UA31533U - Method for correcting immune status of patients with non-alcoholic steatohepatitis - Google Patents

Abstract

A method for correcting the immune status of patients with the non-alcoholic steatohepatitis comprises the use of immune correcting drugs. Thymogen is used with this aim at a dose of 50 g, intramuscularly once a day for 7-10 consecutive days.

Description

Description of the invention

A useful model refers to the field of medicine, namely to internal diseases. 2 The relevance of the subject of the useful model is related to the widespread incidence of chronic pathology of the liver and biliary tract both in Ukraine and in other CIS countries, especially in the last 10-15 years. At the same time, along with diseases of viral origin (chronic viral hepatitis B and C), as well as alcoholic liver damage, according to medical statistics, liver pathology of non-viral and non-alcoholic origin and, above all, non-alcoholic steatohepatitis (NAST) attract more and more attention. . It is believed that in 70 modern conditions, NASH is the second most common chronic diffuse liver injury after chronic viral hepatitis.

It has been established that in the pathogenesis of NASH, disorders of the immune system play a significant role. At the same time, there is a concept of "two impulses", which explains the formation of NASH, based on the adverse effect on hepatocytes of factors accompanied by the development of oxidative stress, increased lipoperoxidation of biomembranes, 72 as a result of which the level of normal cellular protection is overcome, necrosis of liver cells occurs, and secondary an inflammatory process develops in the parenchyma of the organ, i.e. NASH itself, which is accompanied by pronounced shifts in the cellular link of the immune response. Therefore, it can be considered appropriate to carry out the correction of violations of immunological homeostasis in order to stop the further progression of this disease.

There is a known method of correcting the immune status of patients with NASH, which involves the appointment of a rational diet, multivitamins and hepatoprotective agents, the administration of antioxidant drugs, in particular ascorbic acid and tocopherol acetate, based on the fact that they, along with antioxidant properties, also have an immunocorrective effect (Stepanov Yu.M. , Filippova A.Yu. Modern views on the pathogenesis, diagnosis and treatment of non-alcoholic steatohepatitis // Modern gastroenterology. - 2004. - Mo1. - P.17-24). 29 But this method is not effective enough and does not ensure the restoration of immunological homeostasis almost in 73 half of NASH patients, especially with frequent exacerbations of the pathological process in the liver.

Therefore, in order to correct the immune status of patients with NASH, it was suggested to introduce thymus preparations to patients with this pathology - takt vin or thymalin | Fadeenko G.D., Kravchenko N.A., Vynogradova S.V.

Prognosis and effectiveness of treatment of non-alcoholic steatohepatitis // Modern gastroenterology. - 2006. - Mo4. - p. 43-171. with

This is the most effective of the existing methods of correcting the immune status of patients with NASH, which ensures the restoration of immune homeostasis in 75-8095 patients with this pathology. However, still 20-2595 patients with yuyu

In NASH, especially with frequent exacerbations of the pathological process in the liver, there are likely shifts in immune indicators, especially those that characterize the state of the cellular link of immunity. In addition, since the composition of these two thymus drugs - both thymalin and tactivin - include ballast proteins along with hormonal compounds, allergic reactions may occur when they are administered, and even autoimmune processes may occur with long-term or repeated use. Therefore, this method of correction of immune status in patients with

NASH needs further improvement. "

The purpose of the useful model was to increase the effectiveness of the existing method of correcting the immune status of 70 patients with nNASH, namely to accelerate the normalization of immunological indicators and prevent possible side effects, including allergic ones. z" This task is achieved by administering thymogen to patients with NASH as a means of immunocorrection.

Thymogen is an immunoactive drug from the group of thymomimetics. Since it is a synthetic agent (dipeptide of I-glutamine and I-tryptophan) and does not contain protein substances at all, thymogen is not capable of causing allergic and autoimmune reactions. In addition, its immunomodulatory effect is almost 100 times higher than that of thymalin and 10 times higher than that of tactivin.

