Gepatonin now pass registration at the Pharmacological Committee of the Ministry of

Health and Social Affairs of Georgia.

Gepatonin  has passed preclinical and clinical trials  in the following organizations:

• The Kiev  Medical  Institute named after Bogomolts, Department Infectious Diseases, Kiev, Ukraine.

• Medical Center Diseases "Dobrobutt", Department of Infectious Diseases, Kiev, Ukraine.

• Clinical and Experimental Research Institute of Tbilisi State Medical University;

• Medical & Biological Scientific Research Centre  – Company <<Alexis>>;

• Laboratory  of  Cell  Signal  Mechanisms  of  the  I.Paladin  Institute  of  Biochemistry  at

• Ukrainian Medical Academy;

• Medical  Research  Institute  of  Physical  Chemistry  at  the  Ministry  of  Healthcare  of

• Russian Federation;

• Pharmacological Department of the Medical University of Russian Federation;

• Fuji  Memorial Institute of the Preclinical Research, Bivako/Japan;

• Tokushima Otsuka Immunology Research Institute, Japan;

• Tokushima Institute  of New Drug Research and Safety Evaluation, Japan;

 

Gepatonin is recommended for the treatment of cirrhosis, hepatitis- A, B, C and over liver disorders.

Clinical trials show that use of the Gepatonin in the treatment of patients with chronic hepatitis C possesses rather a high efficiency in the treatment of patients with viral hepatitis C disease:

• Unpleasant feelings in the right hypochondrium disappeared, the general condition considerably improved.

• Expressed positive dynamics of indicators of ALT, AST, thymol test, GGT, the general bilirubin is obvious.

• Application of GA- Gepatonin is expedient at patients with chronic hepatitis C which have contraindications to carrying out PVT.

• Gepatonin action does not depend on a genotype of a virus of hepatitis C, but to some extent depends on a stage of fibrosis of liver: clinical and biochemical improvement was more expressed at fibrosis F2 and F3.

• Most likely Gepatonin can be applied to the radical treatment of chronic hepatitis C, practically without contraindications. It is not excluded that Gepatonin in a combination with PVT can be applied in treatment not only for not respondents, but also persons with an adverse genotype of IL28 v, at which efficiency of standard PVT within 20-25%.

• In 2 months after completion of treatment, the PCR-test for HCV remained negative with 60% of patients.

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Molecular Mechanism of the Gepatonin Anti-Hepatitis C Action.

Getting (penetration) into the body hepatitis C virus causes suppression of the immune system by inhibiting  Interferon’s  (IFN) production by mononuclear immune cells.  Interferon’s inhibit protein synthesis within the infected cells and reduce viral replication in host cells. Inhibition protein synthesis destroys both the virus and infected host cells and restricts the entry of the virus in neighboring cells. Another function of interferon’s, such as interferon-γ (INF-γ), is to directly activate mononuclear immune cells, such as T-killer, NK-cells, macrophages and others.

 

Activated  cells  release  cell  lytic  cytotoxins perforin, granzymes,  and granulysin  and  trigger apoptosis, programmed cell death of the hepatitis C virus infected target cells.  Viral spread also limit by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. Release of IFN-ƴ from cells is also induced by cytokines, such as interleukin 1, interleukin 2, interleukin

12; tumor necrosis factor can also enhance interferon-ƴ production. During prolonged HCV infection many complex processes play critical roles in the development of liver damage. One of these processes includes enhanced production of free radicals, causing liver oxidative stress, increase HCV disease activity in chronic hepatitis, causes liver injury leading to fibrosis and eventually hepatocellular carcinoma.

 

The results of pre and clinical trials of the medical preparation Gepatonin,  allows  to submit a scheme   of the   molecular mechanisms Gepatonin anti-hepatitis C virus-action, which leads to the high efficiency of the Gepatonin treatment of patients with chronic hepatitis C virus disease.

 

In the treatment of chronic hepatitis C using   Gepatonin crossing an inactive form of the disease occurs from 1 to 7 treatments for all patients. In addition, the transition to an inactive form has a permanent effect. In patients treated with the control exerted over four years and in

95% of cases (for lack of provoking factor) activation was not found.

