Method for treating helicobacter-associated chronic duodenal ulcer
FIELD: medicine, gastroenterology.
SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.
EFFECT: higher efficiency of therapy.
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The present invention relates to medicine, namely to therapy (gastroenterology), and can be used to improve the efficiency of treatment of Helicobacter pylori associated peptic ulcer disease.
In recent years, established the leading role of the bacterium Helicobacter pylori (HP) in the etiology and pathogenesis of peptic ulcer. This allowed us to include peptic ulcer disease to infectious diseases. Therefore one of the important tasks of pharmacology has been research aimed at finding drugs and their combinations, can cause eradication, i.e. the destruction of the pathogen, thereby eliminating the etiologic causes of diseases as peptic ulcer disease without eradication remains a “chronic relapsing suffering” (J.J Keller et al. 1996). If successful H. pylori therapy ulcers subcourse faster and better than traditional anti-ulcer treatment. While H. pylori therapy is equally effective with the defeat of the duodenum and stomach (Habu Y., Mizuno, S., Harada, S. et al. 1998).
The mainstay of therapy, according to rational pharmacodynamic approach of HP-associated diseases (chronic gastritis and peptic ulcer disease), taken three - and four-part scheme of eradication. Basic drugs are inhibitors “proton pump” and/or colloidal subset is at bismuth in combination with various antimicrobial means, active against HP (“Maastricht Treaty”, 2000). However, when conducting eradication therapy in recent years has revealed serious problems in connection with the growing resistant HP strains to antibiotics.
Due to the fact that, due to recurrence of the disease pharmacological tools are used repeatedly, there is a risk of development of resistance to them HP. (Ivannikov ACTING, 1998, 1999; Kudryavtseva L.V., Isakov V.A., 1999; Shcherbakov P.L., 1999).
The resistant HP strains are more difficult pharmacological eradication and reduce the effectiveness of modern treatment regimens by 30-50%, which makes their use uneconomical (Ivannikov ACTING, 1999).
A special place among the risk factors of chronic diseases of the digestive system involves the suppression of immune protection as a failure of adaptation possibilities, against which there is a decrease the body's resistance to Exo - and endogenous factors (Ushkalov 1990, Wiefelstede 1991, Bepanthen 2000, Tdzaaah 2002).
The problem of studying the efficacy of immunomodulators in the treatment of diseases associated with invasion HP is currently very topical and provides a basis for rational search for new ways of eradication of HP (Kononov A.V., 1997, 1998).
Known regimens of mnogoobr. the us and based on the empirical approach to the development of optimal treatment regimens for diseases.
So described using quadrakey amoxicillin - bismuth Kolodny subcitrate - metronidazole - omeprazole (proceedings of the international Symposium “Diagnosis and treatment of diseases associated with Helicobacter pylori” the Possibility of H. pylori therapy in the treatment of inflammatory and erosive-ulcerative gastroduodenal diseases, and prevention of neoplastic changes in the stomach. Pediatrics, No. 2, 2002, Nboullis et al. This scheme combines the antibiotic amoxicillin, gastroprotective and antibacterial agents bismuth callitroga of subcitrate, antimicrobial agent metronidazole and antisecretory means of the proton pump inhibitor omeprazole. Despite the efficient eradication of this regimen has some shortcomings: to metronidazole marked the development of resistance HP, it lowers the eradication, in addition, patients incorrigible secondary immunodeficiency in the face of infectious diseases and antimicrobial therapy, which is not marked in the diagram with an immunomodulator and without the use of metronidazole.
Developed the use of ozone therapy, the administration of low doses of ozone for the eradication of HP in the treatment of peptic ulcer disease (PRF No. 2098099), in this case also happens correction of immunodeficiency in the local systems and about what his immunity.
