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Method of treating viral hepatitis c. RU patent 2496512.

IPC classes for russian patent Method of treating viral hepatitis c. RU patent 2496512. (RU 2496512):

A61P31/14 - for RNA viruses

A61P1/16 - for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

A61K38/05 - Dipeptides

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FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to gastroenterology and may be used for treating hepatitis C. For this purpose, an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof is introduced into the patient. The above agent may be administered in a combination with pegylated interferon and ribavirin. The group of inventions also refers to a pharmaceutical composition for treating viral hepatitis C. This group of inventions enables disclosing a new drug preparation having a manifested antiviral effect and being effective in treating viral hepatitis C.

EFFECT: what is developed is the effective combination of the drug preparations for treating viral hepatitis C, which allows reducing the rate of side effects of the antiviral therapy substantially.

39 cl, 3 ex

The technical field to which the invention relates

This invention relates to medicine and concerns the application or pharmaceutically acceptable salts for treatment of viral hepatitis C.

The level of technology

Viral hepatitis C remains one of the most pressing health problems in the world. Large number of infected (with nearly 200 million people), high risk of developing chronic infection (60-80%), which is the cause liver cirrhosis or hepatocellular carcinoma (15-25% of cases), development of the system of extrahepatic lesions of organs and tissues of human origin, the lack of a vaccine to prevent the development and spread of infection cause the necessity of developing effective treatments for hepatitis C [Abdurakhmanov D.T. Perspectives in the treatment of chronic hepatitis C. Clinical Hepatology 2010; 3:3-11].

Modern therapy of hepatitis C interferon α2a or α2b in combination with ribavirin allows to achieve a sustained virologic response (SVR) in 54-73% of cases [V.T. Ivashkin, Lobzin Y.V., GI and others]. Efficacy and safety of 48 weeks treatment interferon α2a and ribavirin are shown from the primary patients with chronic hepatitis C. Wedge. . tera., 2007, 16(1), 1-5.]. When infection subtype 1b of hepatitis C virus (HCV), which prevails in circulation on the territory of Russia, the percentage of the effectiveness of therapy significantly reduced and is 40-50%.

Thus, there is a need to develop a more efficient, affordable and cost-effective drugs and treatments of hepatitis C who have fewer side effects.

The authors of the present invention unexpectedly it was revealed that for treatment of hepatitis C can be used . The has antiviral effect against the virus of hepatitis C, both individually and in combination with interferon and ribavirin.

Previously not supposed to use for the treatment of viral hepatitis. Moreover, previously not known combination with interferon and ribavirin.

Thus, the objective of this invention is to provide a new treatment for hepatitis C as well as providing a combination of drugs, which possesses high efficiency in treatment of viral hepatitis C, in comparison with the most efficient combination of drugs that was used to create this invention.

Disclosure of the invention

The above objectives of the invention are solved by means of objects of the invention contained in the attached formula.

This invention relates to medicine and includes a method of treatment of viral hepatitis C, which envisages the introduction of patient efficient amount or pharmaceutically acceptable salts.

Additionally, the invention relates to a method for the achievement of sustained virological response in the treatment of viral hepatitis C, including the introduction of patient efficient amount of pegylated interferon, ribavirin and or pharmaceutically acceptable salts.

In a preferred embodiment of the invention, is entered in the drug . Dose or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight. Single dose may be 100 mg. The duration of reception can be from 3 weeks to 12 months. For treatment of hepatitis C by reducing the side effects of antiviral therapy, such as grippopodobnyy syndrome, arthralgia, myalgia, and the exacerbation of chronic pancreatitis, depression, hair loss, leukopenia or neutropenia.

The invention also relates to a method of treatment of viral hepatitis C, providing for the introduction of patient efficient amount of pegylated interferon, ribavirin and or pharmaceutically acceptable salts.

Structural formula is the following:

In addition, the invention is a pharmaceutical composition for the treatment of hepatitis C, containing an effective quantity or pharmaceutically acceptable salts. Effective number or pharmaceutically acceptable salts may be 0.1-10 mg/kg body weight.

The invention also includes pharmaceutical combination for the treatment of hepatitis C, including interferon, ribavirin, and or pharmaceutically acceptable salt.

Further, the invention relates to the set for the treatment of hepatitis C, including interferon, ribavirin, or pharmaceutically acceptable salt, and instructions for use.

The invention also relates to the application of or pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for treatment of viral hepatitis C.

Additionally, the invention involves the use of or pharmaceutically acceptable salts in combination with interferon and ribavirin for the treatment of hepatitis C.

Viral hepatitis C, which are treated in accordance with the invention can be acute or chronic hepatitis C.

The method of treatment of hepatitis C, according to the invention, provides for reduction of side effects of antiviral therapy. These side effects of antiviral therapy may constitute grippopodobnyy syndrome, arthralgia, myalgia, and the exacerbation of chronic pancreatitis, depression and/or hair loss.

Preferably, is entered in the drug . Dose or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight.

interferon used in conjunction with and ribavirin, can represent interferon α2a or interferon α2b.

In a preferred embodiment of the invention, the dose is 100 mg with the introduction of 1 time per day; the dose of pegylated interferon is 100 mcg at introduction 1 time a week; the ribavirin dose is 1000 mg per day with the introduction of daily.

The duration of reception , preferably from 3 weeks to 12 months.

can be used as a pharmaceutically acceptable salts obtained by interaction with sodium hydroxide, potassium hydroxide, magnesium carbonate, lithium hydroxide, calcium carbonate routine ways, widely described in the literature.

