RU2472498C1 - METHOD OF TREATING CHRONIC GASTRODUODENITIS ASSOCIATED WITH INFECTION CAUSED BY BACTERIA Helicobacter pylori IN ALLERGIC DISEASES - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gastroenterology, allergology and immunology, and may be used for treating chronic gastroduodenitis associated with an infection caused by bacteria Helicobacter pylori (H.pylori). What is presented is a method of treating chronic gastroduodenitis associated with the infection caused by bacteria Helicobacter pylori in the patients with allergic diseases, involving a therapeutic course of eradication wherein the therapeutic course of eradication is preceded by prescribing the probiotic ecoflor and the immunomodulator tiloron with underlying permanent basic therapy of the allergic disease; the therapeutic course of eradication is also followed by prescribinf ecoflor and tiloron simultaneously. For the purpose of HP-infection eradication, there may be prescribed particularly clarithromycin, lansoprazole and metronidazole lymphotropically.

EFFECT: method provides higher clinical effectiveness of chronic gastroduodenitis associated with the infection caused by bacteria H Pylori in the patients with allergic diseases.

6 cl, 4 tbl, 2 ex

Description

The invention relates to medicine, namely to gastroenterology, allergology and immunology, and can be used to treat chronic gastroduodenitis associated with an infection caused by bacteria Helicobacter pylori (H. pylori) in patients with allergic diseases.

Approximately more than 60% of the world's population is currently infected with the bacteria Helicobacter pylori (HP) [1]. In recent years, the role of HP bacteria in the development of coronary heart disease, atherosclerotic lesions of the blood vessels of the brain, a number of autoimmune diseases, and also allergic conditions has been closely studied. There is evidence-based evidence of the association of this infection with chronic gastritis, gastroduodenitis, peptic ulcer of the stomach and duodenum, urticaria, malignant tumors of the stomach - adenocarcinoma and extranodal B-cell lymphoma [2]. According to the data of P.Ya. Grigoriev et al., In Russia every 10th adult suffers from certain diseases of the digestive system, which puts the diagnosis of HP infection and the selection of optimal treatment regimens for this infection among the most important tasks of modern medicine.

Chronic inflammatory process in the gastrointestinal tract, associated with HP infection, in about 40-50% of cases causes chronic urticaria, which is accompanied by 50% detection of antibodies to the high affinity IgE receptor [3]. In 40 of 107 children with chronic urticaria, IgG antibodies to HP were detected. At the same time, active gastritis was confirmed in 30 of 32 HP-positive patients, and increased IgE was determined in 64% of HP-positive and in 39% of HP-negative patients. The eradication of HP infection did not lead to a complete cure, however, it reduced the severity of the process and reduced the need for antihistamines.

In accordance with the recommendations of the Consensus Maastricht-3 [4], indications for the eradication of H. pylori bacteria are:

peptic ulcer of the stomach and (or) duodenum (regardless of the stage of the disease);

MALT ohm;

atrophic gastritis;

conditions after resection for gastric cancer;

close relatives of patients with cancer of the stomach;

functional dyspepsia;

gastroesophageal reflux disease (GERD);

long-term use of non-steroidal anti-inflammatory drugs;

iron deficiency anemia of unknown origin;

idiopathic thrombocytopenia.

Important requirements for the eradication therapy of HP infection were published in the Recommendations for the diagnosis and treatment of H. pylori infection in adults with peptic ulcer of the stomach and duodenum of the Russian Gastroenterological Association and the Russian group for the study of bacteria H. pylori [4]:

- in controlled studies, achieve the destruction of H. pylori in at least 80% of cases with a course duration of no more than 7-14 days;

- cause no more than 5% of side effects requiring a forced withdrawal of therapy by a doctor or patient discontinuation of medication according to the scheme recommended by the doctor.

H. pylori bacteria are sensitive to the vast majority of penicillin antibiotics and most cephalosporins (cefuroxime, cefoxitin, cephalexin), and their minimum inhibitory concentration for 90% of the bacteria does not exceed 0.5 mg / l.

In vitro macrolides and fluoroquinolones also show rather high activity against H. pylori bacteria and their MPC-90 below 0.5 mg / L. Antibiotics of other groups (gentamicin, tetracycline, rifampicin) are also very effective. Metronidazole and nitrofurans when taken by mouth have less activity than antibiotics.

Among the antiulcer drugs, none have significant activity against H. pylori bacteria in vitro, except for bismuth salts, tripotassium dicitrate (De-nol), subsalicylate, subgallate.

Despite the in vitro activity, when prescribed in vivo, the above listed antibacterial drugs are not at all so highly effective. One of the reasons for this is a decrease in the activity of antibacterial drugs in the acidic environment of the stomach. It was shown [5] that the activity of penicillin and ampicillin in an acidic environment decreases more than 10 times, cephalexin - 16 times, ciprofloxacin - 10 times, and erythromycin - more than 100 times. The latest generation macrolides (clarithromycin, Vilprafen® Solutab), unlike erythromycin, are much more stable in an acidic environment. A slight change in activity is observed in tetracycline and furazolidone. The activity of metronidazole and de-nol does not change at acidic pH values, so they are successfully used in the treatment of HP infection.

In our country, as the first line eradication therapy, P.Ya. Grigoriev and Yakovenko E.P. [6] recommended the following schemes:

PPI, de-nol and amoxicillin for 10 days;

IPP, De-nol (10 days), amoxicillin (first 5 days) and josamycin (subsequent 5 days);

PPI, amoxicillin and nifuratel or nifuroxazide (10 days).

Monitoring the effectiveness of therapy (achieving eradication) is carried out 4-6 weeks after the end of treatment. For control, it is advisable to use non-invasive methods, primarily respiratory (C13-carbon test or Helik-test). With a negative test result (eradication of H. pylori bacteria), further treatment is not required.