 

After four courses of treatment recommended control analysis of the presence of virus (PCR). When negative results every six months during the two years it is necessary to operate the control PCR.

If after four treatments PCR showed the presence of virus, hepatitis should be continued, and

 

after seven treatments once again make PCR analysis.

 

The end result of the total elimination of the virus occurs in 60% of cases.

 

The amount of therapy depends on the severity of the person and the dynamics of treatment.

 

Cirrhosis

 

When using the preparation Gepatonin in most cases achieved regression of disease as evidenced by the fact that the preparation Gepatonin has very strong hepatoprotektorna characteristics and affects the recovery process of the exchange of substances (protein, lipid,

 

and carbohydrate).  Regardless  of  the  etiology  of  cirrhosis  (viral,  alcoholic,  autoimmune)

 

improve the condition occurs in 91% of cases.

 

The amount of therapy depends on the severity of the person and the dynamics of treatment.

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CTL- T-killer cells , NK-cell- natural killer cell, MF- macrophage, DK-dendrites’ cell, NF- neutrophils, Cytotoxin-granzymes, and granulysin,  Fas L -  is a homotrimeric type II CTL an NK- cell transmembrane protein. Fas L recognize, interact and bind with   Fas (death receptor), which spans the membrane of the cancer or infected "target" cells. This high specifically interaction between Fas L and Fas surface receptors usually leads to apoptosis, or cell death.

·    Gepatonin  activates  mononuclear  cells,  cytotoxic-T  cells  (T-killer  cell)  s,  T-helper, Natural killer cells (NK-cells), macrophages, neutrophils. Activated cells release infected cell lytic  perforin and cytotoxin-granzymes, and granulysin and trigger apoptosis - programmed cell death of the hepatitis C virus infected target cells.  A second way to induce apoptosis is

 

via cell-surface interactions between the T-killer cells,  NK-cells cells and the infected cells. The final result is apoptosis of the hepatitis C virus infected target cells.

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Gepatonin increases p53 activity, which kills virus-infected cells by promoting apoptosis of the hepatitis C virus-infected target cells.

·    Gepatonin activates the production of  Tumor  Necrosis  Factor  (TNF-α),  which induce release   Interferon-ƴ.   Both cytokines   TNF-α and   IFN-ƴ kill virus-infected cells by promoting apoptosis of the hepatitis C virus-infected target cells.

·    Gepatonin with high Anti-oxidant activity neutralizes free radicals and reduces the oxygen with two unpaired electrons, inhibits oxygen stress and decrease chronic  HCV disease activity in patients.

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Anti-inflammatory and antifibrotic effects of plant regulatory peptides in patients with steatohepatitis and cirrhosis. Opportunities of primary liver cancer prevention.

 

 

Anatolyy Pechinka¹, Levan Kakliani², Zurab Gogitidze³, Sergii Konovalenko, Iryna Miroshnychenko

 

 

1 - Shupyk NMAPE, Department of Infectious Diseases, Kyiv, Ukraine

2 - Department of Internal Medicine, University Hospital of Tbilisi, Georgia

3 – Regul Medical Information Center

4 - RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kyiv, Ukraine

5 - Kyiv City Center for Radiation Protection of Kyiv Population from the Consequences of the Chornobyl Catastrophe

 

 

 

Abstract

 

 

The pathogenesis of steatohepatitis, which develops on the background of non-alcoholic fatty liver disease and may be the cause of liver cirrhosis, is considered in the article. Also, the paper focuses on the prospects of using peptide drugs for the treatment of liver cirrhosis. The study found that the preparation of plant regulatory peptides GEPATONIN has pronounced hepatoprotective, anti-inflammatory and anti-fibrotic effects, which is confirmed by the elastometry data of the shear wave. The results of this work indicate that the use of the drug GEPATONIN was accompanied not only by the normalization of the inflammatory panel of the liver and triglycerides, but also by a likely decrease in the level of glypican-3 - the main factor that causes the development of primary liver cancer. Gene protector and immunocorrector harmonizing metabolic processes in the liver, as well as suppressing inflammation and preventing excessive output of hepatocytes in apoptosis, has a positive effect on the prognosis of the disease. Reduced expression of glypican-3 in patients in the study group indicates that GEPATONIN is able to control the level of pro-oncogenic trigger proteins, thus reducing the risk of primary liver cancer.

