-60 - 3 people <60 - 0 people 8 > 80 - 5 people 120-100 - 2 people 60-80 - 4 people 100-80 - 7 people <60 - 3 people 80-60 - 3 people <60 - 0 people 10 > 80 - 5 people 120-100 - 1 people 60-80 - 2 people 100-80 - 7 people <60 - 5 people 80-60 - 2 people <60 - 2 people 12 > 80 - 2 people 120-100 - 1 people 60-80 - 5 people 100-80 - 5 people <60 - 5 people 80-60 - 3 people <60 - 3 people fourteen > 80 - 2 people 120-100 - 1 people 60-80 - 4 people 100-80 - 2 people <60 - 6 people 80-60 - 6 people <60 - 3 people 16 > 80 - 1 pers., 120-100 - 0 people 60-80 - 3 people 100-80 - 0 people <60 - 8 people 80-60 - 6 people <60 - 6 people eighteen > 80 - 1 pers., 120-100 - 0 people 60-80 - 2 people 100-80 - 0 people <60 - 9 people 80-60 - 4 people <60 - 8 people twenty > 80 - 0 people 120-100 - 0 people 60-80 - 2 people 100-80 - 0 people <60 - 10 people 80-60 - 2 people <60 - 10 people

The viral RNA detected in the blood at the beginning of the study in 100% of cases in patients of both groups was detected in 5 patients of group I and in 1 patient of group II by the end of the course of treatment.

The data presented indicate that the pharmaceutical composition in accordance with the present invention exhibits unexpectedly higher, compared with the prototype, hepatoprotective activity in the treatment of hepatitis of alcoholic and viral etiology, acting on various etiopathogenetic links of hepatitis of viral and alcoholic etiology, and is unexpectedly highly effective in the treatment of these diseases, which constitutes an unexpected technical result of the present invention.

Literature

1. Shulpekova, Yu.O. Acute viral hepatitis / Yu.O. Shulpekova // Attending physician. - 2005. - No. 2. - S.20-23.

2. RF patent No. 2201247 ("BIOLOGICALLY ACTIVE ADDITIVE TO REDUCE ALCOHOL DEPENDENCE WITH HEPATOPROTECTIVE PROPERTIES"), publ. 03/27/2003.

3. Berskon B.M. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), sylimarin, and selenium - Med. Klin. (Munich), 1999 Oct 15; 94 Suppi 3: 84-9 (PubMed Abstract).

4. Marshall A.W. et al. Treatment of alcohol-related liver disease with thioctic acid: a six month randomized double-blind trial. - Gut. 1982; 23 [12]: 1088-93 (abstract of PubMed).

5. Kozhoka T. G. Medicines in parasitology and gastroenterology, problems of production and provision of the population. - M.: MIEMP, 2006, pp. 99-100.

6. Orient H., Hansen B.E. et al. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial. - J Hepatol. 2006 Oct; 45 [4]: 539-46. Epub 2006 Jim 30 (PubMed Abstract).

7. Arase Y. et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. - Cancer 1997; 79 [8]: 1494-500 (PubMed abstract).

8. Van Rossum T. G. et al. Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998; 12 [3]: 199-205 (PubMed abstract).

9. http://www.gastroportal.ru/php/content.php?id=706&pr^print

10. Application for US patent No. 2005123628, filed December 3, 2003, publ. 06/09/2005.

11. Narovlianskii AN, Deriabin PG, Vershinina MIu, Mezentseva MV, Ershov FI. [Effect ofinterferon inductors on infection induced by hepatitis C virus and activity ofmRNA cytokines in cell cultures SW-13 and MT-4] - Vopr Virusol. 2002 Nov-Dec; 47 [6]: 17-21 (PubMed abstract).

12. Chuikova K.I., Gulyaeva O.M., Kovaleva T.A. The use of cycloferon in viral hepatitis B and B + C against the background of opium addiction. [http: //xxt2006.chtd.tpu.m/uploads/pdf/787_864.pdf].

13. H.V. Hamster Cycloferon - an alternative to interferon therapy. -Online magazine "Provider", No. 20, 2000 [http://www.provisor.com.ua/archive/2000/N20/cyclopheron.htm].

Claims (20)

1. A pharmaceutical hepatoprotective composition for the treatment and / or prevention of hepatitis of viral and / or alcoholic etiology, containing in a therapeutically effective amount of thioctic (alpha-lipoic) acid, flavanolignans, glycyrrhizic acid or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, characterized in that further comprises a therapeutically effective amount of flacoside, selenium, or a pharmaceutically acceptable derivative thereof and acridonoacetic acid, or a pharmaceutically riemlemoy salt. 2. The pharmaceutical composition according to claim 1, characterized in that the hepatitis of viral etiology is hepatitis caused by hepatitis A virus, or hepatitis B virus, or hepatitis C virus, or hepatitis D virus, or hepatitis E virus, or hepatitis G. 3. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt of glycyrrhizic acid is sodium glycyrrhizinate. 4. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable derivative of selenium is selenium methionine or selenium oxide. 5. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt of acridonoacetic acid is an N-methylglucamine salt of acridonoacetic acid. 6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of thioctic (alpha-lipoic) acid is in the range from 300 to 600 mg. 7. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of flavanolignans is in the range from 150 to 300 mg. 8. The pharmaceutical composition according to claim 7, characterized in that the flavanolignans are silymarin. 9. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of glycyrrhizic acid or its pharmaceutically acceptable salt is in the range from 75 to 150 mg. 10. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of flacoside is in the range from 50 to 100 mg. 11. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of selenium or its pharmaceutically acceptable derivative (in terms of selenium) is in the range from 50 to 150 μg. 12. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the therapeutically effective amount of acridonoacetic acid is in the range from 150 to 300 mg. 13. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a form suitable for oral administration. 14. The pharmaceutical composition according to p. 13, characterized in that it is made in the form of tablets. 15. The pharmaceutical composition according to p. 13, characterized in that it is made in the form of a suspension for oral administration. 16. The pharmaceutical composition according to p. 13, characterized in that it is made in the form of gelatin capsules. 17. The pharmaceutical composition according to clause 16, characterized in that it is made in the form of hard gelatin capsules. 18. The pharmaceutical composition according to clause 16, characterized in that it is made in the form of soft gelatin capsules. 19. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of suppositories. 20. A method for the treatment of hepatitis of viral and / or alcoholic etiology, including oral administration of the pharmaceutical composition according to any one of claims 1 to 18, 1-2 doses 2-3 times a day.

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