A prototype of the invention is selected known method of treatment of Helicobacter pylori associated chronic duodenal ulcer by medical therapy, comprising: colloidal bismuth subcitrate - dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; omeprazole in a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin 1000 mg 2 times a day, after meals (at 8.00 and 19.00, respectively), within 7 days; furazolidone - in dose of 200 mg 2 times a day, after meals (Breakfast and dinner), within 7 days. The prototype method is described in the article “evaluation of the effectiveness of the scheme eradication of HP Omeprazole, de-Nol, Flemoxin, furazolidone in patients with peptic ulcer of the duodenum” proceedings of the III International Symposium “Diagnosis and treatment of diseases associated with HP No. 2, volume 10, 2000, P.41-42. (In the title are trade names of drugs: De-Nol-colloidal bismuth subcitrate (international name), Flemoxin - amoxicillin (generic name).
According to the authors, the purpose of colloidal subtitrat bismuth (De-Nol, manufacturer Yamanouchi Europ B.V., the Netherlands)with gastroprotective and antibacterial effect at the dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; omeprazole, antisecretory preparation of the t (Omez, manufacturer Dr. REDDY's LABRATORIES", India) at a dose of 20 mg 2 times a day, before meals, within 10 days of amoxicillin, a broad-spectrum antibiotic, resistant to penicillinase (Flemoxin Solutab, manufacturer Yamanouchi Europ B.V., the Netherlands)- 1000 mg 2 times a day, after Breakfast and dinner (8.00 and 19.00, respectively), within 7 days; furazolidone (antibacterial drug)(producer JSC "Kursk plant medicines", Russia) at the dose of 200 mg 2 times a day after a meal (Breakfast and dinner), within 7 days allows you to achieve eradication in 85% of cases. The advantages of this scheme is that it is according to the literature, the minimum resistance HP.
However, therapeutic effects on the proposed scheme are not satisfied with technology developers, because in the end does not resolve one of the main reasons, namely, secondary immunodeficiency, contributing to the development of resistance and disease recurrence.
Therefore, the authors postavlenie the task of eliminating HIV in the level of humoral and cellular immunity. To this end, we have proposed to the basic four-part scheme Omeprazole - colloidal bismuth subcitrate, amoxicillin - furazolidone” additional use of immunomodulator licopid. When this study was accidentally discovered the effect of the immunomodulator on aradi is the situation and the restoration of the morphological characteristics of the mucous membrane of the gastroduodenal zone.
A new technical result of the invention in this regard can be formulated as:
1. strengthening eradication (as will be shown below, from 73.7% in the prototype to 95, 5% in the proposed method,
2. reducing the probability of a new aggravation of the disease and increasing resistance of HP to antibiotics by eliminating the conditions for transition of microorganisms in an inactive form (as will be shown below, in the proposed method, unlike the prototype, after treatment in patients not detected coccoid forms of HP (in the prototype at 10,5% detected)
3. faster recovery indicators cover-pit epithelium, epithelium inserted departments antral glands (in the proposed method, within days, in the prototype within days)
4. improving clinical effectiveness (after treatment according to the previous method of 85.4% of patients diagnosed inactive antral gastritis, in the control group - 52,5% % of patients)
5. a greater increase in lysozyme activity of saliva (for 95.2% of patients versus 78.9% in the prototype)
New technical result is achieved due to the fact that in the proposed method in medical therapy, including:
- colloidal bismuth subcitrate - dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; - omeprazole in a dose of 20 mg 2 times a day, to whom the Riem food within 10 days; amoxicillin 1000 mg 2 times a day, after meals (at 8.00 and 19.00, respectively), within 7 days; furazolidone - in dose of 200 mg 2 times a day, after meals (Breakfast and dinner), within 7 days, additionally comprising Likopid at a dose of 10 mg orally 1 time a day before Breakfast.
Thus, the treatment by the proposed method looks like this: quadroma in combination with an immunomodulator: colloidal bismuth subcitrate - dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; omeprazole in a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin 1000 mg 2 times a day, after Breakfast and dinner (8.00 and 19.00, respectively), within 7 days; furazolidone - in dose of 200 mg 2 times a day, after meals (Breakfast and dinner), within 7 days and in addition to the Quad-immunomodulator therapy Likopid (manufacturer: ZAO “Peptic” at the Institute of Bioorganic chemistry RAS) at a dose of 10 mg orally 1 time a day before Breakfast.