 

 

Key words: steatohepatitis, cirrhosis, glypican-3, GEPATONIN, hepatocellular carcinoma.

 

 

 

Introduction. Non-alcoholic fatty liver disease (NAFLD) is a disease that results from excessive fat accumulation (mainly triglycerides) in the form of steatosis in the liver in people who do not consume alcohol in amounts capable of causing liver damage. [1,2]

NAFLD and non-alcoholic steatohepatitis (NASH) are more common in women aged 40-60 years, but there are reports of this type of pathology in younger patients. NAFLD is a type of liver steatosis or fatty hepatosis that occurs in people who do not abuse alcohol and is most commonly associated with insulin resistance and metabolic syndrome. The term "NAFLD" has several synonyms: non-alcoholic liver steatosis, fatty liver, fatty infiltration of hepatocytes. [3,5,7].

One of the most characteristic phenomena in this disease is the accumulation of fat in the functioning tissue of the liver. In the future, it leads to the replacement of this tissue with adipose tissue, which eventually causes the development of chronic inflammation. Isolated liver steatosis is a relatively benign condition with minimal risk of progression to more severe liver disease. [4,6,8].

The development of inflammatory processes on the background of fatty dystrophy leads to damage hepatocytes and the progress of non-alcoholic, or metabolic, steatohepatitis, which is one of the stages of NAFLD, and steatohepatitis gradually leads to liver cirrhosis. [9,10]. This mechanism also works with viral, toxic (alcohol) lesions as an additional damaging factor.

Non-alcoholic fatty liver disease occupies one of the leading positions among diffuse liver diseases. The relevance of the study of NAFLD is due to

both the prevalence of the disease and the risk of developing cirrhosis and hepatocellular carcinoma (HCC) (Figure 1).

The proportion of patients with NAFLD in the adult population ranges from

6.3% to 33% with a median of 20% in the global population. In some countries, the incidence is 46% [11]. The progression of the disease also increases the risk of liver cirrhosis and liver failure. Studies have shown that a quarter (27%) of patients with NAFLD develop fibrosis within 9 years, and one in five (19%) have cirrhosis of varying degrees of severity [12,13].

It is established that the stage of fibrosis, and not the severity of inflammation, is the prognostic factor that determines the subsequent fate of patients and the likelihood of complications. In this regard, it is important to look for predictors of progression of liver fibrosis to individualize therapy and follow- up of the patient. At the present stage, it seems interesting to study gene

polymorphisms in the development or progression of diseases.

The G-allele of the PNPLA3 gene is positively correlated with the triglyceride content of liver tissue, and its  loss of activity may be directly related to

inflammation of the liver tissue. Concerning the association of PNPLA3 with the development and progression of liver fibrosis in histologically confirmed NAFLD, regardless of obesity, diabetes mellitus and steatosis, convincing data have also been presented [15]. The participation of this gene in liver cirrhosis formation and transformation in HCC has been proved [16], regardless of external factors (obesity, alcohol consumption). The polymorphism of the PNPLA3 / 148M gene is today an independent genetic factor for the development and progression of NAFLD and non-alcoholic steatohepatitis.

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Figure.1 Scheme of progression of non-alcoholic fatty liver disease.

A. Accumulation of lipid (triglyceride) droplets inside hepatocytes causes steatosis. Steatosis associated with inflammation, cell death and fibrosis progresses and non-alcoholic

steatohepatitis develops, which can turn into cirrhosis.  People with cirrhosis have an

increased risk of developing hepatocellular carcinoma.

 

B. Histological sections showing the normal state of the liver, steatosis, steatohepatitis, and cirrhosis. Collagen fibers are colored in blue by the Masson method. A portal triad (PT) consisting of a hepatic artery, a portal vein, a bile duct and a central vein (CV) is shown [14].