Positive effects achieved by carrying out the invention, are the following. Unexpectedly revealed a new drug for the treatment of hepatitis C, has a pronounced antiviral effect. Besides, we have developed an effective combination of drugs for the treatment of viral hepatitis C. Also unexpectedly has resulted in considerable improvement of the most important indicators of the effectiveness of antiviral therapy, such as a rapid virological response (lack of RNA virus of hepatitis C in serum in the study of sensitive test system in 4 weeks after starting treatment), early virologic response (lack of hepatitis C virus RNA in the serum in the study of sensitive test-system 12 weeks after starting treatment), the immediate virological answer (in the absence of hepatitis C virus RNA in the serum in the study of sensitive test-system for 24 and 48 weeks after starting treatment) and sustained virologic response in patients with chronic hepatitis C (lack of hepatitis C virus RNA in the serum in the study of sensitive test system 24 weeks after the end of treatment).

Additionally, during the treatment of the GHS for the invention achieved a significant reduction in the frequency of side effects of antiviral therapy, such as leukopenia, neutropenia, grippopodobnyy syndrome, arthralgia, myalgia, and the exacerbation of chronic pancreatitis, depression, hair loss.

Realization of the invention

Still insurmountable was screening of drugs in experimental models infection caused by the virus of hepatitis C.

For this purpose, we developed an experimental model of the infection caused by the hepatitis C virus in vitro in cultures of primary and transplanted cells sensitive to the replication of the virus of hepatitis C. As a result, were isolated and identified cell pathogen versions of virus HCV, belonging to different genotypes, including the most common in the Russian Federation, the pathological consequences of infections that are difficult to treat with interferon, genotype 1b. Reproduced acute and chronic infection caused by the virus of hepatitis C in the cultures of cells of different origin. Thus, in regard to hepatitis C unique opportunity not only for the screening of compounds, but also for preclinical evaluation of antiviral drugs.

Example 1

The purpose of this study was to evaluate the antiviral activity on the experimental model of the infection caused by the hepatitis C virus in cell cultures.

In work used strain of hepatitis C virus (HCV), belonging to genotype 1b. The strain was isolated from the serum of a patient with chronic viral hepatitis C, identified as hepatitis C. use The infectious dose of the GHS, equal 10,0 tissue doses ( 50 )/20 ml.

Were used highly sensitive to action HCV primary fibroblasts obtained after 9-day-old chick embryos (FEC), as well as culture kidney cells of the embryo pig (pig kidney cells)obtained from the collection of cell cultures Institute of Virology RAMS. They were used in the form of one-day monolayer of cells grown in 24-well plates plastic panels. Cell culture pig kidney cells and FEC were grown in a medium 199 10% serum embryo calves, with the addition of glutamine and antibiotics (100 IU/ml).

Contagious take into account the GHS based on the results of titration of the cell cultures pig kidney cells cultural liquid samples, selected from HCV infected crops FEC or pig kidney cells on 2 and 5 days after infection. The results taken into account, as a rule, on the 6-7th day after infection, when developing the maximum action of the virus, using the formula reed and turns into a hissing drone to count the titre of virus of hepatitis C.

The results are shown in tables 1-4.

Table 1

Antiviral activity on the model of HCV infection in the cultures of the FEC. Research of samples on the 2nd day after infection and the treatment of cells with the drug.

Processing time

Titles of hepatitis C virus (lg 50 for cell cultures pig kidney cells) in the samples of the environment, selected from the cultures of the FEC, on the 2nd day after infection and processing in concentrations (g/ml):

500,0

50,0

5,0

0,5

0,05

0,005

Virus control

At the time of infection

5,5

6,2

6,5

6,0

5,0

5,5

6,5

24 hours before infection

4,5

5,0

6,5

24 hours after infection

2,5

1,8

6,5

Table 2

Antiviral activity on the model of HCV infection caused by the cultures of the kidney cells of the embryo pig (pig kidney cells). Research of samples on the 3rd day after infection and the treatment of cells with the drug.

Processing time

Titres of virus hepatitis With lg 50 for cell cultures pig kidney cells) in the samples of the environment, selected on the 3rd day after infection and processing in concentrations (g/ml):

500,0

50,0

5,0

0,5

0,05

0,005

Virus control

At the time of infection

3,0

3,5

2,3

3,3

24 hours before infection

3,5

3,2

3,0

3,3

24 hours after infection

1,25

<1,0

3,3

Table 3

Antiviral activity on the model of HCV infection caused by the cultures of the kidney cells of the embryo pig (pig kidney cells). Research of samples of the 4-th day after infection and the treatment of cells with the drug.

Time processing

Titles of hepatitis C virus (lg 50 for cell cultures pig kidney cells) in the samples of the environment, selected on the 4th day after infection and processing in concentrations (g/ml):

500,0

50,0

5,0

0,5

0,05

0,005

Virus control

At the time of infection

4,2

5,0

5,5

4,1

4,4

4,1

4,6

24 hours before infection

3,8

3,4

3,8

3,0

3,4

4,6

24 hours after infection

2,6

1,3

4,6

Table 4

Antiviral activity on the model of HCV infection caused by the cultures of the kidney cells of the embryo pig (pig kidney cells). Research of samples on the 5th day after the infection, and the treatment of cells with the drug.

Processing time

Titles of hepatitis C virus (lg 50 for cell cultures pig kidney cells) in the samples of the environment, selected on the 5th day after infection and processing in concentrations (g/ml):

500,0

50,0

5,0

0,5

0,05

0,005

Virus control

At the time of infection

5,5

7,0

5,5

5,0

5,5

6,7

24 hours before infection

6,0

4,5

6,7

24 hours after infection

2,8

1,8

6,7

It is shown that in the early period after processing of the cells FEC , most pronounced antiviral properties it has for its entering in the culture FEC 24 hours after infection. As was shown in samples of cultural liquid, selected through 48 hours after being infected cells, in these conditions suppressed infectious activity of HCV in the cultures of the FEC. In control, raw FEC HCV titers in this period reached 6,5 lg 50 /20 ml. Making immediately after infection also resulted in a decrease in HCV titers of 1.0-1.5 lg. 2.0 lg HCV titers decreased provided treatment cells 24 hours before infection.

