The method of treatment of viral hepatitis in

 

(57) Abstract:

The invention relates to medicine and relates to a method of treatment of viral hepatitis C. the Method includes the selection of recombinant yeast vaccine against hepatitis b, preferably in a volume of 1 ml, 1 time per month for three months, in addition you can use nukleinat sodium. The technical result is to shorten the hospital stay. 2 C.p. f-crystals, 2 tab.

The invention relates to the field of medicine and the use of known hepatitis b vaccines in the treatment of chronic carriers of hepatitis b and patients with chronic viral hepatitis C.

The problem of chronic viral hepatitis is highly relevant both in medical and social terms. Chronic hepatitis b virus causes slowly progressive disorders of the liver, which can reach the degree of cirrhosis (20%), to cause hepatocellular hepatocarcinoma (primary liver cancer) and to cause death of the patient.

According to experts there are 350 million carriers of hepatitis b virus in Russia - more than 7 million Annually in our country is registered not less than 135 thousand new Viru several times more likely to develop hepatocarcinoma or liver cirrhosis.

Treatment of patients with chronic viral hepatitis b infection is a difficult task, and conventional treatment of carriers of hepatitis b virus does not exist.

Currently known and widely used for the prevention of hepatitis b recombinant yeast vaccine production NPK "Chembiotech Ltd(RF patent N 2088664, 1997, registration card N 96/144/5317).

Known for attempting fialuridine - antiviral medication for the treatment of 15 patients with chronic hepatitis.

However, in 7 of them have developed the strongest lactic acidosis due to pronounced liver damage, 2 patients died, 5 were made urgent liver transplant, but 3 patients died. Identified complications make it impossible to use the known drug. Russian medical journal, vol. 3, No. 12, July 1996.

Known use of various drugs for the treatment of viral hepatitis b - adjuvant, a mixture of streptokinase, fibrinolizina and heparin, n-aminometilbensana acid.

SU 1 197674 B 1983, A 61 K 35/80.

SU 1 132951, 1983, A 61 B 10/00.

The main causal antiviral drug sufficiently proven; used for the treatment of khron is n-A, realizaron (C. N. Sorenson "Viral hepatitis" 2nd ed., St. Petersburg, 1998, 145).

However, the presence of contraindications to assign interferonoterapii - autoimmune diseases (thyroiditis, thrombocytopenia, neutropenia, and others), depression, coronary heart disease, diabetes, renal failure, and others (C. N. Sorenson "Viral hepatitis" 2nd ed., St. Petersburg, 1998, 145); side effects - flu-like syndrome, fatigue, worsening of mood, depression, alopecia, cytopenia, Hypo - or gipertireoidizmom, the formation of neutralizing antibodies to interferon (H. T. Apraksina, BC 1996, so 4, N 3, 177) limit the use of interferons. These drugs are used in the course doses duration from 12 weeks to 12 months, they are rather expensive, which limits their applicability.

Therapeutic effect interferonoterapii in chronic hepatitis b is observed only in 25% of patients (Pietro Andreone et al. "Hepatology" 1996, 24, 774-777).

It is known the use of interferon daily or 3 times a week for 16-24 weeks. When applying the above treatment regimens transient response is achieved in 30-56% of patients, the disappearance of HBsAg is achieved in 7-11%. The value of persistent resp is.

The use of known means requires long-term use to achieve the desired result associated with the disappearance of the manifestations of the disease, determined on the basis of the results of various clinical and diagnostic research. Typically, the treatment of such patients requires prolonged their stay 16-24 weeks in the hospital, which is associated with a specific cost of funds.

Object of the invention is the expansion of the means intended for the treatment of viral hepatitis C. the problem is solved using known recombinant yeast vaccine, previously used for the prevention of hepatitis b, which set new, previously unknown properties, allowing its application for a new purpose. Namely, studies have shown that the vaccine production NPK "Combitech" activity, allowing its use as a therapeutic drug in cases of chronic viral hepatitis b and chronic carriers of hepatitis C.

First proposes the use of recombinant yeast hepatitis b vaccines for the treatment of chronic carriers of hepatitis b virus and ill and, used to include patients in the study were:

- Age from 16 to 55 years,

- Increased serum activity of Alt is not less than 2 times the upper limit of normal within 6 months before the study began.

From observations excluded patients that previously used immunosuppressants, steroids or antiviral drugs, as well as patients who abused alcohol or drugs.