If the result is positive, repeated therapy is carried out according to a different scheme, using other antibiotics, in particular, a classic second-line scheme can be prescribed - quadrotherapy, including PPI, Denol, tetracycline (from 12 years old) and metronidazole [6]. If nitrofurans were not used during the first-line therapy, then nifuratel or nifuroxazide is prescribed instead of metronidazole.

In the studies of several authors, it was found that pathogenic H. pylori strains are able to realize their cytotoxic effect against the background of a decrease in both the local protective mechanisms of the mucous membranes of the gastrointestinal tract and systemic immunity, are able to evade the control of specific immunity mechanisms and to the formation of immunodependent forms of inflammation [7].

HP bacteria in connection with the production of a number of enzymes are capable of exerting an immunosuppressive effect, in particular, actively influencing the differentiation of T-lymphocytes in the direction of the prevalence of Th-2 type and aggravate the allergic process. Many researchers have described that Th1 and Th2 negatively affect the activity of opposite clones, and excessive activation of one of the types of T-helpers, normally in equilibrium, can direct the immune response according to one of the development options [8].

Immune imbalance in infection caused by HP bacteria is manifested by a violation of non-specific defense factors, namely: a decrease in lysozyme, bacterial activity of serum and complement, an increase in the content of immunoglobulin G, and deep violations of the T-cell immunity: a decrease in the relative content of total lymphocytes and T-lymphocytes (CD3), a decrease in T-helpers (CD4) and an increase in T-cytotoxic (CD8), especially pronounced during a prolonged course of the inflammatory process. In addition, the causative agents of Helicobacter pylori infection (HP infections) extremely quickly change their properties, are capable of recombination between circulating strains, and this underlies their growing resistance to antibiotics [9].

Since microorganisms are able to change local and general immunity, to evade a specific immune response, the appointment of immunomodulators is additionally required. Injections of cycloferon and derinate were used, and imudon and lycopid, which have anti-infective and anti-inflammatory effects, were prescribed by mouth.

However, their mechanism of action is different.

Cycloferon, for example, is a low molecular weight inducer of interferon with pronounced interferonogenic activity that lasts for three days, which determines, first of all, its high antiviral activity. Cycloferon also has an immunomodulatory and anti-inflammatory effect. The main producing cells of interferon after the introduction of cycloferon are macrophages, T and B lymphocytes.

Derinat has a modulating effect on the cellular and humoral parts of the immune system and nonspecific resistance of the body, which leads to the optimization of the inflammatory response and the specific immune response to bacterial, viral and fungal antigens.

Imudon is a mixture of bacterial lysates, including Lactobacillus acidophilus, Lactobacillus delbrueckii ss lactis, Lactobacillus helveticus, Lactobacillus fermentum, Streptococcus pyogenes groupe A, Streptococcus sangius groupe H, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae ss pneumoniae, Fusobacterium nucleatum ss fusiforme, Corynebacterium pseudodiphtheriticum, Candida albicans, for local application in dentistry and otorhinolaryngology. It increases the content of salivary lysozyme, helps to increase the number of immunocompetent cells, and increases the content of secretory immunoglobulin A in saliva.

Lycopid - glucosaminyl-muramyl dipeptide, stimulates the bactericidal and cytotoxic activity of phagocytes, enhances the proliferation of T and B lymphocytes, increases the synthesis of specific antibodies and is mainly used for chronic infections of the lungs, skin and soft tissues.

All of the above immunomodulatory drugs have a positive effect on the course of the chronic inflammatory process, but practically do not affect the differentiation of T-lymphocytes, which reduces their effectiveness in the treatment of diseases of the gastrointestinal tract in patients with atopy [9].

Evaluation of the effectiveness of eradication therapy by immunological parameters when using these immunomodulatory drugs was carried out only before and after treatment, and was not traced for a longer period, except for imudon, where only indicators of pro-inflammatory cytokines in saliva were evaluated after a year. However, immunological disorders were characterized by a longer period of preservation of activity of T-cells - Th-2 type, which was manifested by the absence of a tendency to decrease in the level of TNFa, IL-6, IL-8 after a course of traditional eradication therapy and did not affect the suppression of HP infection.

According to its biological effect of the above immunomodulating drugs for HP infection, the most favorable immunomodulating effect was obtained with cycloferon. However, immunological indicators of the activity of the inflammatory process were studied only before and after eradication therapy after 4 weeks, which does not allow us to judge the effectiveness of eradication therapy in longer periods.

Eradication therapy of both the first and second lines was supplemented by the appointment of modern probiotics. Studies conducted both in Russia and abroad showed an increase in the effectiveness of treatment and a decrease in adverse reactions with the parallel appointment of probiotics. When using the standard triple first-line regimen with parallel administration of the Linex probiotic, an increase in the percentage of eradication of H. pylori bacteria was shown to increase from 84% to 92%, and the frequency of side effects of eradication therapy was reduced [10].

It was shown that with the endolymphatic and lymphotropic methods of administering antibiotics, their concentration in the lymph was 2-4 times higher than with the traditional method of administration. The main transporters of the antibiotic to the site of inflammation are lymphocytes, which are capable of adsorbing up to 50% of the antibiotic located in the lymph node on its surface, while the concentration of the antibiotic on the lymphocyte is 10 times higher than in the liquid part of the lymph and blood [11].

The endolymphatic administration of metronidazole at a dose of 688.7 μg / ml is accompanied by the achievement of this concentration in lymph within 1 hour after administration. After 24 hours, the dose is reduced by only 50% and at the therapeutic dose (2.1 μg / ml), 72 hours remain. After the introduction of T-activin, directly into the lymphatic vessel on the right foot, already on the 2nd day after surgery on the abdominal organs, dendritic macrophages cooperate with T-lymphocytes and plasma cells, which contributes to the synthesis of class A, M, G immunoglobulins [ 12].