  

Glypican-3 (GPC3), an oncofetal proteoglycan, attaches to the cell membrane, usually found in the liver of the fetus, but not in the healthy liver of the adult. However, in patients with HCC GPC3 is overexpressed and its expression predicts poor prognosis. Studies have shown that GPC3 functions in the progression of HCC by binding to molecules such as Wnt signaling proteins and growth factors. [17-19]

 

According to D. Baumhoer et al. [20], positive expression of glypican-3 is also observed in individual high-grade dysplastic nodules, indicating their carcinogenic orientation. Elevation of  glypican-3 is also considered as a prognostic factor for HCC in patients with cirrhosis. Glypican can enhance mRNA expression of HCC-related genes and participate in the neoplastic process in the cirrhotic liver. Therefore, GPC3 can serve as a precursor biomarker in liver cirrhosis. [21,22]

 

Moreover, GPC3 was used as a target for molecular imaging and therapeutic intervention in HCC. [23] Magnetic resonance imaging focused on GPC3, positron emission tomography and near-infrared tomography for early detection of HCC have been investigated, various GPC3 immunotherapeutic protocols have been developed, including the use of humanized anti-cytotoxic DNA / cytotoxic treatments, immunotoxin therapy, and genetic therapy. [24,25]

 

GEPATONINis the first gene protector and immunocorrector based on plant regulatory peptides to be used in clinical practice. It is known that GEPATONINpeptides, due to their relatively small size (15-98 kDa), can affect not only membrane receptors but also penetrate cells through membrane pores. This enables them to interact with intracellular structures: regulatory peptides and genes, ligands and enzymes. Studies have also demonstrated that GEPATONINpeptides are intracellularly capable of altering the active potential of participants in the regulatory cascades: mRNA-associated proteins, caspases, protein kinases, prointerleukins, interleukins, and the like.

 

The history of the discovery and study of the immunotropic and gene- protective properties of  GEPATONIN is set out in professor George Alexidze's monograph “ GEPATONIN. New Immunotherapy and Anticancer Drug”, which was released in 2014 in the USA - Lambert Academic Publishing. Feb 12, 2014).

 

The uniqueness of GEPATONINis that plant peptides under conditions of reduced antitumor  immunity  due  to  aggressive  tumor  activity  or  after  antitumor

 

chemotherapy restore immune surveillance and promote apoptosis of cancer cells. [26]

 

In opposite conditions, that is, in conditions of hyperproduction of immunocompetent molecules in inflammatory processes, in particular in the liver and kidneys (in hepatitis, cirrhosis, nephritis), plant peptides are able to reduce the intensity of peptide-peptide interactions and prevent undesirable damage to healthy сells. [27]

 

This paradox can be explained by the evolutionarily formed properties of regulatory peptides - self-assembling and the natural intention for harmonization.

 

Aim of research. In order to study the hepatoprotective, anti-inflammatory and antifibrotic action of GEPATONIN, we formed two groups of patients diagnosed with steatohepatitis, liver cirrhosis.

 

Materials and methods

Based on the Department of  Therapy of the University Clinic of  Tbilisi

(Georgia), from 2016 to 2019 experience in the use of GEPATONINwas obtained in

34 patients (25 women and 9 men aged 44 to 65 years) with steatohepatitis (23) and cirrhosis liver (11). To study the hepatoprotective, anti-inflammatory and anti-fibrotic properties of GEPATONIN, a control group of patients - C (N = 34) was recruited.

 

The study group received the following treatment: ademetionine 400 mg 2 times a day tablets orally, verospiron capsules 50 mg 2 times a day, triamterene with hydrochlorothiazide (25 mg + 12.5 mg tablets) orally and GA-

40 on a pulse schedule - 400 μg of the solution of regulatory peptides per day injected intramuscularly for 28 days, a total of 6 courses for 28 days with breaks in 1 week.

 

The control group received therapy according to the scheme: ademetionin

400 mg 2 times a day tablets orally, verospiron capsules 50 mg 2 times a day, triamterene with hydrochlorothiazide (tablets 25 mg + 12.5 mg) orally.

 

We monitored ALT, AST, GGT, C-reactive peptide, and triglyceride levels for treatment at 35, 75, 105, 140, 175, and 210 days of follow-up. Such distribution of control points is conditioned by the scheme of therapy in the study group: 28 days is the introduction of GEPATONIN, then 7 days of break - and control for 35 days, then another 28 days of therapy, 7 days of break - and control for 70 days, etc. As a marker of the risk of primary liver cancer, we used the expression level of glypican-3 (GPC-3).