Pharmacodynamic action of licopid as immunomodulator muramylpeptides series, having in its structure glikopeptid involves the normalization of immunochemical and functional system homeostasis. Glycopeptides bacteria of the intestine by the regulators of the immune system. These endogenous bacteria protect their host from another (often patoh is the R) bacteria and viruses and increase nonspecific resistance of the organism to various factors. (Iehovae, Nevsimalova, 1996).
LIKOPID (Manufacturer: ZAO “Peptic” at the Institute of Bioorganic chemistry, Russian Academy of Sciences), white lyophilized powder. Solubility: soluble in water and physiological solution (1 g/ml) pH value: at a concentration of 1x10** 3 mol/l in water pH=4,2 RK=5,48 represents N-acetyl-glucosaminyl-1-4-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP). This substance was isolated from anticancer drug blastasia representing digest the cell wall of lactic acid bacteria Lactobacillus bulgaricus and is a natural stimulant of the human immune system. In the body of a healthy person source GMDP is a normal flora of the intestine. With GMDP related immunostimulatory effects of bacterial origin.
Dosage form: white, round uncoated tablets, with a total weight of 0.35 g containing 0,g GDP and a total weight of 0.1 g containing 0.001 g GMDP. The dose of 0.1 g, which is prescribed in the scheme selected for the correction of secondary immunodeficiencies associated with chronic diseases of any localization according to the indications for the drug, in our study this HP associated peptic ulcer of the duodenum. The necessity of application of licopid in strictly fixed dose of 10 mg is due to the fact that this is the usual dose for correction W is the hexadecimal format of immunodeficiency.
The study included patients with peptic ulcer disease duodenal ulcers associated with HP, with localization of the ulcer in the duodenal bulb, in the acute phase of relapse with chronic H. pylori antral gastritis (type b). Formed groups were matched for age, sex, duration of disease and concomitant pathology of the gallbladder and pancreas. On the test of licopid in the scheme of therapy of H. pylori was obtained the consent of the subjects themselves and the permission of the Ethical Committee at the health facility, which conducted the study.
Depending on the form of therapy, patients were distributed as follows.
The control group (19 persons) (prototype), who received the “Quad” regimen: colloidal bismuth subcitrate (De-Nol, manufacturer Yamanouchi Europ B.V., the Netherlands) at a dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; omeprazole (Omez, manufacturer Dr. REDDY's LABRATORIES", India) at a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin (Flemoxin Solutab, manufacturer Yamanouchi Europ B.V., the Netherlands) - 1000 mg 2 times a day, after Breakfast and dinner (8.00 and 19.00, respectively), within 7 days; furazolidone (manufacturer JSC "Kursk plant medicines", Russia) at the dose of 200 mg 2 times a day, after receiving the seek (Breakfast and dinner), within 7 days.
The main group (n = 21)treated treated kvadroshou: colloidal bismuth subcitrate - dose of 240 mg 2 times a day, 30 minutes before a meal (Breakfast and dinner), for 10 days; omeprazole in a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin 1000 mg 2 times a day, after Breakfast and dinner (8.00 and 19.00, respectively), within 7 days; furazolidone - in dose of 200 mg 2 times a day, after taking food (Breakfast and dinner), within 7 days and in addition to the Quad-immunomodulator therapy Likopid (manufacturer: ZAO “Peptic” at the Institute of Bioorganic chemistry RAS) at a dose of 10 mg orally 1 time a day before Breakfast for 30 minutes
The patients were examined according to the scheme
1. The definition of the baseline before treatment - endoscopic method (fibrogastroduodenoscopy) was used to detect changes in the gastric mucosa characteristic of peptic ulcer disease (HP-associated chronic gastritis), and also with the aim of taking biopsy mucosal antral and fundic departments for carrying out morphological studies.