Thus, endolymphatic and lymphotropic therapy allows you to:

- create a high concentration of drugs in the lymphatic system, in the tissues of the localization of the pathological focus;

- reduce the dose of toxic drug substance, without loss of effect;

- reduce the toxic effect of the drug substance;

- affect lymph (composition, rheology, metabolism);

- optimize the functions of the lymph nodes (barrier, metabolic, immune, etc.).

The immunomodulatory effect of probiotics expands the possibilities of their use and opens up wider prospects for the use in complex eradication therapy of HP infection. The effectiveness of probiotics in the treatment of HP-associated gastroduodenal diseases in children has been shown. At the same time, a high percentage of reinfection was also noted, which was approximately 20% per year in children [13].

The efficacy of Lactobacillus reuteri bacteria in children [14] was assessed against the background of sequential therapy (5 days omeprazole and amoxicillin, then 5 days omeprazole and clarithromycin + tinidazole) and a decrease in dyspepsia symptoms against the background of probiotic was shown (4.1 versus 6.2 points) . Under the condition of acid resistance of the strain (and it is proved for S. boulardii, L. rhamnosus GG, L. reuteri, L. plantarum, L. acidophilus) probiotics can have a direct antagonistic effect against HP bacteria. They can compete with HP for nutrients, produce metabolites that inhibit their growth (volatile fatty acids, lactic acid, hydrogen peroxide, pyroglutamate).

Many strains produce bacteriocins - antibacterial substances that inhibit the growth of other microbes, and the adhesion of probiotics to the intestinal epithelium ensures their interaction with the local immune system. [fifteen].

All of the above gives reason to include probiotics in the program of eradication therapy of gastroduodenitis in patients with allergic diseases.

A known method of treating Helicobacter-associated chronic duodenal ulcer [16] by drug therapy, including the introduction of colloidal bismuth subcitrate, omeprazole, amoxicillin, furazolidone, in addition to this, an immunomodulator - lycopide (at a dose of 10 mg orally 1 day later was added 1 day tomorrow) 10 days).

The inclusion of an immunomodulator of lycopide in the treatment program for HP infection increased the effectiveness of eradication therapy, but did not allow to track its effectiveness in a longer period, which entailed repeated courses of antibacterial therapy, and this increased the percentage of side effects, especially in patients suffering from allergic diseases.

This method uses only a short course of immunomodulating therapy without taking into account the severity of immunological disorders and changes from the intestinal microflora. The nature of immunological changes in the long term (36 months) is also not traced, which does not make it possible to fully judge the effectiveness of eradication therapy after the inclusion of this immunomodulator.

Given the effect of bacteria of HP infection on the state of local and general immunity, the likelihood of recurrence of HP infection increases as the positive effect of the immunomodulator on the state of the immune response decreases. According to the annotation to lycopid, it is known that its protective effect lasts up to 6 months. In addition, this method was used in patients without indicating the presence of allergic diseases.

There is a method of complex treatment of duodenal ulcer associated with Helicobacter pylori [17], which is administered omeprazole, amoxicillin, clarithromycin and a local immunomodulator Imudon 8 tablets per day with an interval of 2-3 hours for resorption in the oral cavity for 10 days . The effectiveness of eradication therapy was monitored throughout the year.

The disadvantage of the proposed method is that imudon was used in a single short course and its immunomodulating effect lasted only 3-6 months. In this case, the effectiveness of eradication therapy after the use of imudon was evaluated only by indicators of local immunity of the oral mucosa, without taking into account changes in the systemic immune response and the mucosa of the lower gastrointestinal tract, as well as changes in the intestinal microflora.

In addition, in patients with allergic diseases, the administration of amoxicillin is always dangerous due to the development of adverse allergic reactions due to the high degree of sensitization of this group of patients to fungal allergens and house dust mite allergens.

A known method of treating diseases associated with infections caused by Helicobacter pylori bacteria, comprising administering a drug in the form of tablets or capsules, which contains, in particular, lansoprazole, clarithromycin and / or metronidazole [18] (RU 96120184, A61K 45/06, 09/20, 09.20 .1999).

The disadvantage of all the proposed methods of treating diseases associated with HP infection in patients with allergies is the rapid formation of resistance to antibacterial drugs of HPA causative agents, the presence of frequent allergic reactions and dysbiotic disorders in traditional eradication therapy only with PPIs and antibacterial drugs, or when using traditional therapy only with an immunomodulator, or only with a probiotic.

The objective of the invention is to increase the effectiveness of the treatment of chronic gastroduodenitis associated with an infection caused by bacteria Helicobacter pylori in patients with allergic diseases and to eliminate the disadvantages of the known methods.

The proposed method is as follows.

A method for the treatment of chronic gastroduodenitis associated with an infection caused by Helicobacter pylori bacteria in patients with allergic diseases consists in prescribing a probiotic - ecoflor and an immunomodulating drug - tiloron against the background of constant basic treatment of an allergic disease, and after the course eradication is again prescribed ecoflora and at the same time the second course of tilorone.

At the same time, in the first year, ecoflor is prescribed 5 g 2 times a day 15 minutes before meals for 15 days, and Tiloron, by mouth, after meals, 250 mg per day for the first day, then Tiloron 125 mg per day every 48 hours 4 more times (750 mg for the first course).

After eradication, ecoflor is prescribed 5 g 2 times a day 15 minutes before meals for 15 days, and tiloron 125 mg after meals, every 48 hours for 28 days.

For eradication of HP infection, in particular, clarithromycin, lansoprazole and lymphotropic metronidazole can be prescribed.