Our proposal for the creation of a useful model is based on the principle established by us for the first time in experimental conditions and then confirmed in the clinic that the administration of thymogen c 20 to patients with NASH not only determines the restoration of immunological homeostasis, but also normalizes the general condition and well-being of patients and, in clinical terms, promotes achieving a stable and long-term remission of NASH, as well as a significant reduction (in the future, the frequency of exacerbations of this disease, especially when repeated courses of thymogen administration are carried out and, thus, determines the achievement of the task of a useful model. In addition, the administration of thymogen has no contraindications, does not cause any - any unwanted side effects, including allergic reactions, and therefore this 29 drug can be prescribed in repeated courses if necessary, depending on the effect achieved. Previously, thymogen was not used for the purpose of correcting the immune status of patients with NASH.

The claimed method is carried out as follows. Patients with NASH who need correction of their immune status are given thymogen 5 Ωkg intramuscularly once a day for 7-10 days in a row against the background of conventional treatment. The laboratory criteria for the effectiveness of the appointment of thymogen are a clear trend towards the elimination of T-lymphopenia, an increase in the number of circulating T-helpers/inducers (СО4 7) and the normalization of the СО4/СО8 ratio, which indicates the restoration of immunological homeostasis. It is the introduction of thymogen that contributes to positive shifts in the above-mentioned laboratory (immunological) indicators in the pathogenetic aspect, and in the clinical aspect to the achievement of stable and long-term remission of NASH, as well as a significant reduction in the frequency of exacerbations of the disease in the future. Because the above-mentioned doses and courses of administration of thymogen were selected by us experimentally. It is at this frequency of administration of thymogen that the optimal dynamics of immunological parameters in the blood is ensured. Therefore, both the proposal for the introduction of thymogen, which is used by us for the first time in the correction of the immune status of patients with NASH, and the scheme of application of thymogen are new.

During the development of the claimed method, two groups of patients with NASH were examined: the main group (61 people), who underwent correction of the immune status according to the claimed method (thymogen), and a comparison group (57 people), who underwent correction according to the prototype method. Both groups of patients who were under observation were randomized by age, sex, stage of NASH and frequency of exacerbation of chronic pathological process in the liver. The introduction of thymogen began, as a rule, directly during the next exacerbation of NASH and 7/0 was carried out mainly in outpatient settings or in a day gastroenterology hospital.

Before the correction of the immune status of patients with NASH in both groups that were under supervision - the main one, which received immunocorrection according to the declared method, and the comparison, in which the immunocorrection was carried out in relation to the prototype method, there was the same clinical symptomatology of exacerbation of NASH, which was characterized by the presence of moderate heaviness in the right hypochondrium, pain or heaviness in the epigastrium, bitterness in the mouth, belching, constipation, or their alternation with diarrhea and flatulence. In such patients, moderate hepatomegaly, sensitivity of the liver edge during palpation, coating of the tongue with a dirty white or yellowish coating was revealed. According to the sonographic examination, along with hepatomegaly, there was an increase in the echo density of the liver.

In patients with NASH, immune disorders were characterized by the presence of T-lymphopenia of various degrees of severity and an imbalance of the subpopulation composition of T-lymphocytes, which mainly consisted in a decrease in the number of CO4 "cells (circulating T-helpers/inducers) on the background of a moderate decrease in the number of T-suppressors/killers (СОВ8'-lymphocytes), while the absolute content of B-cells (СО227) in the blood in most cases had only a moderate tendency to decrease (Table 1). Along with quantitative disorders on the part of the cellular link of the immune response in patients with NASH , who were under supervision, there was also a significant decrease in the functional activity of T cells, which was evidenced by a significant decrease in the indicator of RBTL with FGA. Fo « o Z x :z» indicators in the main group and the comparison group.