Morphological method was used to determine HP. The fundic biopsies (2), antral (2) departments, angle (1) of the stomach were fixed in 10% formalin, were carried out in ascending alcohols fortress, was poured into paraffin. Prepared with the on the sledge microtome serial sections with a thickness of 5-7 and painted with application review colors, viewed in the light microscope Biolam with zoom lens 40x, ' 90s, the eyepiece 15. Series of sections were stained with hematoxylin and eosin, alcian blue and Schiff's reagent. HP was detected in smears-prints of the gastric mucosa stained by Romanovsky. In the analysis of structural changes were taken into account activity, the severity of the process and structural changes of the gastric mucosa according to the Houston modification Sydney system classification of gastritis. For this purpose, we used a visual analogue scale morphological changes of gastric mucosa in chronic gastritis (M. Dixon et al., 1996).
At primary diagnosis helikobakterioza (at the time of admission of patients with ulcers) was used quick test "FastRead H. pylori" (manufacturer CQI medical Products Inc., Canada). Express-test HP is screeningroom immunochromatographic test for detection of antibodies against HP in serum, plasma and whole blood. The method includes a unique combination of conjugated protein, specific binding of antibodies and antigens adsorbed on the solid phase. With the passage of the test sample through the membrane antireligiose protein conjugate binds with antibodies against HP sample. Thus formed complex is fixed anti-Christ. s solid phase in the zone "TEST" on the plate, forming a red bar. Accordingly, in the absence of specific antibodies in the tested sample in the TEST area of platinum is not detected bands. In the further migration of the sample through the membrane in the area of "CONTROL" appears pink band, confirming the quality of the reagent.
Values method was used to determine the activity of lysozyme is to change the degree of light transmission of microbial suspensions of the test culture of Micrococcus ysodeicticus under the influence of lysozyme studied fluid compared with: indicator source of microbial suspensions. From daily microbial culture M.lysodeicticus suspension was prepared in phosphate buffer. Suspension has standardized on the FEC at a green light filter (length [wavelength 540 nm) in cuvettes with optical path length of 3 mm To determine the activity of lysozyme was poured in a test tube microbial suspension and diluted phosphate buffer gastric juice or saliva. One hour and incubated in a thermostat at 37°C. and then measured on FEC wavelength, from the testimony read a standard (% light transmission suspension). The normal activity of lysozyme saliva corresponds to 40%, and gastric juice is 70%.
Molecular-biological method of polymerase chain reaction (PCR) was used to identify clinical material (gastric juice) specific fragments of genomic DNA of Helicobacter. For vyd the ing DNA from gastric juice by centrifugation prepared supernatant. After twice washing the supernatant was dried and re-resuspendable. After that the supernatant contained the purified DNA. Tubes prepared reagents were placed in nests heater DNA amplifier and exhibited the desired program. Because the PCR product is a DNA fragment having a specific size, one of the available methods of its detection is elektroforeticheskoe separation of the reaction mixture in an aerosol gel. Heliotherapies the film Mikrut -300 (Photo-250, Photo-125) through a red filter. Positive samples should contain a strip located on the same level as the positive control lane. Negative samples should not contain any of the bands except those that are generated by primers and below are specific fragment.
Evaluation of the immunological status was included to determine the total number of T - and b-lymphocyte subpopulations of T-lymphocytes, immunoglobulins a, M, G.
The definition of indicators of cellular immunity (CD3+, CD4+, CD8+ lymphocytes) was carried out using a set of monoclonal antibody production in Nizhny Novgorod research Institute of epidemiology and Microbiology of the Russian Federation Ministry of health on a fluorescent microscope (Leitz (Germany). Quantitative determination of indicators of humoral immunity (immunoglobulins A,M,G) about Tilos by radial immunodiffusion according to Mancini using monospecific sera against IgA, IgM, IgG production Nizhny Novgorod research Institute of epidemiology and Microbiology of the Russian Ministry of health. The principle is based on measuring ring precipitation formed when making the test serum in the wells of agar, in which pre-dispersed monospecific anticigarette. The diameter of the ring of propitiatio directly proportional to the concentration of the studied immunoglobulin.