In this case, clarithromycin is used before meals, 500 mg 2 times a day for 7 days, lansoprazole, before meals, 30 mg 2 times a day for 14 days, and metronidazole 50 mg once a day for 10 days.

Metronidazole is injected lymphotropically into the region of the inguinal lymph nodes, 50 mg in 100 ml of saline dropwise 1 time per day for 10 days, while the place of metronidazole administration is alternated: one day - in the right inguinal region, another day - in the left.

1250 mg (10 tablets) are used for a second course of tilorone and 2000 mg (16 tablets) for the entire course of immunomodulating therapy.

Ecoflor - a combined preparation with active lactobacilli and bifidobacteria immobilized on enterosorbent, is a probiotic. The Ecoflor preparation used a consortium of antagonistically active bifidobacteria of the species Bifidobacterium bifidum and Bifidobacterium longum, as well as lactobacilli of the species Lactobacillus casei, Lactobacillus plantarum and Lactobacillus acidophilus. The basis of enterosorbent is composed of structured activated carbon particles coated with a second layer - minerals that provide selective sorption activity and enhance the difference between external and internal pressure. Manufacturer - Vector-BiAlgam company (abstract for the drug). In the intestine, these bacteria “land” from the sorbent and actively fill the intestinal tract. The combination of beneficial bacteria and sorbent can significantly increase their protection when passing through the stomach, where conventional dry preparations lose more than 90% of their activity.

Tiloron is a low molecular weight synthetic inducer of interferon, which stimulates the formation of alpha, beta and gamma interferons in the body. The main producers of interferon in response to the introduction of tilorone are intestinal epithelial cells, hepatocytes, T-lymphocytes, neutrophils and granulocytes.

After taking Tiloron inside, the maximum production of interferon is determined in the sequence intestine - liver - blood after 4-24 hours. In human leukocytes, it also induces the synthesis of interferon, stimulates bone marrow stem cells, depending on the dose, enhances antibody formation, reduces the degree of immunosuppression, and restores the ratio of T-suppressors and T-helpers. In addition, tilorone increases the expression on the cell membranes of antigens of the main histocompatibility complex of class 1 (HLA) and class 2 (HLA-DR), necessary for the development of a specific protective immune response, increases the number and activity of NK cells, and causes targeted polarization of Th0 mainly Th1-type response modulates the inflammatory response depending on the phase of inflammation [9].

Lansoprazole is a specific inhibitor of H ⁺ -K ⁺ -ATPase. It is metabolized in parietal cells of the gastric mucosa to active sulfonamide derivatives that inhibit sulfhydryl groups of H ⁺ -K ⁺ -ATPase. It blocks the final stage of hydrochloric acid secretion, reducing basal and stimulated secretion, regardless of the nature of the stimulus (annotation to the drug).

The most active against HP bacteria is clarithromycin. Unlike other macrolides, which in an acidic environment undergo enhanced hydrolysis, clarithromycin is stable in gastric acid. Monotherapy with clarithromycin leads to the destruction of HP in 54% of cases [19]. Clarithromycin also has a mild immunomodulatory effect, has little effect on the intestinal microflora (annotation to the drug).

Metronidazole is an antiprotozoal and antimicrobial drug derived from 5-nitroimidazole. The mechanism of action is the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with the DNA of the cell of microorganisms, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria. Indications for use are giardiasis, cutaneous leishmaniasis, trichomonas vaginitis, trichomonas urethritis, gastritis or duodenal ulcer associated with Helicobacter pylori (drug summary).

The diagnosis of gastroduodenitis associated with HP infection in patients with a verified diagnosis of allergic diseases was confirmed by the following methods:

1. The endoscopic method (fibrogastroduodenoscopy using a fiberoscope of the company “Olimpus” -Japan) - to detect changes in the gastric mucosa characteristic of gastritis, duodenitis, peptic ulcer, as well as to take targeted biopsy of the mucous membrane of the antrum and fundus to conduct morphological research and PCR diagnostics to detect the DNA of HP bacteria.

When analyzing structural changes, the activity, severity of the process and the nature of the structural changes in the gastric mucosa were taken into account according to the Houston modification of the Sydney classification system for gastroduodenitis. For this, a visual-analogue scale of morphological changes in the mucosa was used (according to M.Dixon et al., 1996). HP bacteria were detected in smears of the mucous membrane stained by Giemsa-Romanovsky.

2. The molecular biological method of polymerase chain reaction (PCR). The method was used to identify in the clinical material (gastric juice, biopsy) specific fragments of the Helicobacter genomic DNA of the banal HP strain, as well as the DNA locus of the toxigenic strain responsible for the production of vacuolating toxin (DNA-technology banal and toxigenic strain test kits ").

3. A urease test in exhaled air (aerotest - Helppile test manufactured by LLC "AMA", St. Petersburg), in which the content of ¹⁴ C is determined in exhaled air after the patient has ingested urea previously labeled with these isotopes. The test is based on the ability of HP bacteria to break down urea to ammonia and carbon dioxide using urease and makes it possible to determine their presence or absence after 5-30 minutes.

4. An enzyme-linked immunosorbent assay for detecting antibodies against HP bacteria of the IgA, IgM, IgG class in blood serum and for detecting cytotoxic HP strains (expressing CagA protein) using the HelikoBest-antibody test system (Vector-Best, Novosibirsk) according to the attached a set of instructions. The ELISA method is auxiliary and may reflect the activity of the inflammatory process and the level of specific immune response.

The advantage of the method is that it reveals the fact of infection not only with manifest, but also with subclinical forms, as well as in the stage of remission of the disease. In some cases, a weak immune response is noted, which makes it difficult to verify antibodies against H. pylori bacteria.