Patients in groups as follows:

the first group consisted of 20 patients with chronic viral hepatitis b (HUGU), moderate activity, receiving on the background of traditional pathogenetic therapy the hepatitis b vaccine;

the second group comprises 10 patients HUGW (moderate activity) receiving on the background of standard therapy in addition to vaccines and nukleinat sodium;

the third group consisted of 15 healthy" carriers of HBsAg, which scheme was introduced vaccine "COMBITECH" and

the fourth group consisted of 10 healthy carriers, receiving together with the vaccine and nukleinat sodium.

The control group comprised 10 patients with chronic hepatitis b and 8 "healthy" carriers.

The vaccine is C per month for three months.

Adjuvant used nukleinat sodium 0.5 g 3 times a day, treatment was started on the day of vaccine administration and continued for 4 more days, so the treatment nukleinat sodium was 5 days.

Before treatment and before each injection of vaccine in all observed in the experimental and control groups took the blood for immunological study, markers of HBV, were traditional biochemical liver function tests.

Criteria for assessment of response to treatment were developed in advance and based on the dynamics of indicators of activity of Alat, studied, and serological profile using the import ELISA test systems for the detection of antibodies and antigens of viral hepatitis C.

To determine the number of HBV markers was performed semi-quantitative monitoring of the studied serum samples. The title took the highest serum dilution giving a positive result, therefore, the title was a quantitative indicator of the level of HBs antigen in the blood sample.

Used monoclonal antibodies for the study of model antigens of the major lymphocyte subpopulations, it was determined the level of immunoglobulins in the blood serum of the main CL is POZITIV the traditional method. Thus was assessed 3 basic immunity.

The obtained results were processed by methods of variation statistics using parametric and nonparametric criteria.

1. Defined standard parameters of the immune status in healthy people, divided into 2 age groups (I - 18 to 25 years, II - 27-65 years).

2. Examined the number in each group of patients was determined mathematically to obtain objective results.

Analysis of the obtained results was carried out in 3 directions:

1. Comparison of indicators from the norm before and after treatment in all groups.

2. The definition of significant differences in experienced 4 groups relative to patients receiving only conventional therapy.

3. Comparison of parameters after treatment in patients receiving the vaccine with nukleinat sodium relative indicators of immunity in patients who receive a single vaccine.

Analysis of the obtained data allowed us to establish that the vaccine promotes the gradual decrease of activity of Alat (PL. 1).

So, in the group of patients HUGW received one vaccine, Alat with 1100+56,0 nmol/C. L. decreased within 5 months of follow-up 276+32C 1248+53,4 to 1083+46,3 (reduction by a factor of 1.2). Normal levels of Alt (SI) - 10881 nmol/C. L.

The positive therapeutic effect of the vaccine against hepatitis b was amplified using as an immunomodulator of nucleinate sodium. This tended more noticeable decrease in the activity of Alt in the second group of patients received the vaccine and a 5-day course of treatment with nukleinat sodium compared with rates in patients who received only the vaccine (23121,6 and 27632,3 respectively).

Interesting data were obtained in the study of the immunological activity of the vaccine against hepatitis b "COMBITECH". Already after the first injection of the vaccine in many patients HUGW there is a decline of HBsAg titer. So, before the introduction of the vaccine in 15% of patients it was determined in dilution from 100 to 1000 IU/l and 6000 IU/l and above - 50% of patients. In the study of blood in the observed group of patients 2 months after the last injection of vaccine, the percentage of patients with HBsAg were found in high titers (6000 IU/l and above) decreased 1.4 times (3511%), respectively in the majority of patients (6511%) titer of antigen decreased significantly.

Two patients with HUGW were detected antibodies to HBsAg in high consle before treatment vaccine highest titer of the antigen was observed in 3442% of patients, then 2 months after the last injection of vaccine, only 1 of 15 patients (77%) were antigen in a specified concentration. 2 patients - 1 month 2 2 months after completion of the course the HBsAg vaccine therapy were not found at all. Moreover, 1 of the HBsAg carrier 2 months after the end of treatment vaccine in serum appeared antibodies to it (their concentration amounted to 11.2 IU/l).

Monitoring of groups of patients who received the vaccine and nukleinat sodium (although these groups are small in number), have suggested that nukleinat sodium enhances the immunogenicity of the vaccine. So the percentage of CHB patients who received a single vaccine, which HBsAg was detected in relatively high concentrations (6000 and above IU/l) was 3511%, in the same group of patients with CHB treated with vaccine with nukleinat sodium, this figure was lower - 1010%.

And in these groups of patients was also observed positive seroconversion. So, one patient with HUGW and one carrier of HBsAg after 1 month after treatment vaccine with adjuvant appeared antibodies to surface antigen (concentration of 15.6 and 12.6 IU/l, respectively).