Changes in the cellular link of immunity in patients with NASH were characterized by a decrease in the number of circulating non-s. ! Y , , o , s in the peripheral blood of lymphocytes with the SOYUZ phenotype (T-lymphopenia) in the main group on average up to (0.78--0.03).109/l at the norm (1.3--0.05 ) 7)9o in relative terms (P"e0.01), which was 1.6 times less than the norm. In the comparison group, the decrease in the number of POP "-cells was 1.69 times in absolute terms and 1.61 times in relative counting (P<0.01). In addition, there was an imbalance in the subpopulation composition of T-lymphocytes, mainly due to a decrease in the number of lymphocytes with the "CO" phenotype, which are characterized by "helper activity" in the majority of observed patients, both in the main group and in the comparison group. Thus, in the main group, the number of T -lymphocytes with the СО4 phenotype" was on average (25.2--1.5)95 (with a norm of 45.3--1.390;

ReO.01), or (0.41--0.023.109/l (with a norm of 0.85--0.03.109/l; P«0.001), which was less than normal values by 1.8 and 25 2.1 times in relative and absolute calculation, respectively. The number of T-suppressors/killers (T-cells with a phenotype with SOV8" in the examined patients with NASH of the main group was (0.034--0.01).109/l (with a norm of 0.42--0 ,02.109/l;

Р«0.01) in absolute terms and (19.6--0.9) 95 (with a norm of 22.1-0.7790; Р«0.05) in relative terms. In this regard, the immunoregulatory index СО4/СО8 (TA/Т5) in the majority of those examined for NASH had a clear tendency to decrease, being on average 1.29 -0.04 in the main group and 1.24 -0, 03 in the comparison group (with a norm of 2.05--0.06; P«0.001). The level of B-lymphocytes changed slightly. Thus, the number of cells with the "СО22" phenotype was moderately reduced: in the main group of patients, on average, it was 1.24 times relative to the norm) and amounted to (0.33-0.02).109/l, and in patients from the comparison group - (0.32--0.01).109/l, which was 1.28 times lower than the norm (Р«0.05).

When determining indicators of cellular immunity, in addition to quantitative assessment of the content of the main populations and 65 subpopulations of T- and B-lymphocytes, the functional activity of the T-cell unit was also analyzed.

The RBTL indicator, which reflects the functional activity of T-lymphocytes, before the start of treatment in the main group was on average 1.75 times lower than normal (37.4-1.995; P«O0.001) and in the comparison group - 1.78 times below the norm (36.8-1.890; Р«0О.001) with a norm indicator (65.5--2.2) of 90. Thus, in all patients who were under supervision with a diagnosis of NASH, before the start of correction of immune status revealed a secondary immunodeficiency state. At the same time, changes in the immunological status in both groups of patients with NASH were the same in relation to the norm, which indicates the homogeneity of the examined groups in terms of immunology.

During the re-examination of patients with NASH after the completion of the immune status correction course, it was established that in the main group (in which the correction was carried out according to the stated method) in most cases, there was also an improvement in the general condition of the patients, a significant decrease in the frequency and severity of their 70 previous complaints, which characterized the presence of exacerbation of steatohepatitis.

At the same time, the patients of the comparison group, in which the correction was carried out according to the known prototype method, had much more frequent health complaints, which were the result of incomplete remission of the chronic pathological process in the liver. They were characterized by moderate heaviness in the right hypochondrium, bitterness in the mouth, the presence of belching, constipation or their alternation with diarrhea, and in a number of patients, heaviness in the epigastrium and flatulence.

During a repeated immunological examination after the correction of the immune status was completed, it was established that in the main group of NASH patients who received thymogen, the immunomodulatory effect of this drug was fully realized, which contributed to the normalization of the studied immunological parameters. Indeed, in the main group of patients with NASH (who were injected with thymogen), a clearly expressed positive dynamics of the studied immunological indicators was noted. At the same time, T-lymphopenia was eliminated, the number of circulating T-helpers/inducers increased (c047), and the ratio of СО4/СО8 normalized (Table 2).