In addition, the titer of antibodies decreases slowly after a course of eradication therapy, and before 5-6 months it is not possible to evaluate the effectiveness of therapy for this test.

5. Ultrasound examination (ultrasound) of the abdominal organs, which was carried out by the apparatus Sim 7000 CFM challenge (Italy) to clarify the concomitant pathology of the pancreas, liver, gall bladder.

At the first stage, we conducted a comparative study of the effectiveness of eradication therapy of chronic gastroduodenitis associated with HP infection in patients with allergic pathology with various methods of using metronidazole: per os and its lymphotropic administration.

The indicators of endogenous intoxication, local and general immunity were studied against the background of the following therapy: clarithromycin before meals 500 mg 2 times a day - 7 days, lansoprazole before meals 30 mg 2 times a day - 14 days and metronidazole after meals 0.25 g 4 times a day for 10 days with the subsequent intake of ecoflora 5 g 2 times a day 15 minutes before meals for 15 days - 1 group (n = 68).

Patients of group 2 (n = 72) underwent eradication of HP infection by applying clarithromycin before meals 500 mg 2 times a day for 7 days, lansoprazole before meals 30 mg 2 times a day for 14 days and metronidazole was administered lymphotropically, in the region of inguinal lymph nodes, 50 mg in 100 ml of saline drip - 10 injections 1 time per day with subsequent administration of ecoflora 5 g 2 times a day 15 minutes before meals for 15 days.

The places of lymphotropic administration of metronidazole were alternated (one day in the right inguinal region, the other day in the left) in order to prevent complications in the form of infiltrates at the injection site.

According to our proposed method, negative results on the urease test after 4 weeks in only 1 group were observed in 84% of patients and in group 2 - in 93%, the frequency of allergic reactions decreased (it was recorded in group 1 in 7.6% of cases and in 2 group - in 1.2%) and dysbiotic deviations in the feces (respectively in 12.4% and 9.2% of cases).

Thus, the study showed an increase in the effectiveness of the treatment of chronic gastroduodenitis associated with HP infection in patients with allergic diseases and a decrease in the frequency of allergic reactions.

At the second stage, we examined 242 patients with a verified diagnosis of chronic gastroduodenitis at the age of 16-49 years, average age 32.4 ± 6.7; m - 134, g - 108. Of 242 patients, HP infection was confirmed in 198 patients (81.8%), m - 140 and g. - 102, of which 63 patients had allergic pathology (31.8%), who, along with the traditional clinical laboratory and endoscopic examination, determined the Leukocyte intoxication index (LII).

LII was calculated according to the formula before and 4 weeks after the course of eradication therapy, as well as after 12 and 36 months:

,

,

where ML - myelocytes, P - stab cells, C - segmented cells, Pl - plasma cells, L - lymphocytes, Mon - monocytes, E - eosinophils in a peripheral blood smear stained according to Romanovsky-Giemsa. An increase in LII indicates an increase in the level of endogenous intoxication and activation of tissue decay processes (normal = 0.74 + 0.11). The inflammatory process markers were also examined: Asl-O (quant.), C-RB (quant.), RF (quant.), Total protein, protein fractions. As a control of LII, biochemical and immunological parameters were determined in donors of the same age group (n = 28).

Assessment of the immunological status included determination of the total number of T and B lymphocytes, subpopulations of T lymphocytes, and the level of immunoglobulins A, M, G [20].

The parameters of cellular immunity (CD3 +, CD4 +, CD8 + lymphocytes) were determined using a set of monoclonal antibodies using test systems for ELISA Vector-Best, Novosibirsk. Quantitative determination of indicators of humoral immunity (immunoglobulins A, M, G) was carried out by the method of radial immunodiffusion according to Mancini using monospecific serums against IgA, IgM, IgG produced by the Nizhny Novgorod Research Institute of Epidemiology and Microbiology of the Ministry of Health of the Russian Federation.

The levels of IgE and sIgA were determined by ELISA using the Vector-Best test system, Novosibirsk [21]. Imbalance in the Th1 / Th2 system - in the dynamics before and after eradication therapy - in terms of the level of pro-inflammatory cytokines: IL-1 β, TNF-α, INF-γ and IL-10 by enzyme-linked immunosorbent assay (ELISA) using the test system LLC "Cytokine ”, St. Petersburg [22].

A control examination was performed 4 weeks after the end of anti-Helicobacter therapy (endoscopic method, morphological method with HP determination, molecular biological method with determination of specific DNA fragments of HP bacteria, immunoserological method).

At an endoscopic examination of 242 patients, duodenal ulcer (YAB duodenal ulcer) was found in 29 patients (12%); erosion of the stomach and / or duodenum - in 101 (41.6%); chronic (non-erosive) gastritis / gastroduodenitis - in 112 (46.4%). 79 patients (32.8%) had concomitant allergic diseases. Allergopathology was represented by bronchial asthma (9 patients), atopic dermatitis (11 patients), allergic rhinoconjunctivitis (12 patients), recurrent urticaria (47 patients).

In patients with allergopathology, endoscopic examination determined damage to the gastric and duodenal mucosa, where chronic gastroduodenitis predominated (in 91% of cases).

The diagnosis of HP infection was confirmed by the urease test, cytological method, PCR method and enzyme-linked immunosorbent assay (ELISA) in the blood serum, where the level of IgG and IgA antibodies to HP was determined; antibodies to HP CagA protein.

The effectiveness of eradication therapy was controlled by a urease test in exhaled air, the dynamics of LII.

Using simple randomization, patients were divided into 2 groups, comparable in age, clinical manifestations and social conditions.

