Method for the treatment of various forms of tuberculosis, including drug-resistant to anti-tb chemotherapy

 

(57) Abstract:

The invention relates to medicine, to tuberculosis, may be used to treat various forms of tuberculosis, including drug-resistant to anti-TB chemotherapy. Enter the immunomodulator Glutoxim at least 1 time per day in a dose of from 30 to 60 mg per day, while the tuberculosis predominantly exudative type of tissue reaction Glutoxim intramuscularly 2 times daily 1 ml of 3% solution; lung tuberculosis predominantly productive type of tissue reaction Glutoxim intramuscularly 2 times per day, 1 ml of 1% solution 3 times a week; in tuberculosis in the background of drug resistance of mycobacteria to Glutoxim administered 2 times daily 1 ml of 3% solution: in the morning, intravenous, in the evening intramuscularly for 2 months daily. The invention significantly reduces the hepatotoxic effects of anti-TB drugs and increases the effectiveness of TB treatment. 4 C.p. f-crystals, 7 PL.

The invention relates to medicine, namely to tuberculosis, may be used in medical practice in complex treatment of patients with different forms of tuberculosis has returned in all countries of the world drug resistant, little is applicable forms. Significantly increased the number of patients with caseous pneumonia, generalized forms of tuberculosis. More than half of the patients have acute tuberculosis with hectic fever, severe inflammatory changes in the blood, hypoalbuminemia. Increased intensity of bacteria and the resistance of mycobacteria to the main antituberculosis drugs.

Drug resistance of Mycobacterium tuberculosis is becoming an increasingly serious obstacle in reaching effect in the treatment of patients, causes the inefficiency of etiotropic therapy, is the most frequent cause of progression of specific process that leads to death.

In these conditions significantly increases the role of medical products that promote recovery and increase of protective forces of an organism (specific and nonspecific immune resistance), as well as improving the endurance of anti-TB drugs and to eliminate their hepato-, OTO-, neuro-, cardio - and nephrotoxic side effects.

Currently, the main method of treatment of pulmonary tuberculosis of yavleniya expensive drugs failover groups possessing poor tolerability and not always available anti-TB institutions.

Previously used in the treatment of tuberculosis immunomodulating agents such as adjuvant [1, 2, 3], T-activin [1, 2, 3], had limited range of action (stimulation of T-active lymphocytes) and could only be used in patients with exudative type of tissue reaction. The use of tuberculin [4] in patients with productive tissue reaction in the face of increasing drug resistance of mycobacteria may cause exacerbation of tuberculosis. With this type of tissue reaction are preferred beta-Leikin [5, 6], which by its characteristics fully complies with the interleukin-1. However, for the treatment of tuberculosis at the present stage, in the face of increasing drug resistance, you need a versatile tool that is applicable to all types of tissue reactions, can have a differential impact on all stages of T-cell immunity, to increase the specific activity of anti-TB drugs, to have cytoprotective effects.

Known drug Glutoxim, which allowed 10.09.98 Parmdefinition biological response with immunomodulatory properties (registration number 982793).

Currently used injectable dosage form for intravenous, intramuscular and subcutaneous injection, representing a solution of the active substance (Glutoxim varying degrees of concentration in aqueous solution of NaCl, namely 0.5% (VFS 42-3195-98), 1% and 3% (VFS 42-3408-99).

According VFS (42-3195-98, 42-3408-99) drug Glutoxim is a chemically synthesized biologically active compound is a Hexapeptide with stabilized by a disulfide bond bis-(gamma-L-glutamyl)-L-cystinyl-bis-glycine disodium salt with the total formula (C20H20N6Na2O12S2).

Drug Glutoxim a representative of a new class of drugs - tipatina [7] with unique biological and pharmacological effects, including:

regulation escalation in the redox state of cells;

modulation of endogenous production of cytokines (IL-1, IL-2, IL-4, IL-6, 1L-8, IL-10, IL-12, IFN, TNF), which determines the immunomodulating properties of the drug;

pronounced differential effects on normal and infected cells.

Being the analogue of key cellular metabolites, the active ingredient of the drug Glutoxim has high and target triggering a cascade mechanism of biochemical reactions in the regulation of metabolism, proliferation and differentiation of cells that forms a broad range of immunomodulatory and cytoprotective effects of the drug. To date, has accumulated significant experience in the use of the drug Glutoxim in clinical medicine, confirming its biological and pharmacological effects.