Cell culture pig kidney cells (line kidney cells of the embryo pigs) infected option HCV - s-13 and treated 24 hours before infection, immediately after infestation of crops and 24 hours after infection. Samples of culture medium were selected on the 3rd, 4th and 5th days after infection and was titrated on the fresh cell cultures pig kidney cells.

The results are shown in tables 2-4. From the data tables indicate that , as in cell cultures FEC infected with HCV, significantly inhibits the replication of HCV isolates pig kidney cells in the case of adding it in the culture through 24 hours after infection of cells. These results remained stable regardless of the length of sampling cultural liquid of cell cultures pig kidney cells treated with the drug. On the 5th day after infection and simultaneous application of the drug cells was found the ability of suppress contagious HCV by 2.2-2.7 lg 50 /20 ml. In the samples of the environment, selected 5 days after infection, there was a significant suppress the production of HCV under the influence of compared with the control: 2.2 lg 50 /20 ml.

Thus, has the ability to suppress the replication of hepatitis C virus in infected cultures fibroblasts 9-day-old chick embryos, leading to a significant reduction titles infectious virus activity. It is shown that the antiviral efficacy of not reduced when using HCV infected cell cultures of other origin - cell lines pig kidney cells-HCV. The infection cell cultures pig kidney cells-HCV shown that effectively suppresses HCV infection not only when added to culture through 24 hours after infection, but 24 hours before infection of cells with the virus. The results indicate significant antiviral activity with infection by the virus of hepatitis C.

Example 2

This study aims to examine the clinical and laboratory efficiency in patients with viral hepatitis C in the combination antiviral therapy (HTP) interferon combined with ribavirin.

Inclusion criteria were: 1) availability in the patient signs of HCV infection detection of antibodies to HCV by ELISA; the presence in the blood serum HCV RNA (quantitative test), genotype 1b; 2) the content of leukocytes in the General analysis of blood from 3.9 to 3.0 x 10 9 /l, the number of neutrophils from 2.0 to 1.5 x 10 9 /l; 3) the lack of surface antigen hepatitis B virus; 4) absence of antibodies to human immunodeficiency virus; 5) absence of other clinically significant diseases of the liver (alcoholic liver disease, the reception of hepatotoxic drugs, autoimmune chronic hepatitis, hemochromatosis); 6) absence of cirrhosis of the liver.

Patients receiving peginterferon α2b subcutaneously at a dose of 100 mg 1 time per week and ribavirin 1000 mg daily for 48 weeks. In the period of treatment was conducted monthly clinical and biochemical monitoring. HCV RNA was determined after 1 month from the start of therapy and then every three months of treatment. All patients held transabdominal ultrasound scanning of organs of the abdominal cavity to initiation of therapy and then every 6 months. This study was approved by the Ethics Committee, and all patients gave informed consent to participate in the study.

In accordance with the (was carried out using the method «envelopes») all patients were divided into two groups, comparable by age and gender, depending on regimens: group 1 (n=52) received pegylated interferon α2b+ribavirin, group 2 (n=58) - pegylated interferon α2b+ribavirin+ 100 mg 1 time in day rate 21 days from the beginning of the OEM. Subsequently was administered according to the same scheme every three months of therapy.

Statistical processing and graphical visualization of the data was carried out in accordance with the technology of the modern computer analysis on IBM-compatible personal computer using Microsoft Excel Office 2007 and Statistica (StatSoft) version 6.0, which functioned in the operating environment of Microsoft Windows 7 Professional.

Research results and their discussion. Under the supervision were 110 patients, of them 69 men (63%) and 41 women (37%) with hepatitis C in age from 19 to 52 years (age 32.2±5.1 years). Average weight of a body made 76.4±8,1 (from 55 to 84 kg). Prescription infection, which was determined from the moment of occurrence of at least one risk factor, ranged from 2.5 to 8 years (table 5). Reliable inter-group differences were not registered.

Table 5

Characteristics of the observed patients (Pitch m)

Indicators

1st group

2nd group

Number patients people.

Men, people

Women, people

Average age, years

30,1±4,2

31,4±3,1

Weight, kg

73,4±3,2

72,8±2,9

Disease duration, years

4,5±1,7

3,9±2,2

The initial activity of ALT, IU/l

115,21±7,24

112,41±8,04

The initial activity of alkaline phosphatase, U/l

247,24±12,5

257,34±16,3

Thymol test, units

5,8±0,9

6,1 about 1.1

Total bilirubin, mkmol/l

23.94 per±0,82

24,01±0,71

Albumins, %

51,98±0,87

52,01±0,74

Gamma-globulins, %

23,69±0,71

23,45±0,84

The number of leukocytes x 10 9 /l

3,4±0,08

3,3±0,17

The number of neutrophils x 10 9 /l

1,9±0,11

1,8±0,14

Leading syndromes all patients suffering from hepatitis C were asthenovegetative (sleep disturbance, fatigue, sweating, loss of appetite, emotional lability), registered in 75 (67,95%) patients; dyspeptic (nausea, belching, feeling of fullness, the severity of the epigastrium and right hypochondrium, constipation and/or diarrhea) occurred in 62 (56,3%) patients. The most common clinical manifestation of the disease was increased liver 94 (85,2%) patients. Splenomegaly is registered in 35 (31,95%) patients. The frequency of occurrence of main clinical syndromes in different groups of patients are presented in table 6. As it is seen from table 6, before the start of therapy, no significant differences between patients of the 1-St and 2-nd groups were not registered.

