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GASTROENTEROLOGY
INVENTION
Patent of the Russian Federation RU2286792

METHOD FOR TREATMENT OF CHRONIC HEPATITIS

METHOD FOR TREATMENT OF CHRONIC HEPATITIS

The name of the inventor: Vengerovsky Alexander Isaakovich (RU); Beloborodova Elvira Ivanovna (RU); Livshits Inna Klimentevna (RU); Beloborodova Ekaterina V. (RU)
The name of the patent owner: Vengerovsky Alexander Isaakovich (RU); Beloborodova Elvira Ivanovna (RU); Livshits Inna Klimentevna (RU); Beloborodova Ekaterina V. (RU)
Address for correspondence: 634021, Tomsk, PO Box 1769, N.G. Zubarevoi
Date of commencement of the patent: 2005.03.05

The invention relates to medicine, in particular to gastroenterology, and concerns the treatment of chronic viral hepatitis. To do this, daily intramuscular injection of reaferon in a dose of 3 million units. Per day in combination with oral administration of lipproxol in a dose of 2g 3 times a day for 15-30 minutes before meals. The course of treatment is 6 months. The method provides normalization of clinical and biochemical parameters during the first month of treatment with different activity of the process and the duration of the disease due to complex antiviral and antitoxic actions in the absence or reduction of the dyspeptic symptom complex.

DESCRIPTION OF THE INVENTION

The invention relates to the field of medicine, specifically to methods for treating chronic hepatitis using a natural hepatoprotector.

There are known methods of etiotropic treatment of chronic hepatitises with proven effectiveness in the assignment of interferons [1,2,3], which are a complex group of natural proteins that are produced by eukaryotic cells in response to various stimuli. These proteins have multifunctional biological activity, encompassing the spectrum of antiproliferative, immunomodulating, antiviral action, as well as inducing differentiation of cells [1]. Of the three groups of interferons, the main drug that has proven effective in treating hepatitis is interferon- . The mechanism of its action on HCV remains not completely clear. It is believed that interferon- Prevents the infection of new cells than suppresses intracellular replication of HCV. As a result, the level of HCV RNA in the serum is reduced [3]. The most commonly used human leukocyte interferon- -reaferon (Russia) [1]. To date, the following scheme of monotherapy with this drug has been adopted: 3 million units. 3 times a week for 6-12 months [1, 3, 4, 5, 6]. A stable positive response is 15-20%, so a constant search for new drugs and treatment regimens is clear [3, 5, 7]. In addition, when carrying out antiviral therapy, it is necessary to monitor not only the effectiveness, but also the presence of side effects. The most frequent of them are: flu-like syndrome (fever, weakness, headache, nausea) [3, 4, 6, 8], thrombocytopenia and neutropenia [1, 8, 9, 10], decreased appetite, weight loss [6, 8 ], Nervousness, depression, irritability [6, 8], sleep disturbances [8]. In order to correct them, and to achieve a better clinical effect, great importance is attached to the use of modern pathogenetic therapy, consisting in the additional prescription of drugs of the hepatoprotective series, ursodeoxycholic acid [1, 6, 7, 9].

The closest to the proposed is the method of treating chronic hepatitis, consisting in the appointment of interferon- And essential in the standard doses used [7]. The disadvantage of this treatment scheme is a difference in the concentration of interferon- In the blood with the mode of its administration 3 times a week and, as a consequence, the possibility of developing the virus's escape. In addition, according to E. Yakovenko when taking essencial inside, dyspeptic disorders are possible, the development of which occurs as a side effect of interferon therapy. It is noted that along with the intake of essential oils it is necessary to administer antioxidants, since the increase of polyunsaturated fatty acids and oxidizability of phospholipids helps to increase the rate of formation of free radicals and increased utilization of antioxidants, which can lead to an increase in cytolysis syndrome.