The task, which is aimed by the invention is a method of treatment of patients with various forms of pulmonary tuberculosis by injecting drug Glutoxim on the background of a comprehensive specific therapy to achieve therapeutic effect due to the regulating effect of the drug on the pathogenetic mechanisms of the development and course of the disease and prevent complications.

In this application the first time it is shown and proved that the use of Glutoxim in clinical practice in the treatment of patients with pulmonary tuberculosis allows for a fundamentally new level to carry out immunological and cytoprotective support of anti-TB chemotherapy.

According to the claimed invention is a method of treatment of various forms of tuberculosis legkij enter Glutoxim in a dose of from 20 to 60 mg per day (depending on the nature of the flow and the severity of the disease) in the period required to achieve a therapeutic effect.

According to the claimed invention tuberculosis predominantly exudative type of tissue reaction Glutoxim intramuscularly 2 times a day for 1 ml of 3% solution.

According to the claimed invention tuberculosis predominantly productive type of tissue reaction Glutoxim injected 3 times a week intramuscularly twice in 1 ml of 1% solution.

According to the claimed invention when drug resistance of mycobacteria to Glutoxim injected 2 times a day for 1 ml of 3% solution, in the morning, intravenously and intramuscularly in the evening for 2 months daily.

According to the claimed invention severe progressive forms of tuberculosis Glutoxim intramuscularly or subcutaneously once 3 times a week for 1 ml of 3% solution.

While the active ingredient of the drug Glutoxim is a chemically synthesized biologically active compound is a Hexapeptide with stabilized by a disulfide bond bis-(gamma-L-glutamyl)-L-cysteinyl-bis-glycine disodium salt, with a total formula - (C20H30N6Na2O12S2).

In Kleene is antituberculosis drugs is assigned Glutoxim intravenously and/or intramuscularly as follows.

In patients with pulmonary tuberculosis predominantly exudative type of tissue reaction Glutoxim assigned in the first two months of chemotherapy in the form of a 3% solution 1 ml 2 times a day intravenously or intramuscularly at a daily dose of 60 mg daily. When the patient's treatment in a day hospital Pets drug 5 days a week (except Saturday, Sunday).

When productive the specific type of inflammation of the 1% solution Glutoxim assigned intramuscularly 2 times a day, 3 times per week at a dose of 20 mg per day.

In cases evolved drug resistance of mycobacteria to anti-TB drugs 3% solution of Glutoxim assigned daily 2 times a day, morning intravenous 1 ml and evening intramuscularly 1 ml for a period of not less than 2 months.

Severe progressive forms of tuberculosis in cases of unclear prognosis of the disease is 3% solution of Glutoxim - 1 ml subcutaneously or intramuscularly 1 time per day, 3 times a week.

The drug Glutoxim patients with pulmonary TB, including drug resistance of mycobacteria, provides:

1. Regulation of immunity. It is known that the nature of the immune response depends on Dominicus is supplied by cytokines and activation of the immune response at the cellular or humoral type [8]. Activation of the drug "Glutoxim" Th1 producing interferon gamma, interleukin 2, tumor necrosis factor alpha and beta, leads to the stimulation of the function of T-lymphocytes and resident macrophages, i.e. to the development of the immune response by the cell type that plays a crucial role in protecting the body from tuberculosis. Also an important function of the pleiotropic cytokine IL-12. Launching its products, Glutoxim regulates the ratio of Th1/ Th2 in the direction of increasing T-cell immunity. Differentially affecting macrophage immunity, Glutoxim, on the one hand, contributes to the activation, proliferation and differentiation of functionally viable resident macrophages of the lung, with other causes apoptosis of infected with Mycobacterium tuberculosis, macrophages (see example 1). Drug Glutoxim inhibits the system P-glycoprotein complex (product MDR-gene), thereby preventing the development of drug resistance of Mycobacterium tuberculosis.

2. Potentiation of anti-TB drugs (see example 2).

3. Prevention of toxic-allergic complications of treatment (see examples 3, 6).

4. Rapid recovery of quality of life is of tuberkuleza (see examples 4, 5, 6)

The invention is illustrated by examples that demonstrate the identified properties Glutoxim in experimental models (examples 1, 2, 3).