Patients of group 1 (n = 118) received therapy: clarithromycin before meals, 500 mg 2 times a day - 7 days, lansoprazole before meals - 30 mg 2 times a day - 14 days, and metronidazole 0.25 g 4 times a day day for 10 days, followed by eco-flora 5 g 2 times a day 15 minutes before meals for 15 days.

Patients of group 2 (n = 124) underwent treatment: before a course of eradication therapy, against the background of constant basic therapy of an allergic disease, a probiotic-ecofloor was administered 5 g 2 times a day 15 minutes before meals for 15 days and an immunomodulating drug - tiloron, inside , after eating, 250 mg per day for the first day, then tiloron - 125 mg (1 tablet) per day every 48 hours - another 4 tablets (for the first course - 750 mg - 6 tablets).

Next, patients of the 2nd group were eradicated by HP infection by applying clarithromycin before meals 500 mg 2 times a day for 7 days, lansoprazole before meals 30 mg 2 times a day for 14 days and metronidazole lymphotropically to the inguinal lymph nodes , 50 mg in 100 ml of saline drip - 10 injections 1 time per day. The place of lymphotropic administration of metronidazole was alternated: one day - in the right inguinal region, another day - in the left.

After a course of eradication therapy, ecoflora was again prescribed 5 g 2 times a day 15 minutes before meals for 15 days and a second course of tilorone 125 mg (1 tablet) after meals, every 48 hours for 28 days. For a second course of tilorone - 1250 mg (10 tablets) and for the entire course of immunomodulating therapy - 2000 mg (16 tablets).

The clinical picture of chronic gastroduodenitis (CG / D) in patients of the 1st and 2nd observation groups was almost the same and was characterized by severe subjective symptoms in 80% of cases and the prevalence of dyspeptic syndrome over pain.

IgA-AT to H. pylori was detected with high frequency in the blood serum of patients with gastroduodenal diseases without allergy, while in patients with allergy IgA-AT to H. pylori was detected 3-4 times less often.

The weakly expressed IgA response to H. pylori in most patients with allergies apparently reflects a low ability to produce IgA in general, which is typical for people with allergic diseases. IgA-AT titers for HP in the blood serum of healthy individuals were lower than in patients.

The level of IgG antibodies to HP bacteria gradually increased during treatment and remained at elevated values for up to 4 weeks with CG / D. Secretory IgA (sIgA), being the most important factor in the protection of the gastrointestinal mucosa (GI CO), provides the immune exclusion of microorganisms, maintains its structure for a long time, and is not cleaved by microbial proteases.

In patients without allergic pathology, the level of sIgA in the exosecret of the oral cavity exceeded normal values (57-260 μg / ml) in 66% of cases, and in patients with allergopathology, an increase in sIgA level compared to the norm was noted only in 25% of cases (p <0.05 ) The level of serum antibodies of the IgE class was elevated both in patients with atopy and without atopy in CG / D.

LII was significantly increased in all patients with CG / D and exceeded the performance of healthy patients by 2.5 times.

Markers of inflammation had no statistically significant deviations compared with healthy patients.

Against the background of the therapy, clinical symptoms in patients of the 1st group persisted 7.6 ± 1.4 days, in patients of the 2nd group - 4.9 ± 1.4 days. An excellent clinical effect was obtained in 62.7% of patients in group 1 and 74.2% of patients in group 2. Good effect, respectively, in 22.8% and 21.7% at p <0.05.

Eradication of HP infection after the first course of treatment was achieved in patients of the 1st group in 78% of cases and in patients of the 2nd group in 93%. The level of IgG antibodies to HP remained at elevated values up to 5 weeks in patients of the 1st group and up to 8 weeks in the 2nd group. The relapse rate after a course of eradication therapy during the first year of observation was in 14.3% of cases in patients of the 1st group and, accordingly, 4.8% in patients of the 2nd observation group.

After 3 years, this indicator increased for the 1st group to 23.8% and in the 2nd group to 7.5% at p <0.005.

Under the influence of the therapy, the frequency of detecting an increased level of IgE in the patients of the 1st group and by 4 times in the patients of the 2nd group decreases by almost 2 times. (Table 1).

When analyzing the indicator of endogenous intoxication - LII, there is a more pronounced decrease in this value in patients of group 2. As can be seen from the data presented in Table 2, LII decreased by 0.6 in patients of the 1st group and by 0.96 in patients of the 2nd group, which indicates a decrease in the inflammatory process in the gastrointestinal tract.

The data in Table 3 confirm the change in the production of cytokines in the direction of increasing INF-γ, which reduces the severity of T-helpers.

From the data of Table 4 it can be seen that tilorone helps to reduce the level of IL-10 and increase the ratio of INF-γ / IL-10, which indicates a change in the imbalance of Th1 / Th2 towards Th1 and a decrease in the clinical manifestations of the allergic process against the background of more effective eradication therapy according to the scheme.

All the data presented confirm that in patients with allergic diseases suffering from gastroduodenitis associated with HP infection, the observation group 2 shows a higher efficiency of eradication therapy of HP infection.

Thus, the use of chronic gastroduodenitis associated with the infection caused by Helicobacter pylori bacteria in complex therapy for allergic diseases of the immunomodulating drug tilorone in combination with ecoflora significantly increases the effectiveness of the therapy.

The possibility of implementing the proposed method is confirmed by the following examples, but is not limited to.