The task solved by this technical improvement is to increase the effectiveness of treatment in the form of achieving clinical and laboratory remission by reducing the activity of the process in shorter periods of treatment, reducing the number of side effects of etiotropic therapy.

The task is solved by a new method of treating chronic hepatitis, consisting in the appointment of reaferon in combination with a hepatoprotector, and reaferon is prescribed in a dose of 3 million units. Daily in combination with the use of hepatoprotector-dietary supplements of natural origin with lipproxol 15-30 minutes before meals, at a dose of 2 g 3 times a day for 6 months.

Liproxol is a complex hepatoprotective drug consisting of epler and lohein in a ratio of 1:12, which corresponds to a combination of 1/3 and 2/3 effective doses of epler and lohein. It is a powder of dark brown color, soluble in water. Liproxol has a pronounced hepatoprotective effect in intoxication with poisons that cause hepatitis (CCl 4 ). The use of liproxol in experimental toxic hepatitis normalizes the disturbed histoarchitectonics of the liver, significantly reduces fatty liver dystrophy (which is a frequent (up to 30% of cases) morphological findings and in viral hepatitis [3]); Improves the excretory function of the liver and reduces hyperfermentemia, hyperbilirubinemia, hypoglycemia, affects hypoproteinemia. It is important to note that lipproxol exhibits the properties of an effective antioxidant, inhibits the genesis of malonic dialdehyde and prevents the excess of diene conjugates and Schiff bases, protects the system of microsomal oxidation. Liproxol normalizes the spectrum of lipids and phospholipids, including the content of phosphatidylcholine and phosphatidylethanolamine.

A distinctive feature of lipproxol is the combination of antioxidant effects with the improvement of the antitoxic function of the liver, restoration of the normal spectrum of membrane phospholipids.

The method is carried out as follows.

The initial stage is the diagnosis of the forms of hepatitis and the degree of its activity by:

1. Study of the functional state of the liver (determination of the activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), total protein and its albumin fraction, total and direct bilirubin, alkaline phosphatase activity, thymol test, fibrinogen and prothrombin index (PTI)) .

2. Study of the parameters of the general blood test.

3. Definitions of markers of viral hepatitis (HbsAg, HbeAg, anti-Hbcor, IgM and IgG, anti-Hbe, anti-HCV), the presence of replication phase by PCR.

4. Ultrasonic examination of the liver, spleen and gallbladder.

5. Studies of the state of cellular and humoral immunity.

6. Assessment of the processes of lipid peroxidation by the level of malondialdehyde content in blood serum.

7. Percutaneous puncture liver biopsy with morphological analysis of the biopsy specimen.

Further, all patients are prescribed reaferon for 3 million units. Daily in the muscle in combination with oral administration of lipproxol in a dose of 2 g 3 times a day for 6 months.

The effectiveness of the therapy was assessed by dynamic monitoring of the parameters of the general and biochemical blood tests 2, 4 weeks after the initiation of therapy and further 1 time per month, PCR and ultrasound at 3 and 6 months, part of the patients at the end of the course of treatment was subjected to dynamic puncture liver biopsy.

Mode of application of the method is selected on the basis of experimental and clinical observations (II):

1. A dose of lipoxol, equal to 2 g, is curative on the basis of animal studies with CCl 4 -hyperate on the effect on survival of animals, the duration of hexenal sleep, the value of the liver mass factor, the degree of obesity of hepatocytes.

2. The expediency of using liproxol 15-30 minutes before meals is due to the physiological preparation of the entire digestive system for assimilating the relatively small (2 g) amount of the drug and, therefore, the greatest absorption efficiency and low probability of mixing with food, which may reduce the therapeutic effectiveness of the drug.

3. Reaferon dose of 3 million units. Daily is due to the pharmacokinetics of reaferon and our clinical observations of patients who received it together with lipproxol. The administration of reaferon in a smaller dose or in a day-time regimen was not effective enough, and a greater dosage increased the risk of side effects of therapy, without increasing its effectiveness.