Example 1. The impact of Glutoxim on the growth of drug-resistant Mycobacterium tuberculosis in cellular and extracellular environment in the culture of lung tissue of mice.

Investigated the effect of Glutoxim on the growth of drug-resistant Mycobacterium tuberculosis (hereinafter referred to HR office) in the presence of anti-TB drugs to which the bacilli resistant (isoniazid and rifampicin). Lung tissue of mice were cultured by the modified method of explantation in silicon perfusion chambers. Pieces of lung tissue (explants) were placed on the cover glass chambers and fixed them to the glass using plasma rabbit. The camera was introduced medium 199. Within 5-6 days of cultivation around the explants formed an extensive zone of eviction and growth of cellular elements, among which was dominated by macrophages and fibroblasts. Along the perimeter of the explants appeared fibroblastic shaft, which was peeled off, forming a ring-shaped structure filled with a variety of mobile cellular elements of the lung tissue. Here is BT) were obtained from patients with tuberculosis. Resistance to isoniazid was 1 µg/ml, rifampicin 50 mg/ml Suspension of the Republic of Latvia in the office environment 199 received without quantitative dosing of microbial bodies of the same volume of sediment HR office).

In the first series of experiments studied the effect of one Glutoxim on the growth of LR MW. Glutoxim of ampoules with 1 ml of 3% solution of the drug was diluted to a final concentration of 1 μg/ml in medium 199 containing 10% bovine serum and suspended HR office. In the control variant used the same nutrient medium with equal loadings of sediment HR office without Glutoxim.

In the second series of experiments studied the effect of Glutoxim on the growth of the HR office in the presence of isoniazid or rifampicin. Isoniazid was diluted in medium 199, containing the same components as in the first series, to a concentration of 1 µg/ml, rifampicin up to a concentration of 50 μg/ml, Glutoxim up to a concentration of 1 μg/ml Was allocated to 5 groups of cameras: 1. Control without drugs; 2. Camera containing one isoniazid; 3. Camera with one rifampicin; 4. Camera containing isoniazid + Glutoxim; 5. Camera containing rifampicin + Glutoxim.

Monitoring the growth of microcolonies HR office and the growth of cellular elements in the area of eviction (ADAP) and its limit is a characteristic morfologicheskie education, known as the "KOs" were counted in 100 fields of view with increasing 21040. At the same time assesses the condition of the cellular elements: their viability, motility, faguoqitirute activity, the state of the internal structures (nuclei, granules, endo - and ectoplasm).

In the first series of experiments, micro-colonies of the Republic of Lithuania, the office appeared in the form of small "KOs" for 3-4 days after inoculation of microbial suspensions as in the control (without Glutoxim) and in the experimental chambers in greater numbers outside the area of eviction and growth of cellular elements and in small quantities within this zone. In the next 3-5 days increased their number and sizes. Table 1 presents the dynamics of growth of microcolonies HR office, under the action of the drug Glutoxim. From table 1 it is evident that when using one Glutoxim at a concentration of 1 μg/ml in the area of eviction and growth of cellular elements, the number of growing microcolonies HR office was significantly smaller than outside it, as evidenced by the high degree of statistical significance of differences. In control cells, the number of microcolonies HR office within the cell array were not statistically different from that outside it.

In control cells the most is dapodi, in their cytoplasm was determined large shapeless inclusion. Many macrophages were outgrowths "KOs" of microcolonies of the office. Fibroblast deformed, granular patterns were lumpy, kernel visually was not determined.

In cells with Glutoxim also showed signs of degradation of cellular elements, but they were not as pronounced. Still some mobility of macrophages, their cytoplasm was seen to be more structural. Part of macrophages formed pseudopodia, testified to the continuation of the process of favoritemovie. Part of fibroblasts deformed, but some have retained the typical veretenoobraznuu form with the correct location of the granules and is clearly visible by the kernel.

Thus, Glutoxim in the absence of anti-TB drugs have contributed to more efficient phagocytosis office in the cellular environment of the culture of lung tissue and reduced the damage of cellular elements due to infection.