 

The level of fibrosis was controlled by ultrasound-shear elastometry. The study group had 11 patients with liver cirrhosis in stage F4 on a METAVIR scale with different levels of fibrosis. Indicators were monitored before treatment and after treatment.

 

 

Results and Discussion

 The study groups were comparable in the pre-treatment phase (p> 0.05). Clinical observations show that in the study group in the first month of therapy there was a tendency to normalize ALT, AST and other biochemical indicators of liver inflammation. Gradually decreased serum triglyceride levels. (Table 1). Similar dynamics of biochemical parameters were recorded in the control group, especially in the first 2 months of observation, but on the 105th and

175th day, the AST marker level increased slightly - to an average of 54.3 IU / l and 49.5 IU / l, respectively. , which formed a statistically significant difference compared to the study group (p <0.05). A statistically significant difference

between the ALT groups is formed from 105 days of observation, and the AST

level from 35 days is maintained until the end of the study (p <0.05).

 

 

With quite positive dynamics of decrease in inflammatory marker GGT in the control group, on day 210, there was a slight increase in it from an average of 21.8 to 34.7 IU / l (p <0.05 when compared between groups). Also, in the control group, expression of the C-reactive peptide after a marked decrease from the level of 9.1 IU / ml to 4.9 IU / ml increased again at the sixth control point to 7.2 IU / ml (p <0.05). (Table 2) It should be noted that there were no such increases in the study group and the levels of AST, ALT, GGT and C- reactive peptide remained within the normal range throughout the observation period from the second control point.

Δ=-1,17 p=0,115

 

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Figure 2. Level of glypican-3 in patients during treatment.

 

Equally interesting was the assessment of glypican-3 (GPC3) protein expression in patients in the study and control groups. In the first five weeks after the start of the treatment protocol, there was a slight decrease in serum GPC3 concentration from 39.9 - 41.4 to 33.6 - 38.3 ng / ml in both observation groups. However, at the third point of control, on the 70th day from the start of pulse therapy, the average expression of GPC3 in patients in the study group showed a sharp decrease to 17.4 ng / ml (p <0.05). This trend persisted - on day 105 of the treatment course, the level of GPC3 in the patients in the study group dropped to 7.1 ng / ml and remained relatively low throughout the

 

observation period. At the same time, GPC3 expression reached the level of

26.6 ng / ml on day 140 of the treatment protocol in patients of the control group, and after 5 weeks it increased significantly again - up to 33.8 ng / ml. At the final reference point, GPC3 activity increased again to 37.7 ng / ml, almost

returning to baseline. A statistically significant difference between the groups

(p <0.05) begins to form after 35 days of observation.

  

All  11  patients  with  cirrhosis in  the  study  group  had  a  statistically significant decrease in liver fibrosis. In 3 of them, to the F3 level on the METAVIR scale, and in the rest - to the initial F4 level: from 35.3 kPa on average, there was a decrease to 12.7 kPa.

 

 

It can be reasonably assumed that the gene protector and immunocorrector GEPATONIN, by harmonizing metabolic processes in the liver, as well as suppressing inflammation and preventing excessive hepatocytes exit into apoptosis, have a positive effect on the prognosis of the disease. Reduced expression of glypican-3 in patients in the study group indicates that GEPATONIN with a high probability is capable of controlling the level of pro-oncogenic trigger proteins, thus reducing the risk of primary liver cancer.

  

 

Conclusions

 

 The results of this work indicate that the use of the drug GEPATONIN was accompanied not only by the normalization of the inflammatory panel of the liver and triglycerides, but also a likely decrease in the level of glypican-3.

 

 The results obtained confirm that the preparation of plant regulatory peptides GEPATONIN has pronounced hepatoprotective, anti-inflammatory and anti- fibrotic effects, which is confirmed by the elastometry data of the shear wave.

 

 Against the background of complex treatment, not only was the gradual regression of the clinical symptoms of the disease, but there was a significant improvement in the general condition and quality of life of patients.