Example 1

Patient U., 43 years old, entered the department on October 13, 2004 with the diagnosis: chronic viral hepatitis C, moderate degree of activity, replication phase. A history of dental treatment in 2001. At a medical examination in 2002, an increase in transaminases was detected, and with further examination, markers of HCV infection. At the time of admission, the patient was disturbed by severe weakness, fatigue, a feeling of heaviness in the right upper quadrant, episodes of dull pain in the right hypochondrium, heartburn, nausea, bitterness in the mouth, flatulence, headaches, sleep disturbance, subfebrile condition. Objectively there was hepatomegaly (liver size according to Kurlov 11 × 10 × 9 cm), tenderness of the liver edge during palpation and increase in its density. Laboratory in the blood: cytolysis syndrome (ALT = 104 units, ACT = 73 units), total bilirubin level 12.5 μmol / l, direct bilirubin 1.0 μmol / l, and protein level 70 g / l, PTI 98 %, Total fibrinogen 1.8 g / l). In OAK pathology was not detected, the level of leukocytes was 6.2, platelets = 238. Activation of LPO processes was observed (MDA level was increased to 7.5 μmol / l). From the markers of viral hepatitis, positive total antibodies to HCV, antibodies to NS3-5, positive HCV DNA PCR were detected. The ultrasound showed a moderate increase in echogenicity, a diffuse heterogeneity in the structure of the liver. In the biopsy of the hepatic tissue - moderate lymphocytic and monocytic infiltration of portal tracts, single step necrosis of hepatocytes, hepatocytes in a state of hydrophilic dystrophy of mild and moderate degree, perigepatocellular fibrosis. Thus, a morpho-clinical diagnosis of chronic hepatitis C, a moderate degree of activity (10 points), a stage of chronicization, a replication phase was exposed.

The treatment was carried out according to the proposed method: a reaferon of 3 ppm was assigned. Daily and lipoxol at a dose of 6 g per day for 6 months. Only the first administration of reaferon showed a rise in body temperature to 37.5, which normalized on its own within 2 hours. After 2 weeks of treatment, there was a positive dynamics of subjective symptoms in the form of relief of pain syndrome, a significant decrease in weakness, a decrease in the degree of manifestation of flatulence, dyspeptic symptoms were stopped. Objectively, the liver size was normalized. By the 4th week of treatment, the feeling of heaviness in the right hypochondrium was suppressed, the sleep normalized, and general weakness continued to decrease. When palpation of the liver, its normal size remained, palpable tenderness disappeared. In biochemical analysis: after 14 days of treatment, there was a positive dynamics of the level of transaminases (ALT = 84 units, ACT = 53 units), and by the end of 4 weeks the cytolysis syndrome was stopped (ALT = 26 units, ACT = 26 units) and in Further, there was no increase in transaminases, and the reduction of LPO processes was noted (MDA level decreased to 5.6 μmol / l). The level of platelets and white blood cells remained within the normal range throughout the course of therapy. HCV RNA in the blood serum was not determined by PCR after 3 months of therapy. Dynamic ultrasound revealed normalization of liver echogenicity. In a biopsy of the hepatic tissue after 6 months, necrosis of hepatocytes is absent, there is a weakly expressed lymphocytic infiltration of the portal tracts, i.e. The activity of the process decreased to a minimum. Thus, there was a decrease in the activity of the process, an improvement in the functional and morphological state of the liver, with good tolerability of treatment, without the development of side effects of interferon therapy.