In the second series of experiments introduction Glutoxim in combination with anti-TB drugs: isoniazid or rifampicin resulted in significant changes in the number of drug-resistant microbe the affected drug Glutoxim on the growth of microcolonies HR office in the presence of the main anti-TB drugs.

Glutoxim had a substantial impact on the growth of the HR office in the cellular environment, as in the presence of isoniazid and rifampicin. The number of microcolonies here was 10 times less when combined Glutoxim with isoniazid and 5 times less in combination with rifampicin compared with that in the extracellular environment. When comparing these data with data obtained in the first series of experiments, the impression on the strengthening of Glutoxim anti-TB activity of rifampicin and isoniazid. It is associated with significant reduction of viability LR MW when activated phagocytic ability of macrophages, resulting in the action of anti-TB drugs is becoming more pronounced.

Characteristic was complete preservation of the viability of the cellular elements of the lung tissue when combined Glutoxim with isoniazid or rifampicin. Macrophages were movable, morphological signs of degradation was absent. Fibroblasts had a characteristic elongated shape, an oval nucleus with nucleoli, there have been perinuclear location granules.

In the control cells without drugs, with one isoniazid or rifampicin cellular elements outside of the cell array in all cases there was abundant growth of microcolonies LR MW.

Thus, Glutoxim in the absence of anti-TB drugs helps to reduce the growth of drug-resistant Mycobacterium tuberculosis in cell medium culture of lung tissue compared with their growth in the extracellular environment about 1.8 times; when combined with isoniazid Glutoxim in the cellular environment leads to a decrease in the population of drug-resistant MW about 10 times, when combined with rifampicin - about 5 times Glutoxim contributes to maintaining the viability and functional activity of cellular elements of the culture of the lung tissue infected with drug-resistant MW, especially when combined with anti-TB drugs.

Example 2. The effectiveness of treatment and immune status with the inclusion of Glutoxim in adjuvant chemotherapy of experimental tuberculosis in mice.

The study was conducted on 180 white outbred mice - males, which were isolated intact (n= 20) and infected untreated (control cultures (n=20). The remaining 140 animals amounted to two groups of control treatment and 4 groups with the inclusion of Glutoxim in comprehensive anti-TB therapy. For modeling experimentate 0.1 mg/0.2 ml per mouse. Treatment of animals was started on day 10 from the moment of infection (detection of single lung lesions productive specific inflammation) and continued for 8 weeks. Glutoxim was administered at doses of 20 and 40 mg/kg, subcutaneously on the background of the two (isoniazid + rifampicin) and three (isoniazid + rifampicin + pyrazinamide) tuberculostatics. Drug was administered in therapeutic doses: isoniazid (H) 10 mg/kg, subcutaneously in 0.2 ml of 0.9% sodium chloride solution; rifampicin (R) 10 mg/kg and pyrazinamide (Z) 20 mg/kg in aqueous suspension were administered per os daily, 5 days a week. For the dynamic monitoring of results of treatment of animals taken out of the experience with a periodicity of 4 and 8 weeks by decapitate. Treatment effectiveness was assessed by severity of tuberculosis infection: dynamics of body weight of the animals, the coefficients of the weight of internal organs (lungs, liver, spleen); indices of lung damage; Visavuori mycobacteria from the spleen (number of colony forming units - CFU). In immunological studies investigated macrophage immunity. Its intensity was evaluated by the reaction of changing the intensity of the recovery nitrotetrazolium blue (hereinafter NBT - test) - spontaneous improvement in therapy of experimental tuberculosis of mice. This therapeutic effect is dose-dependent and is most evident when using the drug in a dose of 40 mg/kg it Should be noted that the purpose of Glutoxim in combination with anti-TB drugs contributed to a significant reduction in the massive growth of the pathogen in the crop from the spleen (1.7 - 1.9 times as compared with the corresponding control).

Table 3 shows the influence of the drug Glutoxim on the efficiency of chemotherapy of experimental tuberculosis of mice (4 weeks of therapy).

Table 4 shows the influence of the drug Glutoxim on the efficiency of chemotherapy of experimental tuberculosis of mice (8 weeks of therapy).

Under the influence of Glutoxim recorded a decrease in the prevalence of specific lung, which was confirmed a significant decrease in the indices of the destruction of this body on 22-35%. In mice treated with Glutoxim on the background of combinations of anti-TB drugs (N+R) or (N+R+Z), there was a steady trend of decreasing ratios of the mass of the liver.