Example 1

Patient S., 24 years old. Suffers from atopic asthma, controlled, and corticosteroids (inhalation of flixotide 125 mcg 2 times a day for the last 5 years), allergic seasonal and year-round rhinitis, remission. Sensitization to house dust mites and birch pollen. Passed 3 courses of ASIT with a good clinical effect. 2 years ago, pains in the epigastric region, nausea after eating and heaviness in the epigastric region on an empty stomach joined. Gastroscopy revealed chronic diffuse gastroduodenitis, gastroesophageal reflux, and HP infection. He turned to a gastroenterologist, 120 mg pilocide therapy was prescribed 4 times a day in combination with tetracycline 250 mg 4 times a day and tinidazole 500 mg 2 times a day for 10 days. However, on the 3rd day from the start of treatment, the patient was forced to discontinue therapy due to severe skin itching, an urticaria rash on the trunk and extremities, and swelling of the face. The patient was also disturbed by bloating, unstable stool, and an admixture of mucus in the feces. He continued treatment at the gastroenterologist with suprastinum in oil of 2.0 ml No. 5, zirtek of 10 mg / day for 10 days, linex 2 drops 2 times a day for 3 weeks. Antibacterial therapy has been canceled.

When contacting the department of immunology one year after the deterioration of the pathology of the gastrointestinal tract. He complained of constant pain in the epigastric region, heartburn after each meal, bloating, unstable stool, an admixture of mucus in the feces, the patient occasionally had itchy skin and elements of an urticaria rash appeared. Tried to be treated independently with antihistamines.

Endoscopically - signs of chronic gastroduodenitis, superficial erosion in the pyloric region, in the biopsy by PCR revealed HP infection, urease breath test - positive (+ 26.7% above the baseline), H. pylori IgA-ATK. - 1: 118, LII - 1.88. The treatment was prescribed: before the course of eradication therapy, the patient took ecoflor 5 g 2 times a day 15 minutes before meals for 15 days and tiloron inside, after meals, 250 mg per day for the first day, then 125 mg (1 tablet) after 48 hours, 1 tablet per day - 4 more tablets, and then clarithromycin - 500 mg 2 times a day, lansoprazole - 30 mg 2 times a day and lymphotropic metronidazole 50 mg - 1 time per day for 10 days with the subsequent intake of ecoflora 5 g 2 times a day 15 minutes before meals for 30 days and 2 weeks after the start of therapy, repeated intake m Tilorone - 1250 mg (10 tablets) per course.

The patient's condition quickly improved. After 5 days, the pain in the epigastric region passed, on the 12th day of the patient, dyspeptic manifestations ceased to disturb, and stool returned to normal. With control gastroscopy on the 16th day of treatment, there are mild signs of chronic gastroduodenitis, no ulcers and erosion. The level of IgA-ATK H.pylori. increased to 1: 232, LII decreased to 0.81. The urease test after 1 and 12 months is negative.

Example 2

Patient S., 41 years old. From the age of 5, he was registered with a doctor of an immunologist-allergist for allergic seasonal rhinitis in the stage of prolonged remission after a course of allergen-specific therapy with allergen pollen of weeds. Chronic gastroduodenitis suffers the last 3 years. Gastroscopy revealed surface erosion in the pyloric region, the urease test was positive. He was treated by a gastroenterologist for chronic gastroduodenitis associated with HP infection with omeprazole, 20 mg 3 times a day after meals in combination with tetracycline, 250 mg 4 times a day, and tinidazole, 500 mg 2 times a day for 10 days. The course of therapy was poorly tolerated, itchy skin, nasal congestion bothered, and occasionally small-pointed, itchy elements of the rash appeared.

Erosions were epithelized, the pains disappeared, but the patient continued to be bothered by pains in the epigastric region at night, nausea in the morning, bloating, unstable stool, an admixture of mucus in the feces. Periodically, skin itching bothered me. There was no rash. He continued treatment with a gastroenterologist regarding intestinal dysbiosis with Linex 2 drops 2 times a day for 3 weeks.

When contacting the department of immunology a year after treatment, a gastroenterologist complained of nasal congestion, persistent skin itching, rashes on the skin of the body, constant pain in the epigastric region, nausea after each meal, bloating, unstable stool, and an admixture of mucus in the feces.

Endoscopically - signs of chronic gastroduodenitis, superficial erosion in the pyloric region, in the biopsy specimen, the HP infection was confirmed by PCR, the urease test was positive (+ 23.1% above the baseline), H. pylori IgA-ATK. - 1: 116, LII - 1.77.

He was prescribed treatment with a hypoallergic diet, elimination of allergens, Xisal (an antihistamine of the 2nd generation) 10 mg per day for 3 weeks + before the course of eradication therapy - ecoflor 5 g 2 times a day 15 minutes before meals for 15 days and Tiloron orally, after meals, 250 mg per day for the first day, then 125 mg (1 tablet) after 48 hours, 1 tablet per day - 4 more tablets, and then clarithromycin - 500 mg 2 times a day, lansoprazole - 30 mg 2 times a day and lymphotropic metronidazole 50 mg - 1 time per day for 10 days, followed by using ecoflora, 5 g 2 times a day 15 minutes before meals for 30 days and 2 weeks after the start of therapy, taking tilorone again - 1250 mg (10 tablets) per course.

The patient's condition improved on the 5th day, itchy skin decreased, nasal breathing recovered, after 11 days the pain in the epigastric region disappeared, on the 14th day the stool returned to normal, but nausea continued to worry occasionally. At control gastroscopy on the 16th day of treatment - moderately expressed signs of chronic gastroduodenitis, single superficial erosion. The level of IgA-AT to H. pylori. increased to 1: 123, LII decreased to 1.08.

The patient continued taking ecoflora and tilorone, as well as overnight omeprazole 20 mg for another 20 days.

The urease test was weakly positive after a month (+ 1.31% over the baseline), and negative after 2 months. The level of IgA-AT to H. pylori is 1: 118 and LII is 0.81. This indicated a positive effect of the proposed scheme, especially in patients who were already undergoing standard eradication therapy.

The additional use of immunomodulators in eradication therapy increases the effectiveness of eradication therapy, but their positive effect lasts no more than 3-6 months. The inclusion of only probiotics in the eradication therapy program does not give the desired effect on the elimination of the pathogen.