Example 2

Patient V., 44 years old, entered the department on 29.09.2004 with the diagnosis: chronic viral hepatitis C, a weak degree of activity. In a history of donation, blood transfusion in 2002, antibodies to HCV were detected accidentally in May 2004. On admission, the patient was disturbed by weakness, fatigue, a feeling of heaviness in the right upper quadrant, nausea, bitterness in the mouth. Objectively, there was a slight hepatomegaly (liver size according to Kurlov 11 × 9 × 8 cm), increased liver density. In the biochemical analysis of the blood there were: cytolysis syndrome (ALT = 102.8 units, ACT = 41 units), total bilirubin level 4.7 μmol / l, and moderate activation of LPO processes (the MDA level was increased to 5.3 Μmol / l). In the general blood test, the platelet count was within the normal range of 192. From the markers of viral hepatitis, positive total antibodies to HCV, to structural and nonstructural proteins, were detected with positive HCV RNA PCR. On ultrasound, there was an increase in echogenicity of the liver. In a biopsy of hepatic tissue - a weak degree of lymphomonocytic infiltration of portal tracts, lobular necrosis of hepatocytes, portal tracts are expanded mainly due to fibrosis, and hydrophilic dystrophy of mild to moderate severity. Thus, a weak degree of activity (7 points), 1 stage of chronicle was determined.

The treatment was carried out according to the proposed method. Positive dynamics began to be observed by the end of 4 weeks of application of reaferon to 3 million units. Daily and liproxol in a dose of 2 g 3 times a day: pain and dyspeptic syndrome were stopped, the severity of the asthenic syndrome decreased significantly. The dimensions of the liver were normalized. In the blood: a decrease in ALT activity to 45.7 units, the level of ACT normalized (27 units). The flu-like syndrome was noted for the first injection of reaferon, the platelet count decreased slightly, but remained within the normal values ​​of 152. After 2 months of therapy, the level of aminotransferase completely normalized, the MDA level came to normal (3.8 μmol / l). After 3 months HCV RNA PCR is negative. By the end of the treatment, biochemical parameters remained within normal limits, HCV RNA was not detected, the ultrasound picture of the liver was normalized. The patient refused the dynamic puncture biopsy of the liver.

Example 3

The patient L., 23 years old, entered the department on 23.12.2004 with the diagnosis: chronic hepatitis C, moderate degree of activity. Since 1996, he suffers from opium addiction, the last 6 months are abstinence. At the time of admission, the patient was disturbed by general weakness, subfebrile temperature, heartburn. Objectively, there was a slight hepatomegaly (liver size according to Kurlov 12 × 10 × 9 cm), increased liver density. In the general analysis of blood, attention was drawn to the increase in COEF to 21 mm / s, which, together with the subfebrile condition and an increase in the level of thymol test, was 5.4 units. Reflected the presence of the syndrome of mesenchymal inflammation. In the biochemical analysis of the blood there were: cytolysis syndrome (ALT = 112 units, ACT = 54 units), total and direct bilirubin levels within the norm. The activation of lipid peroxidation processes was expressed in an increase in the MDA level to 9.1 μmol / l. From the markers of viral hepatitis, positive total and early antibodies to HCV were detected with positive HCV RNA PCR. On ultrasound, there was an increase in echogenicity of the liver and a smoothness of its edge. In the biopsy of the hepatic tissue, weak lymphoid infiltration of the portal tracts, monocellular and step necrosis of hepatocytes, mainly hydrophilic dystrophy, but there is also fatty degeneration, portal fibrosis. Thus, a moderate degree of activity (11 points), 1 stage of chronicle was determined.

The treatment according to the proposed method was carried out. After 14 days of application of lipproxol in a dose of 2 g 3 times a day and reaferon of 3 million units. Daily there was a positive dynamics on the part of subjective status: all the above complaints were stopped, the temperature returned to normal. In the blood: a decrease in ALT activity to 65 units, ACT to 30 units, after 4 weeks ALT level came to normal. The level of thymol test and ESR normalized and by the end of 4 weeks of therapy. The ultrasound picture of the liver did not differ from normal. Given the presence of subfebrile condition and before the start of therapy, the presence of an increase in body temperature to 37.5-37.7 during the first 6 days of treatment was not regarded as a manifestation of influenza-like syndrome. The platelet count remained within the normal range throughout the course of therapy. After 3 months, HCV RNA was not detected. In a biopsy of the hepatic tissue after 6 months, only a weak lymphoid infiltration of the portal tracts.