Table 6

The occurrence of main clinical syndromes in patients observed patients prior to initiating therapy, %

Symptoms

1 group

2 group

Dyspeptic

54,2

58,4

0,701

66,2

69,7

0,839

Hepatomegaly

80,8

89,6

0,279

Splenomegaly

29, 5

34,4

0,546

of the skin and eyes

14,5

20,2

0,622

By sex, age, food conditions of life and work, but also at the place of their stay, the group observed patients were matched.

Group 1 patients observations carried the cure is worse adverse reactions were recorded more frequently than in patients in group 2 the data presented in table 7.

Table 7

The frequency of detection of side effects of antiviral therapy in %

Side effects

1 group

2 group

Grippopodobnyy syndrome

72,4

50,3

0,019

Arthralgia

62,1

44,6

to 0.089

Myalgia

58,3

32,4

0,012

Exacerbation of chronic pancreatitis

6,2

0,666

Depression

36,1

12,4

0,003

Hair loss

38,4

14,1

0,004

Zitopeniceski syndrome

63,8

25,9

0,045

Weight reduction

44,8

34,8

of 0.332

Patients of the second group the side effects such as flu-like syndrome, the frequency of occurrence of myalgia, depression, hair loss and syndrome were reported in smaller percentage of cases, compared with patients in group 1 (p<0.05).

The monitoring showed that in 62.2% of patients receiving combination antiretroviral therapy + , registered subjective feeling better (improvement of health and disappearance of weakness) compared to the 1st group of 15.4%, p<0.05.

In the combination antiviral therapy identified the following side effects such as a reduction in the total number of cells and neutrophils (table 8). In the 1st group during the HTP leukopenia has been observed with early deadlines (4 weeks. therapy) 71% of patients, and neutropenia 69% of patients, these indicators remained significantly reduced during the course of treatment compared with the 2nd group (p<0.05). Patients of the second group lakopenia observed in 35% of cases, neutropenia registered in 4 of 6% of patients. Sharply reduced indicators of cells and neutrophils, which could cause a dose adjustment or cancellation of the HTP in this group of patients was recorded.

Table 8

Hematological indexes on a background of treatment (Pitch m)

Indicators

1 group

2 group

leukocytes x 10 9 /l

Prior to treatment

3,4±0,08

3,3±0,17

After 1 month. therapy

2,3±0,12

3,1±0,14*

After 2 months. therapy

2,4±0,16

4,0±0,18*

After 3 months. therapy

2,3±0,11

3,8±0,16*

After 6 months. therapy

2,7±0,14

4,1±0,21*

After 12 months. therapy

3,0±0,10

3,7±0,18*

neutrophils x 10 9 /l

Prior to treatment

1,9±0,11

1,8±0,14

After 1 month. therapy

1,2±0,08

2,0±0,07*

After 2 months. therapy

1,1±0,06

2,3±0,05*

After 3 months. therapy

1,0±0,05

2,0±0,04*

After 6 months. therapy

1,2±0,06

2,3±0,05*

12 months. therapy

1,5±0,04

2,1±0,06*

Note: here and further * - reliability of differences between the indices of 1-St and 2-nd gr., p<0.05.

Assessing the effectiveness of the application of in complex therapy of patients with CHC the authors studied the influence on biochemical and virological . significant data presented in table 9 and 10).

Table 9

Indicators of liver metabolism in the treatment of patients with CHC (Pitch m)

Indicators

1 group

2 group

ALT, IU/l

After 1 month. therapy

68,24±4,37

49,21±3,78*

After 3 months. therapy

89,47±5,34

56,21±4,34*

After 6 months. therapy

64,73±5,43

50,38±4,78*

After 12 months. therapy

49,34±4,38

41,34±3,52*

Alkaline phosphatase, U/l

After 1 month. therapy

221,41±10,21

200,04±12,43*

Through 3 months. therapy

205,24±8,73

161,02±5,02*

After 6 months. therapy

197,36±5,64

154,23±4,73*

After 12 months. therapy

195,48±4,03

155,03±3,72

The TA unit

After 1 month. therapy

5,03±0,01

4,24±0,41*

After 3 months. therapy

4,94±0,03

3,84±0,04*

After 6 months. therapy

4,79 ħ 0.09

3,90±0,03*

Through 12 months. therapy

5,04±0,08

4,03±0,02*

bilirubin, mkmol/l

After 1 month. therapy

22,48±0,94

18,47±0,08*

After 3 months. therapy

21,79±0,74

16,24±0,17

After 6 months. therapy

20,73±0,54

17,13±0,21

After 12 months. therapy

21,36±0,98

17,04 ħ 0.09*

Albumin, %

After 1 month. therapy

52,04±1,19

54,09±1,23

After 3 months. therapy

53,74±1,41

55,47±1,62

After 6 months. therapy

55,03±2,38

56,43±2,05

After 12 months. therapy

54,16±1,17

55,36±1,64

γ-globulin, %

After 1 month. therapy

23,47±0,84

21,02±0,34*

After 3 months. therapy

22,98±0,97

of 19.91±0,23*

After 6 months. therapy

23,04±0,88

20,01±0,31*

After 12 months. therapy

22,76±0,11

21,32±0,08*

As can be seen from the data presented in table 9, in the 2nd group of patients was achieved greater improvement of indicators of cytolysis and cholestasis.

Direct virological response (reduction in HCV RNA to undetectable levels) was registered by 79.3 percent of patients in group 2, additionally taking , which was statistically significant in comparison with the results of the patients in group 1 (p=0,035) received only combined

antiviral therapy, these are shown in table 10. As can be seen from table 10, early virologic response also significantly more frequently registered in patients of the 2nd group (p<0.05).