One carrier HBsAg antibodies anti HBsAg appeared 2 months after lacanada changes of immune status in patients suffering from chronic viral hepatitis b and in carriers of HBsAg.

As can be seen from table 2, patients HUGW 1 month after administration of the vaccine registered significant reduction in the number of T-suppressor cells, increased levels of T-helper cells, immunoglobulin classes a, M, G, with the fall of the concentration of zero cells. These changes can be characterized as reflecting the unconditional activation of immunological reactivity as the decline in the number of T-suppressors and null lymphocytes also indicate potentsiirovannye immune system function.

After the second vaccine injection dynamics of the immunological status was different. So, registered a drop of T-suppressor cells, T-helper cells, immunoglobulin A, which indicates the suppression of immunological activity in this period of the survey.

After the third injection of vaccine notable changes from baseline of the T-suppressor cells, T-helper cells, null cells, immunoglobulin G was not. At the same time, the number of Ig A, Ig M in the first case significantly increased in the second - significantly decreased.

These data suggest that to enhance the immunological Olga HBsAg primary vaccine has led to a decline in the level of T-suppressors, B cells, immunoglobulins M and increased Ig A.

Thus, the analysis of the research suggests that to enhance the effectiveness of the vaccine used for the treatment of HBsAg carriers should be used immunokorrigiruyuschy drugs.

The following are specific examples of the application of the subject invention for the treatment of viral hepatitis C.

Example 1. Patient N., 43 years old, was admitted to the clinic of infectious diseases, Voronezh 22.09.98, (history N 3238) with complaints expressed General weakness, malaise, loss of appetite, dull pain in the right hypochondrium.

From the anamnesis it is known: since 1997 suffer from chronic viral hepatitis C. Constantly emphasizes General weakness, decreased performance, irritability. Indicators Alat for two years, diseases always exceeded the normal 5-6 times, always in the serum was detected HBsg. Conducted traditional therapy (vitamins, hepatoprotectors) brought short-term positive effect. In August 1998 the patient's condition deteriorated - increased weakness, appeared dull pain in the right hypochondrium, decreased body weight 4-5 kg and the patient was sent to the clinic investirovanie: General condition is satisfactory, skin and visible mucous membranes pale pink. Muffled heart sounds, rhythmic, pulse 78 beats per minute, satisfactory qualities, rhythmic. Tongue moist, coated thin white bloom. The abdomen is soft, moderately painful during deep palpation in the right upper quadrant. The liver is thick, 2.5 cm is below the edge of the costal arch. Spleen not palpated. Feces and urine of normal color.

Laboratory data:

General. an.blood: HB - 130 g/l, er. - 3,81012/l, a blood clot. - 204109/l lake. - 3,0109l, p - 4, s - 54, e - 3, l - 28, m - 11, ESR - 2 mm/hour.

An.urine - without a pathology.

Biochemical blood test: bilir.tie. "no, bilir.free. - 22 mmol/l thymol.Ave. to 12.5 ed, PETIT - 84%, glucose - 5.1 mmol/l, Hollister. - 6.2 mmol/l, Alat - 889 nmol/S. L. (at the rate of 28.0-189 nmol/C. L.).

By ELISA in the serum revealed: HBsAg, antiHBc I gM.

Data ultrasound diffuse changes in the liver, hepatomegaly.

Given the data of anamnesis, clinical and laboratory findings, the patient is diagnosed with chronic hepatitis b moderate activity.

On the background of traditional pathogenetic basic therapy (Riboxin, LIPOSTABIL, vitamins of groups B, C, E) patient was assigned to vaccinate is s, the second and third vaccine conducted 27.10.98, and 25.11.98, respectively.

1 month after the first injection of the vaccine Alt decreased to 423 nmol/C. L. During dynamic observation of the patient intoxication gradually decreased, appetite improved, gradually disappeared weakness, increased body mass, the patient was able to afford physical activity (1-2 months after vaccine therapy).

Dynamics of indicators of cytolysis of hepatocytes: through 1 month. after the second vaccine injection Alat - 257 nmol/C. L., a month after the third injection Alat normalized fully - 177 nmol/C. L. After considerable physical exertion of the patient transaminase levels again increased to 600 nmol/S. L. (4 months after completing the course of treatment with the vaccine, but then Alat independently decreased to 265 nmol/C. L. Thymol test during the whole observation time ranged from 5 to 9 units

2 months after vaccine therapy in serum appeared antibodies to HBsAg in the amount of 174 IU/l

The patient continues to be on the observation.