 

 At this stage, the inclusion of GEPATONIN in the treatment regimens of steatohepatitis and cirrhosis of the liver is quite reasonable, especially since this drug is able to significantly reduce the risk of hepatocellular carcinoma and significantly reduce  the  degree  of  liver  fibrosis.  Such  properties  make  it possible to consider GEPATONIN as a potential drug for delaying or even avoiding the terminal stage of liver cirrhosis, in which indications for transplantation arise.

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1. Clinical Trials GEPATONIN on Patients with Chronic Hepatitis C Viruses  Diseases

 

P. V. Doroshchenko

Chief physician of “Dobrobut”

doctor of the highest category,

Odessa

 

EXPERIENCE OF APPLICATION OF THE PREPARATION GEPATONIN

AT VIRUS HEPATITIS C

 

In modern conditions, the liver constantly is exposed to various influences from the environment. The range of exogenous toxic factors extends: alcohol, xenobiotics (artificial dyes and preservatives in foodstuff, medicines with toxic effects), excessive loading fats in a diet, and also the infections caused by hepatotropic viruses, parasitic invasions.  Relevance of a problem of viral hepatitis C (HCV) is caused by high prevalence HCV infection (to 6% on the globe) and sufficient percent of synchronization of an HCV infection (from 33 to 92% infected, depending on a virus HCV genotype), making the main share among all chronic defeats of a liver. On infection frequency virus hepatitis C is on the first place among all infections which are transmitting through blood: in the world, there are about 300 million HCV infected. According to modern data, only in the USA there are registered 3 million people infected with HCV. From them 8–10 thousand people die annually and the majority of transplantations of a liver is carried out to the patients sick with HCV. In Europe, the number of infected HCV makes to 2% of all populations.

Due to the difficulty of creation of a specific vaccine against the hepatitis C, the virus which was characterized by high mutational variability of hepatitis C and ability "to escape" from immune supervision, the indicator of incidence of HCV can treble by 2010 (according to World Health Organization (WHO data). The problem is aggravated with that for a long time at the majority of HCV infected the asymptomatic course of a disease takes place. The latent course of disease allows to consider that the percent of revealed HCV sick is much lower than the index of infection of the population.

Now HCV infected are most often young people, mainly men at the age of 20 years, 38–40% from them catch at intravenous administration of drugs. Approximately at half of the patients the way of infection does not manage to be established. The main way of a HCV transfer is parenteral (transfusions, organ transplantation from the infected donors, intravenous administration of drugs). Infection is possible sexually, the child from the mother and also at household contacts.

The genome of a virus of hepatitis C contains the unary thread of RNA coding intracellular synthesis of structural and nonstructural proteins. Infection by an RNA-genomic virus of hepatitis C is one of the leading reasons of incidence and mortality around the world, causing a wide range of defeats of a liver from an asymptomatic carriage to a terminal stage of disease. As a result of a long persistence of a virus of hepatitis C in an organism the chronic disfunction of a liver leading to development as cirrhosis, and a hepatocellular cancer develops.

Pathogenesis of an HCV infection is connected with direct cytotoxic action of a virus and violations of immunological reactions that leads to injury of a liver and other bodies. Morphologically there develop inflammatory and necrotic and degenerate pathological processes of a parenchyma and biliary tract system of a liver.  Both in the present, and in the future chronic hepatitis C remains extremely important problem for health care around the world. Despite measures for decrease in prevalence of an HCV infection, at huge number of earlier infected patients, disease progressing in cirrhosis and hepatocellular carcinoma will proceed. The progressing course of chronic hepatitis C with cirrhosis formation (from 2,4 to 24%) and development of primary cancer of a liver – a hepatocellular carcinoma (at 5%) assumes application in tactics of treatment of an HCV infection not only antiviral therapy but also hepatoprotective preparations.

The main objective of treatment of patients with chronic hepatitis C is achievement of elimination of a virus from an organism, the prevention of progressing of the specific pathological process and disease recurrence, and also improvement of a functional condition of a liver. Now therapy of an HCV infection is provided with application of antiviral preparations (IF-s interferons, analogs of nucleosides), having direct etiological and pathogenetic value. Correction of functional insufficiency of a liver as a result of hepatotoxic effects of a virus of hepatitis C demands the application of preparations of the hepatoprotective property allowing not only to improve its function, but also to cause a reduction of fibrogenesis.