2. Control examination after 6 weeks from the end of the H. pylori therapy (endoscopic method, the morphological method definition HP, molecular-biological method with determination of specific DNA fragments HP, immunological method, values method with determination of lysozyme in saliva and hungry (on empty stomach portion of the gastric juice).
RESEARCH RESULTS AND DISCUSSION
Figure 1 shows the morphological picture of active H. pylori antral gastritis, severe infiltration by neutrophils, plasmacytoma, metaplasia, venules enlarged, hemorrhage, imposition of mucus in the lumen of the pits and on the apical surface of the surface epithelium of the detected Helicobacter pylori. Sample biopsies taken before treatment. These changes are characteristic for all investigated samples.
Figure 2 presents the morphological picture of the superficial antral gastritis. Find areas of metaplasia, infiltration. The way the biopsies taken 6 weeks after quadrakey eradication. These changes characterize the samples of biopsy specimens of patients who received only kvadroshou.
Figure 3 presents the morphological picture of the inactive antral gastritis. Detects a decrease in the infiltration of the submucosal layer and own plates, activation of the local immune system, manifested in the appearance of lymphoid follicles with light centers. These changes are characteristic of a group of patients treated with Likopid.
Example 1 illustrates the proposed method)
Extract from the history of Patient Boars IV 37 years (study group), no history of the disease 2484.
Patient Boars IV 37 years old, was in the hospital with 15.10.2000 on 30.10.2000, was admitted with a diagnosis of peptic Ulcer localization of ulcers in the duodenal bulb, the diagnosis is made when conducting FGDs in the outpatient setting (surveyed 12.10.2000). Dynamic summary: upon receipt of a complaint of spontaneous pain in the left hypochondrium, epigastrium, belching air, bloating, rumbling unstable chair up, palpation tenderness in the epigastrium. During examination: smear-fingerprint was detected cytologically HP (analysis from 17.10.00), cytological diagnosis was confirmed by polymerase chain reaction (PCR) samples of gastric juice, taken when re-EGD (analysis dated 17.10.2000), were taken at the same time the biopsy specimens of the gastric mucosa to the morphological study, morphologically were identified: active Helicobacter associated gastritis in the acute stage (opinion on the biopsy sample from 17.10.2000) - severe infiltration by neutrophils, plasmacytoma, metaplasia, venules enlarged, hemorrhage, imposition of mucus in the lumen of the pits and on the apical surface of the surface epithelium of the detected Helicobacter pylori. Morphological conclusion: Active diffuse antrum-gastritis associated with HP.
Simultaneously, the patient was taken a blood sample for immunological analysis of 16.10.2000), the examination detected a secondary immune deficiency in the systems of the cell (CD3:c 23,1% CD4: 23,5%; CD8: 20,45%) and humoral immunity [IgA: 1,31 g/l; IgM: 1,34 g/l; IgG: the rate of 8.75 g/l), were simultaneously conducted analyses of lysozyme saliva and gastric juice (17.10.2000)showed a reduction in the secretory activity of lysozyme saliva-to 26.4% (average 40%), gastric juice 37% (average 70%).
The patient received kvadroshou: colloidal bismuth subcitrate (De-Nol”, “Yamanouchi Europe B.V., the Netherlands) at a dose of 240 mg 2 times a day, 30 minutes before Breakfast and dinner for 10 days; omeprazole (Omez”, “Dr. Reddy's Labratories”, India) at a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin (“Flemoxin Solutab”, “Yamanouchi Europe B.V., Netherlands) -1000 mg 2 times a day, after Breakfast and dinner (8.00; 19.00), within 7 days; furazolidone (JSC “Kursk plant drug medium is in”, RF) at the dose of 200 mg 2 times a day, after Breakfast and dinner for 7 days; in addition, the patient was assigned immunomodulator Likopid, as was identified secondary immunodeficiency, at a dose of 10 g inside. Within 10 days 1 time per day before Breakfast on the first day of eradication therapy. Under the action of therapy of spontaneous pain in the left upper quadrant, epigastric pain, eructation of air was stopped on day 4, bloating, rumbling on day 2 unstable stool was observed up to 10 days, palpation tenderness in the epigastrium to 4 days.