As evidenced by the data presented in the table, the multiplicity of the increase in the number of the total T-lymphocyte population after the completion of immunorehabilitation of patients with NASH in the comparison group was 1.27 times (P "0.05), while in the main group - 1.63 times (which was equal to 1.27--0.03.109/l in absolute calculation; P«0.001 and 72.1--1.995 - in relative terms; P«e0.01). Along with a clear tendency to eliminate T-lymphopenia, when using thymogen in the immunorehabilitation of patients with NASH, we noted a significant increase in the number of T-helpers/inducers. At the same time, this indicator was (0.79-0.02).109/l in absolute (Р«0.001) and (44.6--1.2) 96 - in relative (Р«0.001) calculation, while in comparison group (0.064--0.01).109/l and (35.7--1.1) 96, respectively (Р«0.05). со со с mucoclic indicators | Norma | Basic blunt (1-6) | Comparison group? Rvozv sh s and their z z s sO22 9

And» pi ' and - . y y y c The number of cells with the phenotype СО8' in patients of the main group after the end of treatment with the use of thymogen was (0.41-0.01).109U/l (when the indicator in the comparison group was 0.4 -0.02.109/l ) in absolute and - 22.0--0.790 "in the comparison group - 21.9--0.790) - in relative calculation. A more positive dynamics of sl from the side of T-lymphocytes can be observed in patients of the main group who took thymogen as part of the treatment of NASH. This was reflected in the increase in patients of the main group of immunoregulatory index СО4/СО8 by an average of 1.53 times (which was 1.98-0.04; Р«О0.001), while in the comparison group the value of this index increased less significantly - in (with 1.91 times (Р«0.05).

Thus, the obtained data allow us to believe that the use of thymogen as a means of immunocorrection ensures almost complete normalization of the immune status of patients with NASH. Based on this, it can be assumed that

That thymogen has significant advantages over other drugs that were used in patients with NAST, in particular thymalin or tactivin, is well tolerated by patients, is affordable, is available in sufficient quantities in the pharmacy network of Ukraine, and therefore the use of this drug is promising in clinical practice.

We give specific examples of the use of the claimed method.

Example 1 60 Patient S., 38 years old, engineer. He has been suffering from NASH for the past 6 years and is registered at the city hepatology center. Exacerbations of steatohepatitis were 2-3 times a year, 4 times in the last year. In connection with the more frequent development of exacerbation of the pathological process in the liver during the last year, he was examined immunologically. At the same time, the presence of secondary immunodeficiency was established, in connection with which, during the period of the next exacerbation of NASH, correction of the immune status was carried out with the help of thymogen. bB Before the correction of the immune status in S., the following indicators of the immunogram were found: POP 7 - 4895 (0.77 G/l), СО4 - 2596 (04 G/l), СО8" - 1995 (0.93 G/l), СОМ/ SOV - 1.32, 20227 - 2095 (0.32G/l); RBTL - 38965. Thus, patient S. had T-lymphopenia, an imbalance of the subpopulation composition of T-lymphocytes, mainly with a decrease in the number of T-helpers (СО4 ) and immunoregulatory index СОМ/СОВ8, a moderate decrease in the absolute number of B-lymphocytes (СО227) and a significant suppression of the functional activity of T-lymphocytes (decrease of the RBTL index by 1.72 times relative to the norm).

In connection with the presence of an immunodeficiency state, along with the generally accepted treatment of exacerbation of NASH (appropriate regimen and diet, Karsil, essentiale H), patient S. received a course of correction of the immune status with the help of thymogen 50 mcg intramuscularly 1 time per day for 7 days in a row

During the repeated immunological examination after the completion of the course of immunocorrection, the following indicators of 70 immunograms were found: СО3" - 7295 (1.3G/l), СО47 - 4595 (0.8G/l), СО8" - 2295 (04G/l), СЯА /СОВ8 - 2.05, 20227 - 2295 (0.4G/l); RBTL - 6395. Thus, under the influence of thymogen, an almost complete normalization of the immunogram of patient S. was noted, namely, the elimination of T-lymphopenia, an increase in the number of circulating T-helpers (СО4"), normalization of the СО2/СОВ8 ratio, the number of B cells (СО22 "), increasing the RBTL indicator to the limit of the norm. Clinically, NASH remission was achieved during the period of immunocorrection. There were no side effects, including those of an allergic nature, for the introduction of thymogen.