At diffusion diseases of a liver, as well as at any pathological process, a number of the general actions is shown. A strict confinement to bed the majority of patients do not need, except for the expressed signs of an aggravation (distinct cholestasis, increase of activity of  Alaninaminotransaminase more than by 4–5 times in blood serum in comparison with norm). The diet structure at patients is quite wide. Alcohol has to be completely excluded, in the period of an aggravation smoked products, fried dishes, refractory fats are limited. At the same time fats are natural cholagogic means and therefore their share in a daily diet (oil, margarine) has to make about 35% from the general caloric content. The amount of protein (vegetable and animal) is recommended within the physiological norm (80–100 g/days), and carbohydrates – 400 - 500 g/days.
At progressing hepatic insufficiency the daily diet of protein decreases to 40 g/days. The amount of table salt at a liquid delay (portal hypertensia) is limited to 2 g/days. The existence of cholestasis significantly limits digestion of fat-soluble vitamins (A, D, E). Besides, at diffusion diseases of a liver, the need for vitamins C, B6, B12 is increased, that it is necessary to consider when developing an individual diet.

 Long time ethiotrpic therapy of chronic hepatitis and cirrhosis was complicated. It was connected with that there were no enough data on the reasons of development of these diseases. Only in 1994 the leading hepatologists offered to consider one of the basic classification principles at diffusion diseases of a liver the ethological. Now it is established that a leading ethological factor in development of chronic hepatitis and cirrhosis are hepatotrophic viruses (B, C, D, G) with a parenteral way of their transfer. The reason of autoimmune hepatitis as independent disease is still insufficiently clear. The mechanism of its development is connected with reactions in the immune system, connected with development of autoantiboides (against microsomal anti-genes of cells of a liver, their nucleus and the proteins specific to a liver). Abuse of alcohol is considered as the possible reason of an acute hepatitis, fatty dystrophy of a liver and cirrhosis. Drugs and some medicinal substances if can have independent etiological value in development of chronic diffusion diseases of a liver, it is rather rare. It is important to note that alcohol, drugs and a number of medicines can promote development of a virus infection and assist thus to progressing of pathological process in a liver. Existence of markers of viruses in serum of blood is not always combined with manifestations of pathological changes in a liver. Probably so-called "carriage" of a virus at which clinical signs and morphological changes in a liver are absent. At considerable number of patients (their about 70%) with chronic hepatitis the pathological process connected with infection by a virus, as though "stiffens" for long term  years and more) at the level of the minimum activity without a tendency to progressing. In the recent past such favorable course of a disease was regarded as chronic персистирующий hepatitis. And at last, at a number of patients the illness from the very beginning gains the moderated and expressed activity of process, rather quickly and steadily progresses and in some years is transformed to cirrhosis, and at some part from them transforms to a hepatocellular  carcinoma. Earlier such option of a disease with a progressing current was called active (aggressive) hepatitis.          

The Chronic Hepatitis (CH) irrespective of an ethiological form can have various degree of expressiveness a syndrome of cholestasis, and at CH alcoholic, cholestatic and choleangiogenic this syndrome is the leader and meets in 11–55% of cases. As clinical manifestation of this syndrome is the skin itch, however it is found only in 10–40% of patients. Emergence of jaundice at a syndrome of cholestasis makes heavier the general condition of the patient. From the preparations influencing certain links of pathogenesis, now are widely used ademethionin and ursodesoxicholic acid. However these preparations are made abroad and from the economic point of view are available to not all patients. At chronic hepatitis suffers the liver parenhim  therefore it is necessary to direct treatment on restoration of its cells. In this regard in the scheme of treatement of chronic hepatitis it is necessary to include medicines which unite the concept "hepatoprotectors". This is a group of medicines with the various mechanisms of action directed on normalization of functions of a liver, potentiation of reparative and regenerative processes, restoration of a homeostasis and increase of stability of body to action of pathogenic factors.