In total, 10 patients with chronic viral hepatitis were treated with the proposed method.

Clinical observations suggest that as a result of the use of the proposed method for treating chronic hepatitis with reaferon in combination with a hepatoprotector-BAD of natural origin, lipproxol, a positive clinical effect is obtained, which consists in the complete disappearance or reduction of the dyspeptic symptom complex, asthenovegetative syndrome, liver size normalization, Process (cytolysis syndrome, mesenchymal inflammation completely stopped or decreased) in a shorter time (during the first month of therapy) compared with monotherapy with reaferon. Moreover, the proposed method of treatment yielded positive results for different clinical course of chronic viral hepatitis (varying degrees of activity, disease duration and pathway of infection), was characterized by good tolerability, absence of a prolonged flu-like syndrome, thrombocytopenia, dyspeptic symptom complex, the main side effects of antiviral therapy, compared to With reaferon monotherapy. An important property of the proposed method of treatment is the antioxidant effect, as evidenced by a decrease in the activity of LPO processes due to the presence of antioxidant activity of lipproxol.

USED ​​BOOKS

1. Gorbakov V.V. Modern approaches to the diagnosis and treatment of viral hepatitis C // Russian Journal of Gastroenterology, Hepatology, Coloproctology. - 1998, №5. - p.61-66.

2. Gorbakov V.V., Abdullaeva H.I., Rakov A.L., Ursov PP Modern concepts of chronic HBV infection // Experimental and clinical gastroenterology. - 2003, №2, p.54-60.

3. Ivashkin VT, Maevskaya MV A new chance to defeat hepatitis C // Clinical perspectives of gastroenterology, hepatology. - 2002, №2, p.25-28.

4. Blokhina N.P. Modern concepts of combined therapy with intron A and rebetol in patients with chronic hepatitis C. // Viral hepatitis: achievements and perspectives. - 2000, №2, p.6-9.

5. Creel P.E. The domestic experience of combined therapy with Intron A and Rebetol in patients with chronic hepatitis C // Viral hepatitis: achievements and perspectives. - 2000, №2, p.10-12.

6. Reisiz A.R. Modern problems of viral hepatitis C in children and adolescents // Clinical perspectives of gastroenterology, hepatology. - 2003, №5, p.23-26.

7. Niderau K. Interferon and essential phospholipids in the treatment of chronic viral hepatitis B and C // Russian Journal of Gastroenterology, Hepatology, Coloproctology. - 1998, N5, p.67-68.

8. Vasenko VI, Plyusnin SV, Kiselev AV, Khazanov AI The effectiveness of treatment of hepatitis C in young men with reaferon - domestic interferon 2 // Russian Journal of Gastroenterology, Hepatology, Coloproctology. - 2003, volume 13, №2, p.51-59.

9. Korochkina OV, Tsybasova AI, Sorinson SN Features of the characteristics of the infectious process in viral hepatitis B, C, D. Current flow. The strategy of etiotropic and pathogenetic therapy // Consilium medicum. - 2002, №1, p.17-20.

10. Jaekel E., Cornberg M., Wedemeyer H., etc. Treatment ofacuet hepatitis With interferon -2b // The New England Journal of Medicine. - 2001, November 15, p. 1-5.

11. Litvinenko Yu.A. Efficacy of joint application of hepatoprotectors in experimental acute toxic hepatitis. Dys.kand.med.nauk. Tomsk, 2003, 130 p.

CLAIM

A method of treating chronic viral hepatitis, comprising administering reaferon in combination with a hepatoprotector, characterized in that the reaferon is administered daily intramuscularly at a dose of 3 ppm. Per day in combination with oral administration of lipproxol in a dose of 2 g 3 times a day for 15-30 minutes before meals, the course of treatment is 6 months.

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Date of publication 06.01.2007gg