According to dispensary supervision at the city hepatology center, there were no exacerbations of the pathological process in the liver for 1 year, NASH remission is quite stable. During immunological monitoring, the immunogram indicators did not significantly differ from the norm, that is, quite long-lasting results of immunocorrection were achieved.

Example 2

Patient M., 40 years old, a worker at a pharmaceutical factory. He has been in the dispensary register at the city hepatology center for NASH for 5 years, he notes exacerbation of steatohepatitis 3-4 times a year.

At another episode of exacerbation of NASH, an immunological examination was performed. Significant changes in the immunogram were noted, which had the character of secondary immunodeficiency. In this connection, the patient was recommended to correct the immune status. in

Before the start of immunocorrection, the following indicators of the immunogram were found: POPs" - 4695 (0.74G/l), CO4" - 2495 (0.38G/l),

CO. 2095 (0.32G/l), SOL/SOV8 - 1.2, 20227 - 19965 (0.3G/l); RBTL - 3695. Therefore, patient M. had significant abnormalities in immune parameters in the form of T-lymphopenia, imbalance of subpopulation composition with

T-lymphocytes, mainly with a decrease in the number of circulating T-helpers (Сс04") and the immunoregulatory index сСрасов, a significant suppression of the functional activity of T-lymphocytes according to RBTL (decrease of this с indicator by 1.82 times relative to the norm).

In connection with the presence of a clearly expressed immunodeficiency state, along with the generally accepted treatment of exacerbation of NASH (Essentiale H, Silibor), the patient was prescribed correction of the immune status according to

Зз5 with the help of thymogen with the introduction of this drug at 50 μg intramuscularly once a day for 10 days in a row.

During the repeated immunological examination after the completion of the immunocorrection, the following indicators of the immunogram were obtained: СО3З" - 7095 (1.26G/l), СО4" - 4595 (0.8G/l), СО8" - 2295 (04G/l), СОМ/СОВ - 2.05, C0227 - 2295 (0.4G/l); RBTL - 6395. Thus, it was established that during the correction of the immune status of the patient M. with the help of "thymogen, almost complete recovery of the immunogram parameters was achieved. At the same time, it was eliminated 2 with T-lymphopenia, the number of circulating T-helpers significantly increased (С0О4 7"), the number of СсОр227 cells (B-lymphocytes) and the immunoregulatory index СО4/СО8, as well as the RBTL index, normalized. » Clinically, NASH remission was achieved during immunocorrection with thymogen. Conducting dispensary supervision for 1 year made it possible to establish the duration of clinical and biochemical remission of the disease. At the same time, according to the data of immunological monitoring, during the entire period of dispensary supervision, such indicators of the immunogram were maintained that corresponded to the limits of the norm. - Therefore, the use of the declared method of correction of the immune status ensures the achievement of the task of a useful model. Among the examined patients of the main group, there were no allergic reactions to the introduction of thymogen. In the 1 comparison group, moderately pronounced allergic reactions to the administration of thymalin were detected in 2 patients (3,590) in the form of allergic dermatitis and urticaria, in connection with which the administration of thymalin was stopped in these patients, and desensitizing therapy (fencarol) was prescribed. se" Thus, the obtained data allow us to believe that the claimed method has significant advantages over the prototype method, which are characterized by a more pronounced tendency to normalize immunological indicators, and in clinical terms - the achievement of stable and long-term remission of NASH, the absence of further exacerbations. In this regard, the conditional economic effect when using the claimed method is about UAH 189 per 1 patient. The method is useful and therefore it can be recommended for wide use in clinical practice.

Claims (2)

The formula of the invention 1. The method of correcting the immune status of patients with non-alcoholic steatohepatitis, which includes the administration of immunocorrective drugs, which differs in that thymogen is administered as an immunocorrective drug. 2. The method according to claim 1, which differs in that 50 μg of thymogen is administered intramuscularly once a day for 7-10 days in a row. b5 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 7, 10.04.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - so so iv) h- so - s;" z - 1 z Se c 60 b5