Table 5 presents the dynamics of the functional activity of peritoneal macrophages was determined by the average cytochemical coasts is calculated by the ratio of the number of cells with activated granules formazan (reduction reaction of NBT - narasinga of tetrazole) to the total number of regarded cells according to the technique of not more than 100.

Marked stimulation drug Glutoxim functional capacity of macrophages in 1.5-2 times compared with the control groups, as evidenced by the dynamics of the factor values of the CCS (see table 5).

The findings suggest that the use of Glutoxim increases the efficiency of the complex therapy of acute progressive generalized tuberculosis in mice.

Example 3. Correction Glutoxim hepatotoxic effect of antituberculosis drugs in experimental studies.

The study was conducted on 30 white outbred rats male, weighing 240-300 g liver Damage caused by the introduction of anti-TB drugs (plum Y. I. , 1989): isoniazid 50 mg/kg, subcutaneously, rifampicin 250 mg/kg orally, pyrazinamide 45 mg/kg orally. Glutoxim applied subcutaneously in doses of 20 and 40 mg/kg the Rate of introduction of all drugs was 14 days. Animals taken out of the experience by decapitate. Liver function was assessed by the activity indicator enzymes in the serum (Alt, AST, bilirubin).

Conducted histological the sky changes and the microcirculation of the liver.

Table 6 presents the biochemical parameters of blood serum of rats. Tuberculostatic caused pronounced changes in the functional state of the liver (see table 6).

Toxic effects of anti-TB drugs on the liver manifested reliable increase of transaminase activity: Alat 1,220,12 mmol/tsp and AST 1,640,07 against 0,930,1 and 1,30,12 in the intact animals (p<0,1 and 0,05, respectively); the level of bilirubin in the serum increased 7.98 times in comparison with the established norm.

Histological studies have shown that under the influence of anti-TB drugs disrupted the structure of the liver. Hepatocytes located in the Central parts of the liver lobules, dramatically increase in volume, rounded, constrict the lumen of the respective sinusoidal, and subjected to protein and fatty degeneration. Revealed portal and vnutritrekovye inflammatory infiltrates. Revealed portal and vnutritrekovye inflammatory infiltrates. Table 7 presents the morphological characterization of rat liver. Significant changes were observed in the vascular system of the liver (see table 7), this indicates a significant reduction factor effective vascularize reduction hepatotoxic effect of antituberculosis drugs. The most pronounced hepatoprotective effect Glutoxim had a dose of 40 mg/kg Thus, the level of aminotransferases were not statistically different from those in the intact group; the level of bilirubin in the serum was 1.5 times lower compared with the control. The morphological examination of preparations of rat liver protected Glutoxim at a dose of 40 mg/kg, there was a trend to normalization of liver structure, as well as the improvement of hemodynamics. While KEV in both Central and peripheral parts of the lobules were not statistically different from the corresponding parameters in the intact group and 3.8-4.5 times the digital data control animals (see table 7).

Thus, experimental studies on rats with liver anti-TB drugs, it was found that Glutoxim has a pronounced hepatoprotective effect contributes to the correction of structural and metabolic abnormalities that occur in the liver.

The invention is illustrated by examples 4, 5 and 6, showing the results of clinical application of Glutoxim in a limited contingent of patients, demonstrating its pharmacological properties and confirming the possibility of Opel to the clinic on 5 September 2000 with complaints of weakness, fatigue, high fever, chest pain, shortness of breath during physical activity, sweating. From the anamnesis it is known that acutely ill. During the examination in the clinic pathology in the lungs, regarded as a specific and patient hospitalized in the first therapeutic Department of the Institute of AF.