Table 10

The effectiveness of antiviral therapy, %

Answer variant

1st group

2nd group

Rapid virologic response

82, 9

89,7

0,405

Early virologic answer

65,9

86,2

0,013

Direct virologic response

60,3

79,3

0,035

Thus, the use of combination therapy for the treatment of patients with hepatitis C, including pegylated interferon, ribavirin, and (in the ), is more effective for treatment hepatitis C. the good tolerability of antiviral therapy in patients with hepatitis C in The operation of the proposed scheme of treatment.

Example 3.

The aim of the research was to study the effect () on the effectiveness of antiviral therapy in patients with lb virus genotype of chronic hepatitis C with initially decreased number of white blood cells and neutrophils.

Under the supervision were 86 patients HCV (anti-HCV «+», HCV RNA «+», genotype 1b) aged from 20 to 52 years (mean age 32±1.2 years). Men - 46 (53,5%), women - 40 (46,5%).

To achieve this goal all the patients were divided into two groups, comparable by age and gender, depending on regimens: group 1 (n=44) received pegylated interferon α2b+ribavirin, group 2 (n=42) peginterferon α2b+ribavirin+. Peginterferon α2b was administered subcutaneously at a dose of 100 mg 1 time per week, ribavirin 1000 mg daily course of 48 weeks. In accordance with (was carried out using the method «envelopes»), was administered 100 mg 1 time per day rate 9 weeks from the start of antiviral therapy, the " for 9 weeks before its ending.

Efficacy was assessed on sustainable virological response at week 24 monitoring after the completion of the HTP. Study of the level of white blood cells and neutrophils in the blood was performed before treatment and at the stages of control HTP(4, 8, 12, 24, 36, 48 week). Reliable inter-group differences were not registered. Before conducting a double-HTP all patients had laboratory signs leiko - and neutropenia (blood in the General analysis of blood from 3.5 to 3.0 x 10 9 /l, the number of neutrophils from 2.0 to 1.5 x 10 9 /l). This study was approved by the Ethics Committee, and all patients gave informed consent to participate in the study.

Table 11 presents characteristics of observed patients with CHC different groups before the start of the HTP.

Table 11

Characteristics of the observed patients (Pitch m)

Indicators

1st group

2nd group

Number of patients per

Men, people

Women, people

Average age, years

31,1±2,02

32,4±2,01

Weight, kg

70,4±1,2

69,8±2,9

Disease duration, years

6.8 ħ 1,7

7,1 about 1.1

The initial activity of ALT, IU/l

free 125,21±7,11

122,13±8,15

The initial activity of alkaline phosphatase, U/l

267,44±14,6

271,34±15,2

Thymol test, units

6.8 ħ 0,9

6,9 about 1.1

Total bilirubin, mkmol/l

23.81 to±1,81

24,04±1,78

Albumins, %

52,23±0,51

52,01±0,54

Gamma-globulins, %

24,22±0,41

24,78±0,39

The number of leukocytes x 10 9 /l

3,1±0,16

3,2±0,12

The number of neutrophils x 10 9 /l

1,8±0,13

1,7±0,12

The number of HCV RNA

3,8 x 10 6

3.7 x 10 6

All patients with CHC registered the following main syndromes: 98% of asthenovegetative syndrome (fatigue, irritability, sleep disturbances, decreased performance and General weakness, malaise, instability of mood, headache), 90,9% dyspeptic syndrome (loss of appetite, abdominal discomfort, nausea, flatulence, belching, and for some patients vomiting). 81% noted the severity and/or pain in epigastria, and/or right upper quadrant (syndrome of the right hypochondrium), which had mostly dull, aching character. Hepatomegaly was recorded in 81% of patients from this group, enlargement of the liver accompanied by a consolidation of its consistency and moderate by morbidity at a palpation. These leading syndromes in the majority of patients (88.2 per cent) were recorded simultaneously. The frequency of occurrence of main clinical syndromes in different groups of patients is presented in table 12. Before the start of therapy, no significant differences between patients of the 1-St and 2-nd groups were not registered.

Table 12

The occurrence of main clinical syndromes in the observed patients before the beginning of the therapy, %

Symptoms

1 group

2 group

Asthenovegetative

75,6

76,2

0,852

Dyspeptic

58,8

57,9

0,720

Hepatomegaly

86,8

88,1

0,226

Splenomegaly

34,4

35,1

0,525

Syndrome «right hypochondrium»

92,8

93,4

0,651

When assessing the dynamics of blood neutrophils in the blood in patients with CHC against the background of the HTP without accounting treatment is established that the share of persons with I degree leiko - and neutropenia before treatment was 83.7 percent of the people. As you continue HTP naturally grew the number of patients with a reduction in the number of leukocytes, neutrophils, depending on the tactics of the treatment. Table 13 presents the dynamics of the absolute values of cells and neutrophils in patients depending on the tactics of treatment. When comparing the different treatment options, the authors found that the use of α2b in combination with ribavirin caused significantly more pronounced decrease of indices compared with a group of patients who received . Thus, in the 1st group of patients minimum value of leukocytes was 2.1±0,16 x 10 9 /l, neutrophils - 1,0 ħ 0.03 x 10 9 /l, while in the 2nd group - 3,4±0,11 x 10 9 /l; 1,9±0,05 x 10 9 /l, respectively (p<0.05).

The analysis of the data on the effectiveness of antiviral treatment showed significantly better results of treatment in patients of the 2nd group compared with the 1st (p<0.05), the data presented in table 14.

Table 14

The effectiveness of antiviral therapy, %

Answer variant

1st group

2nd group

Rapid virologic response

80,7

88,5

0,405

Early virologic response

66,2

85,8

0,013

Direct virologic response

61,1

73,7

0,035

Steady virologic response

44,8

65,5

0,028

Thus, we can assume a possibility of augmentation of the antiviral effect drug at his appointment in combination with an OEM. This property drug has been registered with the study of the remote results of the treatment, namely sustained virological response.