When the test call after 6 weeks (18.12.2000) subjective patient had no complaints. If gastroduodenal endoscopy after 6 weeks showed a good positive dynamics: the disappearance of hyperemia of the mucous membrane, scarring ulcers.
When you re taking a biopsy (25.12.2000) morphologically:
the decrease in lymph leukocyte infiltration with reduced severity of vascular reactions, swelling and hemorheological changes, intestinal metaplasia in the surface epithelium and glands cells, lymphoid follicles with broad pale centers, a significant improvement in cover-pit epithelium and epithelium of the glands. The nucleus of epithelial cells located in basal, clearly defined borders of epithelial cells, the height of the cover-pit epithelial cells in normal limits. About Voss is yavlenie slizeobrazujushchej properties of the epithelium testified positive histochemical tests what characterized the recovery slizeobrazujushchej functions cover-pit epithelium, the absence of Helicobacter pylori (data was confirmed by PCR from 18.12.2000)
Conclusion: superficial gastritis
Control blood improvement cell (CD3: to 39,3); CD4: to 43.6%); CD8: to 25.8%) and humoral immunity (IgA: to 2.22 g/l; IgM: to 1.54 g/l; IgG: to 11.2 g/l).
Example 2 (illustrates the prototype)
Prototype (using quadrakey without immunomodulator):
Sick of Buravov VA 34 g (control group) no history 3201.
Admitted to the hospital 26.5.2001 with a diagnosis of peptic Ulcer localization of ulcers in the duodenal bulb, the diagnosis is made when conducting FGDs in the outpatients Department (surveyed 25.5.2001). Dynamic summary: in response to complaints about pain in the left hypochondrium, epigastrium, constant nature and worse at night, belching air, bloating, rumbling, unstable chair, palpation severe pain in the epigastrium. During examination: smear-print cytologically - HP, cytological diagnosis was confirmed (PCR) samples of gastric juice, taken when re-EGD (analysis from 28.5.2001), at the same time were taken biopsies of the gastric mucosa to the morphological study, morphologically active Helicobacter-associated ha the threat in the acute stage (opinion on the biopsy sample from 28.5.2001) - marked infiltration of neutrophils, plasmacytoma, metaplasia, venules enlarged, hemorrhage, imposition of mucus in the lumen of the pits and on the apical surface of the surface epithelium of the detected Helicobacter pylori.
Conclusion: Active diffuse antrum-gastritis associated with HP.
At the same time the patient had taken a blood sample for immunological analysis from 28.5.2001)identified secondary immunodeficiency in cellular systems (CD3: 20% CD4: 22%; CD8: 19%) and humoral immunity [IgA: 1.27 g/l; IgM: 1,33 g/l; IgG: 7,g/l)were simultaneously conducted analyses of lysozyme saliva and gastric juice (from 28.5.2001)showed a reduction in the secretory activity of lysozyme saliva-27,4%, (average 40%), gastric juice 38% (normal 70%).