In the presence at the patient of markers of viruses in combination with clinical signs of activity of process, anti-virus therapy is shown. Thus creation of optimum conditions for carrying out such treatment is important. It provides complete elimination of alcohol, restriction of medicines. Now the main ethiotropic means for the treatment of virus diffusion defeats of a liver is interferon.  For the treatment of virus hepatitises the greatest distribution has interferon, both received of culture of leukocytes, and recombinant, created by means of genetic engineering (an intron A, Ropheron A, Reapheron, Realdiron). Now it is considered expedient to combine purpose of interferon with other preparations. There is the sufficient clinical experience, allowing to recommend in 15–20 days prior to purpose of interferon glucocorticoids (Prednisolon of 20-30 mg per day). Purpose of adsorbents, the means normalizing structure of microflora of intestines, vitamins C by microcells, pancreatic fermented preparations is as well recommended.

Work Purpose.  To study the efficiency and safety of the immunomodulating preparation GEPATONIN in the treatment of viral hepatitis C.

Materials and  Methods. GEPATONIN– represents immunomodulating complex of biologically active peptides received of ecologicaly pure plant material in a form of peptide type lyophilized powder.  After carrying out biochemical researches about quantitative and qualitative structure it was revealed that the preparation contains some hundred small peptides with a molecular weight of 10-50 kD. For definition of structure, the method of highly effective liquid chromatography (HPLC) with the subsequent tandem mass spectrometry of masses with use of LTQ FT ICR of a spectrometer of masses (Hybrid-2D-Linear Quadrupole Ion Trap, Fourier Transform Ion Cyclotron Resonance Mass Spectrometer) (Thermo Electron Corp) was used. It should be noted that the majority of the endogenous peptides present at a human body possessing biological activity (cytokines, hormones, antibodies, dephensins, alarmins ), have just a quantitative amino acid structure from 10 to 50 and respectively low molecular weight. This fact is explained by that small molecules are easier transported in organism tissues, and also have a high tropism to ligand interaction with membrane receptors. Also, it should be noted that these small active peptides work in very small nano - and pico-concentration.

In preliminary preclinical and clinical tests on volunteers there is established ability of the immunotherapeutic preparation GEPATONIN to restore in blood quantitative and functional indices  B and T of cellular systems of immunity, in particular, T-helper cells, T-cytotoxic cells, T-killers (NK), macrophages, granulocytes; to normalize ratio of T-helper and T-suppressor cells, to induce production of cytokines, including interferon-gamma; to restore functional activity of stem hemopoietic cells; to normalize level of the content in blood of leukocytes, erythrocytes, neutrophils, platelets, lymphocytes and other uniform elements of blood.

The preclinical assessment of safety which is carried out according to requirements "The guide to experimental (preclinical) studying of new pharmacological substances" (M, 2000), with application of toxicological, pathomorphological, biochemical, hematologic methods, did not reveal any essential differences of indicators of experimental groups of animals from control group that testifies to lack of toxic influence of medicine GEPATONIN in studied doses.

Due to these properties of the medical preparation GEPATONIN, we counted expedient to include immunomodulating GEPATONIN complex in the scheme of therapy of chronic viral hepatitis C and to study its efficiency and safety.

In research of efficiency and safety of application of GEPATONIN in complex therapy of chronic hepatitis C 30 patients were included:  26 men and 4 women aged from 21 up to 48 years; 21 patients had a diagnosis: virus hepatitis C, stage 1b; 9 patients have a virus hepatitis C, a stage 3а. During treatment patients received from 3 to 8 courses GEPATONIN, the number of courses of therapy depended on the expressiveness of positive dynamics of clinical disease manifestations. The diagnosis of an HCV infection was confirmed by means of PCR-tests. During therapy there was carried out PCR-diagnostics after each course of application of GEPATONIN, and also the remote control in 2 months after treatment. Before initiation of treatment and after each course of application of GEPATONIN, control of the following indicators was exercised: Alaninaminotranspherase, Aspartataminotranspherase  (ALT, АSТ), thymol test, GGT, general bilirubin.

Results and  Discussion. During carrying out treatment by the preparation GEPATONINat 1 patient the PCR-test became negative after 3 courses (3,3%), at 9 patients – after 4 courses (30%), at 6 patients – after 5 courses (20%), at 6 patients – after 6 courses (20%), at 5 patients – after 7 courses (16,6%) and at 2 patients – after 8 courses (6,6%). In 2 months after the negative PCR-test for HCV at 18(60%) patients, the negative result remained. (Tab. 44)