Example 2. Patient B., aged 45, was admitted to the clinic of infectious diseases 23.09.98, with a diagnosis of Chronic is when a random survey was detected HBsAg, and since then, 2-3 times per year, this token is detected continuously. When multiple biochemical analysis of blood serum of liver dysfunction was not detected. Viral hepatitis B was not sick. Ultrasound of the liver - without a pathology.

Admission: no complaints, active, no intoxication. Skin and visible mucous membranes are pale pink color. Heart sounds rhythmic, pure, pulse was 80 beats per minute, satisfactory qualities, tongue cleaner, the abdomen is soft, painless. Liver and spleen are not enlarged.

Laboratory data: General.an.blood: HB - 132 g/l, er. - 4,51012/l, a blood clot. - 244109/l lake. - 4,7109/l, p - 1, p - 65, e - 1, l - 29, m - 4, ESR - 3 mm/hour.

An.urine - without a pathology.

Biochemical blood test: bilir.tie. "no, bilir. free. - 25 mmol/l thymol. so to 2.0 units, PETIT - 80%, glucose - 4.1 mmol/l, Hollister. - 6.0 mmol/l, Alat - 55 nmol/S. L. (at the rate of 28.0-189 nmol/C. L.).

By ELISA in the serum revealed: HBsAg.

The ultrasound results - without a pathology.

Given the data of anamnesis, clinical and laboratory findings, the patient is diagnosed with chronic carriers of HBsAg.

Patients received therapy vaccine "Combitech".

The first injection in the x2">

2 months after vaccine therapy in serum appeared antibodies to HBsAg in the number of 27.2 ME/l

Indicators of cytolysis of hepatocytes during the whole observation time remain normal.

Example 3. Patient P., 59 years old, was admitted to the clinic of infectious diseases 8.12.98 was diagnosed with Chronic hepatitis b, severe degree of activity" (history N 4296).

Upon receipt complained of dull pain in the right hypochondrium, anorexia, expressed General weakness, fatigue, weight loss, heartburn.

From the anamnesis it is known: the patient himself for 30 years, periodically disturbed dull pain in the right hypochondrium, sometimes itching, mild weakness. In 1989 he was first diagnosed with Chronic viral hepatitis, nedifferencirovannaja. Since 1996 repeatedly in the serum of the patient was found to have HBsAg. Indicators of cytolysis of hepatocytes remained consistently high numbers - Alat 600 nmol/C. L. up to 2113 nmol/S. L., violations of pigment metabolism have been noted.

Has repeatedly been hospitalized in the gastroenterology departments of various hospitals in the city. The expressed activity of pathologic centralnye fibrous septa with uneven edges. Portal tracts expanded sclerotic (fibrous), step necrosis, fields of hepatocytes with matte glassy cytoplasm.

Conducted therapy (detoxification remedies, vitamin therapy, hepatic) gave short-term positive effect.

Admission: General condition is satisfactory, icteric staining of the skin and mucous no, hemorrhages and no scratches. Heart sounds rhythmic, clean, muted. Pulse 82 beats per minute, satisfactory qualities, rhythmic, wet tongue, lined with thin white bloom, the abdomen is soft, painless. Liver dense, 2-3 cm below the right rib, spleen not palpated. Feces and urine normal color.

Laboratory data: General. an. blood: HB 120 g/l, er. - 3,961012l, a blood clot. - 234109l lake. - 5,3109/l, p - 3, s - 65, e - 6, l - 22, m - 4, ESR - 3 mm/hour.

An. urine - without a pathology.

Biochemical blood test: bilir.tie. - 0 mmol/l, bilir.free. - 22 mmol/l thymol.Ave. - 9 unit, PETIT - 80%, glucose of 5.5 mmol/l, Hollister. - 5.5 mmol/l, Alat - 1278 nmol/S. L. (at the rate of 28.0-189 nmol/C. L.).

By ELISA in the serum revealed: HBsAg, antiHBc IgM.

Data ultrasound diffuse changes in the liver, hepatomegaly.

In spite of traditional pathogenetic therapy (gemodez, salt solutions, vitamins of groups B, C, E, Riboxin, antispasmodics, LIV-52) the patient's condition did not improve, and biochemical indicators even worse: PTI decreased to 59%, Alt increased to 1350 nmol/S. L. it was Decided to carry out a course of vaccine "Combitech" with adjuvant (nukleinat sodium). The first injection of the vaccine was made 28.12.98, (in the above scheme). On the same day and 4 the next day the patient has been nukleinat sodium 0.5 g 3 times a day. The second injection of the vaccine was 28.01.99, third - 28.02.99, and in January and February, starting from the day of vaccination and for the next four days the patient received nukleinat sodium 1.5 g per day.