Also was carried out the comparative characteristic of the basic biochemical parameters in 2 groups of patients with CHC to OEMs and 24 weeks after the end of the HTP. The most significant data are presented in .15.

Table 15

Indicators of liver metabolism of CHC patients before treatment and 24 weeks after the end of the HTP (Pitch m)

Indicators

1 group

2 group

To HTP

24 weeks after HTP

To HTP

24 weeks after HTP

ALT, IU/l

free 125,21±7,11

56,85±8,56

122,13±8,15

39,42±6,39*

Alkaline phosphatase, U/l

267,44±14,6

228±17,11

271,34±15,2

169±12,45*

Thymol test, U/l

6.8 ħ 0,9

6,6±0,81

6,9 about 1.1

5,8±0,92

Albumin, %

52,23±0,51

51,23±0,11

52,01±0,54

54,01±of 0.26*

Gamma globulin, %

24,22±0,41

23,67±0,51

24,78±0,39

20,56±0,42*

Note: * - reliability of differences between the indices of 1-St and 2-nd gr., p<0.05.

As can be seen from the data presented in .15, indicators of cytolysis and cholestasis significantly improved in patients of the 2nd group through 24 weeks after therapy. Application patients of the 2nd group showed significantly meaningful best a distant result in the restoration of metabolic liver.

Thus, the appointment of the drug in combination with dual antiviral therapy is a new method of treatment of HCV infection.

The inclusion of in combination antiviral therapy led to an increase in the frequency of sustainable

the virological response in patients with chronic hepatitis C (CHC), which increased the efficiency of treatment by 20.7%.

Example 4

The aim of the research was to study the effect of treatment on the effectiveness of antiviral therapy in primary CHC patients in achieving sustained virological response.

Under the supervision were 142 patients with CHC (66 men, women 76 aged from 18 to 62 years, the average age of 36.5±1,4 years). The criterion for inclusion in the study was that patients confirmed (unaccounted-clinical-laboratory data) CHC in the phase of replication (HCV RNA+), virus genotypes 1b and 3a. Absence of antibody to human immunodeficiency virus; the absence of other clinically significant diseases of the liver (alcoholic liver disease, the reception of hepatotoxic drugs, autoimmune chronic hepatitis, hemochromatosis); absence of cirrhosis of the liver. All patients were comprehensively examined using clinical and laboratory and instrumental methods of investigation. The diagnosis of chronic hepatitis C confirmed by the detection of serum IgG specific antibodies to antigens of hepatitis C virus (anti-HCV IgG, anti-HCV total.) and HCV RNA - by polymerase chain reaction (PCR) with the definition of the genotype and the amount of virus. In the period of treatment was conducted monthly clinical and biochemical monitoring. HCV RNA was determined after 1 month from the start of therapy and then every three months of treatment. All patients held transabdominal ultrasound scanning of organs of the abdominal cavity to initiation of therapy and then every 6 months. In addition, as a control group examined 56 practically healthy individuals with a body mass index of less than 25 kg/m 2 , the lack of markers of viral hepatitis and normal levels of immune-biochemical parameters.

Body mass index in all patients included in the study was 18-25 kg/m 2 . Genotype 1b was registered by 54.9% of the surveyed in the other cases (45,1%) was registered For genotype. Viral load is varied from 240 thousand to 12 million IU/ml

To clarify the degree of activity and stage of disease 84 patients was performed needle biopsy of the liver: the average of the YOKE of the Knodell amounted to 6,02±0,71 points, and the index fibrosis score Desmet - 1,08±0,92 points.

Patients receiving peginterferon α2b subcutaneously in a dose of 1.5 mg/kg/ week and ribavirin (800-1200 mg / day) daily. The period of treatment was: in genotype For and availability of rapid virological response is 24 weeks, in genotype lb and availability of early virological response at 48 weeks.

This study was approved by the Ethics Committee, and all patients gave informed consent to participate in the study.

In accordance with (was carried out using the method «envelopes») all patients were divided into two groups, comparable by age and gender based from regimens: group 1 (n=74) received pegylated interferon α2b+ribavirin, group 2 (n=68) - pegylated interferon α2b+ribavirin+ 100 mg 1 time per day, a course of 12 weeks from the start of the OEM. Subsequently was administered in the same dosage past 12 weeks HTP.

The groups were matched for sex, age, genotype of the virus, and biochemical parameters (table 16, 17).

Statistical processing and graphical visualization of the data was carried out in accordance with the technology of the modern computer analysis (on IBM-compatible personal computer using Microsoft Excel Office 2007 and Statistica (StatSoft) version 7.0, operated in the operating environment of Microsoft Windows XP Professional.

Table 16

Characteristics of the observed patients (Pitch m)

Indicators

Healthy

1st group

2nd group

Number of patients per

Men, people

Women, people

Average age, years

35,3 about 1.1

35,2 ą 1.3

36,1±1,4

BMI, kg/m2

21,2±2,12

21,5±2,09

21,1±2,01

YOKE, tenths

5,99±0,82

6,01±0,55

index fibrosis

1.16 ą 0,71

1,11±0,32

the genotype of the virus

viral load

<800 000 Me/ml

>800 000 Me/ml

Table 17

Characteristics of the observed patients biochemical parameters (Pitch m)

Indicators

Healthy

1st group

2nd group

The initial activity of ALT, IU/l

22,74±0,69

125,31±5,19

126,84±8,22

The initial activity of alkaline phosphatase, U/l

119,59±1,83

259,56±7,13

237,11±6,22

Thymol test, units

2,11±0,06

2,69±0,14

3,59±0,11

Total bilirubin, mkmol/l

17,13±0,28

24,51±0,69

to 26.04±0,61

Albumins, %

62,44±0,36

51,81±0,69

53,24±0,59

Gamma-globulins, %

18,07±0,15

22,58±0,40

21,57±0,31

Concomitant therapy have been well-tolerated by all patients. The frequency of adverse events in patients 2 groups was known side effects and ribavirin. Assessment of the content of cells and neutrophils in the blood of patients with CHC against the background of the OEM according to the scheme of treatment is given in table 18.