With 29.5.2001 patient received scheme (taken as a prototype): colloidal bismuth subcitrate (De-Nol”, “Yamanouchi Europe B.V., the Netherlands) at a dose of 240 mg 2 times a day, 30 minutes before Breakfast and dinner for 10 days; omeprazole (Omez”, “Dr. Reddy′s Labratories”, India) at a dose of 20 mg 2 times a day, before meals, for 10 days; amoxicillin (“Flemoxin Solutab”, “Yamanouchi Europe B.V., Netherlands) - 1000 mg 2 times a day, after Breakfast and dinner (8.00; 19.00), within 7 days; furazolidone (JSC “Kursk plant medicines”, Russia) at the dose of 200 mg 2 times a day, after Breakfast and dinner for 7 days. Under the action of therapy of spontaneous pain in the left hypochondrium, epigent the AI, eructation of air was stopped on day 7, bloating, rumbling on day 5 unstable chair up to 14 days, palpation tenderness in the epigastrium to 6 days. When the test call after 6 weeks 14.7.01 patient complained of belching air, unstable stool, discomfort in the epigastrium, worse at night and turns into a slight pain. If gastroduodenal endoscopy after 6 weeks was observed ulcer scarring, reduction of round-cell infiltration, edema and restoration of the surface epithelium, the analysis of smear-print from 15.07.01 - incomplete eradication - coccal forms HP, PCR analysis from 15.07.01 weak signal on the DNA fragments HP, morphologically - reducing round-cell infiltration, edema and restoration of the surface epithelium in some places was observed preservation of infiltration and areas of metaplasia. In addition, in this group of patients revealed increased as cell immunodeficiency BG3+19,4%, CD4+21,3%, CD8+18,6%and humoral IgA 0,93, IgM l,19, IgG 5,54 under the action of antibiotic therapy, as well as reduced activity of lysozyme (saliva or 39.8%, gastric juice 46,3%). Analyses from 16.7.01).
In patients treated kvadroshou with Likopid, 6 weeks was diagnosed mostly inactive antral gastritis (85%), and the intensity of the inflammatory process in the coolant in the ensiles. Despite a significant reduction in the severity of gastritis, superficial gastritis was observed in some patients in the control group (10.5 per cent).
After 6 weeks after end of therapy structural indicators cover-pit epithelium, epithelium inserted departments antral glands were recovered faster than in the control. Infiltration was detected predominantly in the surface layer of the mucous membrane. In addition, the patients of the main group was observed activation of the local immune system, manifested in the emergence of the private record of lymphoid follicles with light centers with a higher level of expression of membrane immunoglobulins in comparison with B-lymphocytes own plate.
These changes occurred in parallel with the improvement of clinical, laboratory and endoscopic indices and expressed the activation of local immune mechanisms of protection. In addition, in all cases there was a decrease round-cell infiltration, edema and restoration of the surface epithelium, which were more pronounced in the use of the investigational immunomodulator in combination with kvadroshou eradication of HP, which indicates the regenerative properties of licopid.
All modes of therapy resulted in increased lysozyme activity of saliva from 95.2 per cent of the patients of the main group and 78,9% of the patients of the control g is PI. In all three cases, 6 weeks after therapy activity of gastric juice of lysozyme was below the normal rate, it has been a distinct trend towards the restoration of activity, more pronounced in the main group. The use of immunomodulator stimulates the nonspecific resistance of the organism, local immunity, thus restoring the activity of nonspecific factors of protection (including lysozyme).
The positive effect
1. The use of immunomodulator licopid helped to increase the efficiency of HP eradication in patients with peptic ulcer of the duodenum in therapy of H. pylori drugs omeprazole-colloidal bismuth subcitrate, amoxicillin-furazolidone.
2. When assigning immunomodulator Likopid in conjunction with the scheme, the eradication of HP was observed earlier reduction of the term or even the disappearance of the activity and severity of the inflammatory process in the stomach and duodenum, as well as more efficient recovery of structural and functional indicators of the mucous membrane of the gastroduodenal zone.
3. The purpose of the immunomodulator since the beginning of the use of combination of omeprazole, colloidal bismuth subcitrate, amoxicillin-furazolidone is indicated in patients with peptic ulcer disease duodenal ulcer to improve on is ragnotti local and General immune protection of an organism.
Thus, the circuit with licopid is more effective, because along with the correction of secondary immune deficiency was identified in this study improved morphological characteristics, a more complete eradication, increase lysozyme activity of saliva and gastric juice at the same time, the scheme quadrature chosen for the prototype, does not imply a complete eradication of the pathogen, improving the cellular, humoral and local immunity, earlier recovery of reparative properties of the mucous membrane of the gastroduodenal zone, in addition, the formation of resistance HP due to incomplete elimination of the pathogen.