When viewed through 1 month after the first injection of the vaccine and the adjuvant patient felt quite satisfactory, gradually decreased cytolysis.

One month after the end of treatment vaccine with nukleinat sodium Alt decreased to 403 nmol/S. L., thymol test - 5%

1 month after the second injection with adjuvant patient serum appeared antibodies to HBsAg in the amount of 15.6 ME/l

Observation of the patient prodoljayuschii media HBsAg (history N 3869).

First surface antigen was detected in serum 4 years ago when a random survey, and since then he reveals constantly 2-3 times a year. Biochemical indices of liver function tests have always been normal. Viral hepatitis In previously didn't hurt.

Upon receipt of complaints the patient does not show, no intoxication, skin, clean, regular color. Heart sounds clean, muted, heart rate of 78 beats per minute, satisfactory qualities. The abdomen is soft, painless. Liver, spleen not enlarged.

Laboratory data:

General. an.blood: HB - 140 g/l, er. - 3,51012/l, a blood clot. - 234109/l lake. - 3,8109/l, p - 3, p - 55, e - 0, l - 39, m - 3, ESR - 5 mm/hour.

An.urine - without a pathology.

Biochemical blood test: bilir.tie. "no, bilir. free. - 28 mmol/l thymol. so to 2.0 units, PETIT - 76%, glucose - 4.7 mmol/l, Hollister. - 5.5 mmol/l, Alat - 178 nmol/S. L. (at the rate of 28.0-189 nmol/C. L.).

By ELISA in the serum revealed: HBsAg.

The ultrasound results - without a pathology.

Given the data of anamnesis, clinical and laboratory findings, the patient is diagnosed with chronic carriers of HBsAg.

The first injection of the vaccine together with nukleinat sodium ke. The second vaccine was 21.12.98, third 21.01.99, on the day of vaccination and the next 4 days the patient received nukleinat sodium at a dose of 1.5 g/day.

One month after the end of treatment in the serum of the patient were detected antibodies to HBsAg in the number 11,2 ME/l

Indicators of cytolysis of hepatocytes remain normal.

The obtained results allow to hope that with vaccine therapy can significantly reduce the percentage of HBsAg carriers, which are the most dangerous to others as the focus of this infection.

1. The method of treatment of viral hepatitis by introducing a drug, wherein the drug use of recombinant yeast vaccine against hepatitis C.

2. The method according to p. 1, wherein the vaccine is administered intramuscularly in a total volume of 1 ml of 1 time per month for three months.

3. The method according to p. 1, characterized in that additionally use nukleinat sodium.

 

Same patents:

The invention relates to new phosphonolipids carboxylic acids of formula I and their salts, where R1denotes a linear alkyl WITH9-C13, R2denotes a linear alkyl WITH8-C12, R3denotes hydrogen, a linear alkyl WITH1-C6or benzyl, n = 0-2, 0-3 m, which have antiviral activity and can find application in medicine

The invention relates to biochemistry, namely to obtain biologically active substances with antiviral activity

The invention relates to medicine, in particular to pharmacology relates to antiviral agents in the form of solid dosage forms containing acyclovir, microcrystalline cellulose, salt of stearic acid, low molecular weight polyvinylpyrrolidone, and, optionally, a dye in a certain ratio, and method of its production

The invention relates to pharmaceutical industry, production of medicines intended to treat herpes infections of the skin and mucous membranes

The invention relates to medicine and can be used for selective destruction of cells infected with RNA of hepatitis C virus(HCV)

The invention relates to Virology and immunology, and can be used for typing of hepatitis C virus (НСV)

The invention relates to the specific prophylaxis of plague, infectious hepatitis and parvovirus enteritis in dogs
The invention relates to specific prevention of diseases of dogs, in particular to the vaccine "Biawak" against distemper, parvovirus enteritis, infectious hepatitis, adenoviroz and leptospirosis dogs
The invention relates to specific disease prevention mink, in particular to the vaccine "Bionor" against plague, viral enteritis, botulism and Pseudomonas

The invention relates to polypeptides, used as immunological reagents for the identification, prevention, and treatment of infections caused by HCV
The invention relates to the field of veterinary Microbiology and biotechnology, in particular the production of vaccines or sera against viral and bacterial diseases of cattle

The invention relates to the field of biotechnology, in particular to the means of specific prophylaxis canine distemper and salmonellosis fur-bearing animals
Up!