Table 18

Hematological indicators on a background of treatment (Pitch m)

Indicators

1 group

2 group

leukocytes x 10 9 /l

Before the beginning of the

5,4±0,08

5,3±0,17

After 1 month.

2,3±0,12

3,1±0,14*

After 2 months.

2,4±0,16

4,0±0,18*

After 3 months.

2,3±0,11

3,8±0,16*

After 6 months.

2,7±0,14

4,1±0,21*

After 12 months. therapy

3,0±0,10

3,7±0,18*

neutrophils x 10 9 /l

Before the beginning of the

2,9±0,11

2,8±0,14

After 1 month.

1,2±0,08

2,0±0,07*

After 2 months.

1,1±0,06

2,3±0,05*

After 3 months.

1,0±0,05

2,0±0,04*

After 6 months.

1,2±0,06

2,3±0,05*

After 12 months. therapy

1,5±0,04

2,1±0,06*

Note: here and further * - reliability of differences between indices of 1-St and 2-nd gr., p<0.05.

Noted that the absolute performance (white blood cells and neutrophils) statistically significantly decreased on 4 weeks of therapy in patients of the two groups. However, a smaller decrease of the content of these indicators registered in the 2nd group compared with the 1st group at all control points of the study (p<0.05).

At the analysis of biochemical parameters of the authors reliably got the best results in patients of the 2nd group compared with the 1st, which are presented in table 19.

Table 19

Characteristics of the observed patients biochemical parameters of 6 months after completion of treatment (Pitch m)

Indicators

Healthy

1st group

2nd group

ALT, IU/l

22,74±0,69

118,32±5,88 p 0 <0,001 p 1-2 <0,001

21,89±1,45 R 0 =1,000

Alkaline phosphatase, U/l

119,59±1,83

261,63±6,99 p 0 <0,001 p 1-2 <0,001

160,24 ħ 4.83 p 0 <0,001

Thymol test, units

2,11±0,06

6,11±0,21 p 0 <0,001 p 1-2 <0,001

4,69±0,19 p 0 <0,01

Note. Here and further: p - probability of erroneous decision of the alternative hypothesis of intergroup differences, p 0 - the likelihood of erroneous decision of the alternative hypothesis that differences with the figures of the control group (healthy), p 1-2 - the likelihood of erroneous decision the alternative hypothesis there are differences between the indicators of the patients of the 1-St and 2-nd groups.

As can be seen from the data presented in table 19, cytolysis syndrome remained pronounced in patients of group 1. The level of ALAT changed from 30,4 to 183,2 U/l and exceeded norm in 36% of patients. The average value of this index was 118,32±5,88 U/l, which was significantly (p 0 <0,001, p 1-2 <0,001) differed from those in the comparison group. In group 2 patients, the average ALAT was 21,89+1,45 U/l and does not exceed the norm of 80% per Indicators of alkaline phosphatase, TA patients of the 1-St and 2-nd groups when comparing also differ reliably, both among themselves and from a group of healthy persons (.19). Noted increase of thymol test and alkaline phosphatase have to 86.4%, and 65.5% of patients in group 1, respectively.

The main result of this study is provided by differences in the frequency of achieving a rapid, early and sustained viral depending on the genotype of the virus (tables 20, 21).

Table 20

Frequency of virologic response when 1b genotype of the virus of hepatitis C in The different treatment regimens

Response type

1 group

2 group

genotype

Rapid virologic response

52,63%

75%

p<0.05

Early virologic response

78,95%

82.5%of

p>0.05

Direct virologic response

71,05%

82.5%of

p<0.05

Sustained virologic response

47,37%

67,5%

p<0.05

Patients of the 2nd group of observations carried treatment, adverse reactions were recorded less frequently than in patients in group 1. The data of the monitoring results are presented in table 22.

Table 22

Side effects

1 group

2 group

Grippopodobnyy syndrome

78,38

51,47

0,001

Arthralgia

63,51

44,12

0,028

Myalgia

58,11

32,35

0,003

Exacerbation of chronic pancreatitis

6,76

2,94

0,444

Depression

36,49

11,76

0,001

Hair loss

37,84

13,24

0,001

Zitopeniceski syndrome

63,51

0,000

Weight reduction

44,59

33,82

0,230

Thus, can be considered as a drug that strengthens the antiviral action together with the appointment with the peginterferon and ribavirin that is manifested in increasing the SVR when 1b genotype on 20,13%with genotype 3a on 17,96%.

Thus, the authors found that the treatment of patients with CHC interferon α2b+ribavirin in combination with has a positive influence on biochemical parameters of patients, which is reflected in the improvement of functional activity of hepatocytes. In addition, the use of in the treatment of chronic hepatitis C is associated with significantly higher rates of SVR against the background of the HTP in patients with 1b and 3a genotypes. With this treatment patients with chronic hepatitis C (genotype 1b and 3a) was associated with a statistically significant decrease in frequency of adverse events HTP.

Example 5

Dosage forms

For the treatment of hepatitis With can be introduced orally, intramuscularly or intravenously as standard dosage forms containing non-toxic pharmaceutically acceptable carriers.

may be given to the patient in doses of 0.1 to 10 mg/kg body weight per day, preferably at doses of 0.5 to 5 mg/kg, more preferably, 1 mg/kg, one or more times a day.

It should be noted that the specific dose for each patient will be depend on many factors, including age, body weight, gender, General health and diet of the patient, time and route of administration of the medicinal product, its rate of excretion from the body and the severity of the disease in this patient under treatment.