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16. Versalovic J, Kibler K, Smell S, Graham DY, Go MF; Mutations in 23s ribosomal RNA confer clarithromycin resistance in Helicobacter pylori // Gut-1995.
The method of treatment helicobacteraceae chronic duodenal ulcer by medical therapy, comprising: colloidal bismuth subcitrate at a dose of 240 mg 2 times a day, 30 minutes before meals: Breakfast and dinner for 10 days; omeprazole at a dose of 20 mg 2 times a day before meals for 10 days amoxicillin 1000 mg 2 times a day after meals at 8.00 and 19.00, respectively, within 7 days; furazolidone dose of 200 mg 2 times a day after eating Breakfast and dinner for 7 days, characterized in that , in addition to drug therapy include Likopid at a dose of 10 mg orally 1 time a day before Breakfast for 10 days.
SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.
EFFECT: higher efficiency of application.
42 cl, 39 ex
SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.
EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.
FIELD: medicine, gastroenterology.
SUBSTANCE: invention relates to methods for treatment of chronic helicobacter pylori-associated gastritis. Method is carried out by monotherapy with the probiotic "Laminolakt" in the dose 3 dragees per 24 h for 1 month. Method provides elimination of Helicobacter pylori cells on the background of activation of the immune response in stomach mucosa by effect on microflora and the colon intestine immune system.
EFFECT: enhanced effectiveness of treatment.
2 tbl, 1 ex
SUBSTANCE: method involves introducing endoscope, clearing injured surface and applying gel produced on Tisol substance base (aqua-complex of titanium glycerosolvate) as medicinal composition via the endoscope. Tisol is administered as aqueous solution of concentration not less than 60% after Tisol. The composition is applied to injured surface in the amount of 2 to 8 ml for one session. The number of treatment sessions is equal to 1 to 7 with 3-5 days long pauses. The composition is prepared by mechanically mixing medicinal microadditives with Tisol substance. The medicinal microadditives are introduced in total amount of 7.26% of composition mass. The ingredients are selected depending on disease. The medicinal composition is applied as 1-2 mm thick layer. When treating the cases of erosion or gastritis, sea-buckthorn oil and/or propolis solution are of preference to be introduced into Thysol as the medicinal microadditives. When treating the cases of gastric or duodenal peptic ulcer, methyluracyl, hydrocortisone, cycloferon or aecol are preferentially introduced into Tisol as the medicinal microadditives. The composition formula is adjusted from session to session on the basis of treatment results visual control and analysis data. Taking meals and drinks is restricted for a patient for half an hour or longer.
EFFECT: enhanced effectiveness in administering drugs into mucous membrane and soft tissues without using needle injectors.
5 cl,4 tbl
FIELD: organic chemistry and drugs.
SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.
EFFECT: effective interleikyn-1beta converting enzyme inhibitors.
64 cl, 35 ex, 35 tbl, 21 dwg
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to compounds of the formula (I):
wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 70 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.
EFFECT: valuable biochemical and medicinal properties of peptides.
106 cl, 9 tbl, 61 ex
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.
EFFECT: valuable properties of agents.
4 cl, 3 tbl, 78 ex
in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the
where W denotes the R1-A-C(R13or
where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C
FIELD: medicine, pharmaceutics.
SUBSTANCE: the suggested composition includes compounds of natural ethers in cancer of mammalian soft tissues (including, the man), for example, in case of diseases of mammary gland. Both dosage and frequency of introduction depending upon a certain symptomatics could be decreased up to the level at which it is necessary to maintain improved level. At weakening the symptoms up to desired level one should stop therapy immediately. At any relapse of disease symptoms patients could need periodic therapy upon lasting basis.
EFFECT: higher efficiency of application.
2 cl, 3 ex, 3 tbl