The synergism of immunomodulators and probiotics significantly increases the effectiveness of eradication therapy in patients with allergic diseases and reduces the percentage of undesirable effects, which was shown in our studies.

Preliminary treatment with a probiotic and immunomodulator helps to normalize the intestinal microflora and increase the local immunity of the gastrointestinal tract, which increases the effectiveness of eradication therapy.

The use of gentle antibiotic therapy in patients with allergic diseases - clarithromycin with high antibacterial activity and immunomodulating effect and lymphotropic administration of metronidazole helps to reduce adverse allergic reactions.

Thus, it is shown that the proposed method provides an increase in the effectiveness of the treatment of chronic gastroduodenitis associated with an infection caused by Helicobacter pylori bacteria in patients with allergic diseases and expands the arsenal of treatment by using the immuno-modulating drug Tiloron for the first time for this purpose in combination with taking probiotic ecoflora.

List of abbreviations used:

AT - antibodies

GERD - gastroesophageal reflux disease

WITH GIT - the mucous membrane of the gastrointestinal tract

IDA - iron deficiency anemia

Gastrointestinal tract

IPP - proton pump inhibitors

ITP - idiopathic thrombocytopenia

LII - leukocyte intoxication index

IPC - minimum inhibitory concentration

NSAIDs - non-steroidal anti-inflammatory drugs

CRP - C-reactive protein

XG - chronic gastritis

HG / D - chronic gastroduodenitis

IgA, IgE, IgG - immunoglobulins (class A, E, G)

IL-1β, IL-6, IL-8, IL-10-interleukins

INF-γ - interferon gamma

HP - Helicobacter pylori bacteria

HP Infections - Helicobacter pylori Infections

SlgA - class A secretory immunoglobulin

TNF-α - tumor necrosis factor alpha

Th1 and Th2 - T-cells of type 1 and 2.

Table 1 Serum IgE in patients with gastroduodenitis associated with HP infection in allergic diseases Group I (n = 118) before treatment Group I (n = 118) after treatment Group II (n = 124) before treatment Group II (n = 124) after treatment Indicators R The concentration of IgE, IU / ml 139.6 128.8 142.4 112.3 P _I-II <0.01 Donors up to 100 IU / ml The detection rate of elevated levels of IgE,% (abs). 47% (55) 26% (31) 46% (57) 11% (14) P _I-II <0.01

table 2 LII in patients with gastroduodenitis associated with HP infection in allergic diseases Group I (n = 118) before treatment Group I (n = 118) after treatment after 12 months Group II (n = 124) before treatment Group II (n = 124) after treatment after 12 months LII indicator LII (conventional units) 1.84 + 1.12 1.24 + 0.62 1.78 + 1.18 0.82 + 0.71 LII from donors 0.74 + 0.11 PI-II <0.05

Table 3 Serum cytokines in patients with gastroduodenitis associated with HP infection in the presence of allergic diseases Before treatment After 1 year 3 years later 1 group 2 group 1 group 2 group 1 group 2 group IL-1β 151.5 ± 22 147 ± 91 128 ± 18.1 101 ± 98 155.25 ± 8 104 ± 97 TNF-α 124.3 ± 49.7 127.3 ± 21 75.4 ± 2.2 22.0 ± 13.1 98.40 ± 11.2 38.0 ± 12.0 64.7 ± 2.3 p <0.05 84.9 ± 2.8 p> 0.05 INF-γ 61.5 ± 2.2 62.3 ± 2.1 68.2 ± 1.9 101.4 ± 2.7

Table 4 The level of IL-10 and the ratio of INF-γ / IL-10 in the blood serum of patients with gastroduodenitis associated with HP infection in allergic diseases Group I (n = 118) before treatment Group I (n = 118) after treatment after 12 months Group II (n = 124) before treatment Group II (n = 124) after treatment after 12 months Indicator IL-10 pg / ml 50.0 ± 4.0 54.6 ± 4.6 51.5 ± 7.6 48.4 ± 6.4 ratio INF-γIL-10 1.23 ± 0.07 1.24 ± 0.08 1.20 ± 0.06 2.09 ± 0.11 p <0.05

Claims (6)

1. A method for the treatment of chronic gastroduodenitis associated with an infection caused by Helicobacter pylori bacteria in patients with allergic diseases, comprising a course of eradication therapy, characterized in that prior to the course of eradication therapy, a probiotic ecoflor and an immunomodulating preparation of tiloron are prescribed, and after a course of eradication, ecoflor and tilorone are prescribed again. 2. The method according to claim 1, characterized in that before eradication, ecoflor is prescribed 5 g 2 times a day 15 minutes before meals for 15 days, and tiloron - after meals 250 mg per day for the first day, then - 125 mg per day every 48 hours an additional 4 times; and after eradication, ecoflor is prescribed 5 g 2 times a day 15 minutes before meals for 15 days and tiloron 125 mg after meals every 48 hours for 28 days. 3. The method according to claim 2, characterized in that clarithromycin, lansoprazole and lymphotropic metronidazole are used for eradication therapy. 4. The method according to claim 3, characterized in that clarithromycin is used before meals 500 mg 2 times a day for 7 days, lansoprazole - before meals - 30 mg 2 times a day for 14 days and metronidazole is lymphotropic at 50 mg in 100 ml of saline drip 1 time per day for 10 days. 5. The method according to claim 4, characterized in that metronidazole is introduced into the region of the inguinal lymph nodes, while the injection site of metronidazole is alternated: one day to the right inguinal region, another day to the left. 6. The method according to claim 5, characterized in that 1250 mg is used for the second course of tilorone and 2000 mg for the entire course of immunomodulating therapy.