Pharmaceutical compositions contain in the amount effective to achieve positive results in the treatment of hepatitis C, and may be entered as standard dosage forms (for example, in solid, semi-solid or liquid form)containing as an active ingredient in a mixture with support or filler suitable for oral, intramuscular, or intravenous injection. The active ingredient may be included in the composition together with commonly used non-toxic pharmaceutically acceptable carriers, suitable for manufacturing solutions, tablets, pills, capsules, pills and any other medicinal forms.

As fillers can be used by various substances such as sugars, such as glucose or sucrose lactose, mannitol or sorbitol, derivative cellulose and/or calcium phosphates, for example, tricalcium phosphate or acid calcium phosphate, as a binder can be used such as starch paste, such as corn, wheat, rice, potato starch, gelatin, tragakant, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If necessary, can be used loosening agents, such as the aforementioned starches and , polivinilpirrolidon, agar or alginic acid or its salt such as sodium alginate.

It may also include optional supplements, for example, agents, regulatory fluidity, and lubricating agents, such as silicon dioxide, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate, and/or propylene glycol.

As additives can also be used stabilizers, thickeners, colors and fragrances.

When preparing the standard dosage form, amount of the active ingredient used in combination with the carrier may vary depending on the patient under treatment, and from a particular way of introduction of medicinal product.

For example, when using in the form of solutions for injection, content of the active agent in them is 0.01-5 wt.%. As a diluents may be used to 0.9% solution of sodium chloride, distilled water solution novokaina for injection, ringer solution, glucose, specific additives for the dissolving. When introduced into the body in the form of tablets, their number is 5.0-500 mg on the standard dosage form.

Dosage forms for use in accordance with the present invention receive by standard techniques, such as, for example, the processes of mixing, granulating, formation of drops, dissolution and lyophilization.

Pelletized form

Tablet formulation gain, using the following ingredients:

The components are mixed and pressed for education tablets weighing 300 mg each.

Suppositories

An example of a suppository:

or pharmaceutically

1-100 mg

acceptable salt

Cocoa butter

number,

necessary to obtain a

suppositories

When necessary, it is possible to manufacture rectalnah, vaginal and urethral suppositories with relevant fillers.

Solution for injection

An example of a solution for injection:

or pharmaceutically

1-50 mg

acceptable salt

Water for injection

2 ml

1. The method of treatment of viral hepatitis C, which envisages the introduction of patient efficient amount or pharmaceutically acceptable salts.

2. The method according to claim 1, where viral hepatitis C represents acute hepatitis C.

3. The method according to claim 1, where viral hepatitis C is a chronic hepatitis C.

4. The method according to claim 1, where is entered in the drug .

5. The method according to claim 1, where dose or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight.

6. The method according to claim 1, where single dose is 100 mg.

7. The method according to claim 1, where the duration of reception is from 3 weeks to 12 months.

8. The method according to claim 1, where for the treatment of hepatitis C by reducing the side effects of antiviral therapy.

9. The method according to item 8, where side effects of antiviral therapy are grippopodobnyy syndrome, arthralgia, myalgia, and the exacerbation of chronic pancreatitis, depression and/or hair loss.

10. The method according to item 8, where side effects of antiviral therapy are leukopenia or neutropenia.

11. The method of treatment of viral hepatitis C, which envisages the introduction of patient efficient amount of pegylated interferon, ribavirin and or pharmaceutically acceptable salts.

12. The method according to claim 11, where viral hepatitis C represents acute hepatitis C.

13. The method according to claim 11, where hepatitis C is a chronic hepatitis C.

14. The method according to claim 11, where is entered in the drug .

15. The method according to claim 11, where dose or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight.

16. The method according to claim 11, where interferon is a interferon α2a.

17. The method according to claim 11, where interferon is a interferon α2b.

18. The method according to claim 11, where dose is 100 mg with the introduction of 1 times in the day.

19. The method according to claim 11, where the duration of reception is from 3 weeks to 12 months.

20. The method according to claim 11, where dose of pegylated interferon is 100 mcg at introduction 1 once a week.

21. The method according to claim 11, where the ribavirin dose is 1000 mg per day with the introduction of daily.

22. The method according to claim 11, where for the treatment of hepatitis C by reducing the side effects of antiviral therapy.

23. The method according to article 22 where side effects of antiviral therapy are grippopodobnyy syndrome, arthralgia, myalgia, and the exacerbation of chronic pancreatitis, depression and/or hair loss.

24. The method according to article 22 where side effects of antiviral therapy are leukopenia or neutropenia.

25. Pharmaceutical composition for the treatment of hepatitis C, containing an effective quantity of or pharmaceutically acceptable salts.

26. The composition according to section 25, in which effective number of or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight.

27. Pharmaceutical combination for the treatment of hepatitis C, including interferon, ribavirin, and or pharmaceutically acceptable salt.

28. Combination item 27, where viral hepatitis C represents acute hepatitis C.

29. Combination item 27, where viral hepatitis C is a chronic hepatitis C.

30. Combination item 27, where is in the drug .

31. Combination item 27, where dose or pharmaceutically acceptable salts is 0.1-10 mg/kg body weight.

32. Combination item 27, where interferon is a interferon α2a.

33. Combination item 27, where interferon is a interferon α2b.

34. Combination item 27, where dose is 100 mg with the introduction of 1 times in the day.

35. Combination item 27, where dose of pegylated interferon is 100 mcg at introduction 1 once a week.

36. Combination item 27, where the ribavirin dose is 1000 mg per day with the introduction of daily.

37. Set for treatment of viral hepatitis C, including interferon, ribavirin, or pharmaceutically acceptable salt, and instructions for use.

38. Application or pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for treatment of viral hepatitis C.

39. Application or pharmaceutically acceptable salts in combination with interferon and ribavirin for the treatment of viral hepatitis C.