On physical examination, a state of moderate severity. The rhythmic heart sounds, heart rate of 108 beats per 1 minute, satisfactory filling. HELL 85/40 mm RT. Art. In the lungs breathing weakened, above the upper lobes of the right lung heard the wet fine basal rales, BH-30 in 1 minute. In the clinical analysis of blood from September 6, 2000 - ESR accelerated to 63 mm/HR, Hg 100 g/l, leukocytes 10,0106; p/I 28%, with/I 61,5%; lymphocytes of 2.5%, monocytes 5%, basophils 0.5 percent. Blood biochemistry: reduced albumin to 28.2 g/l, elevated fibrinogen to 9 g/l, increased urea to 16.5 mmol/l; total bilirubin increased to 41 µmol/l; ALT 1.2 mmol/L. Serological reactions with tuberculous antigen: RPK - 57.E.; RPG - 43,0.E., then there is the over production of antibodies. Immunology: the number of T-lymphocytes and their subpopulations (CDs, CD4, CDs) decreased, respectively, to 46.5% and 656 cells/ mm3; 25% and 352,7 cells/mm3; 19% and 268 cells/mm3.

Review Ranchi upper lobe of the right lung, combined with caseous necrotic heterogeneous tricks, grouped lesions in the surrounding tissue. In the middle lobe rounded infiltrate 6,04,0 see6total infiltration, lots of melting of caseosa, in10group exudative lesions. Left lung is emphysematous, in the lower part of the multiple different-sized pockets. Method for smear microscopy and culture identified office (hereinafter referred to Mycobacterium tuberculosis) with LU (hereinafter - drug resistance to streptomycin and isoniazid.

Clinical diagnosis of Infiltrative tuberculosis of the right lung in the phase of decay screenings in C6WITH10the left lung, MBT (+)".

The patient on the background of a comprehensive specific treatment: isoniazid/drip; rifampicin, pyrazinamide, ethambutol, the course of Glutoxim within 6 months (2 months/drip 3% to 1.0 ml in the morning and 3% - 1.0 ml/m in the evening, the next 4 months 1% - 1.0 ml/m 2 times per day 3 times per week).

On the background of therapy after 2 months installed mild symptoms of intoxication, the improvement of hematological parameters of blood: decreased erythrocyte sedimentation rate of 16 mm/h; normalization of leukocytes and p/I of neutrophils; increase in lymphocytes from 2.5% to 31%. Normalization of biochemical pokiea - to 4.4 mmol/L. Subpopulations of T-lymphocytes and humoral response was not statistically different compared with the original data, i.e., remained depressed.

Rg and TMG from November 2000 registered a pronounced positive dynamics: the resolution infiltrative Atlanticheskogo component, resorption of inflammatory changes, part of the focus groups, the reduction and closure of some cavernous. The patient continued therapy in the same volume with further improvement.

Discharged after 6 months in a satisfactory condition, bazillion since September 2000 (after 1 month of therapy), the cavity decay is not determined within 3 months of starting treatment.

After normalization of biochemical parameters after 2 weeks of initiation of therapy with Glutoxim in the future throughout the massive anti-TB therapy of any toxic or allergic manifestations is not received, indicating that efficiency Glutoxim as drug tracking, basic anti-TB therapy.

Example 5

Patient E. , born in 1960, he entered the medical Department Spbniif 12.09.00 with complaints of cough with vyd is: the disease is diagnosed when contacting the clinic. When Rg-survey - 2-sided lesion of the lung tissue. Nonspecific therapy without effect. After consultation of TB patients hospitalized in the internal medicine Department Spbniif.

On physical examination, a state of moderate severity, the rhythmic heart sounds, pulse 86 beats per 1 minute, satisfactory filling. HELL 140/100 mm RT. senior harsh Breathing, wheezing is not heard. In the clinical analysis of blood ESR up to 32 mm/h, WBC - 9,8106; p/I 10%;/I 50%; lymphocytes - 16%; monocytes - 9%; eosinophils - 6%. Biochemical indices of the blood within normal limits. Immunological indicators: reduction CD4up to 22% 444,5; a sharp decline in CD8to 11.6% and 234,9 cells/mm3the increase of the coefficient CD4/CD8to 1.9. Identified over production of antibodies RPK to 90.E.; RGL 50.E.; ELISA 2,283.E. Overview Rg 21.08.00 from (from another institution): in the upper lobes of both lungs on the background of inflammatory changes detected many polymorphic lesions, which merge to form infiltrates, among which the thin-walled cavities from 4.0 to 2.0 cm in diameter. The apical pleura thickened. Smear and culture of sputum for MW is positive, the office is resistant to kanamycin and ethionamide.

Clinical diagnosis: Dissimilar is not complex therapy: in/drip isoniazid 15 mg/kg of body weight, rifampicin-0.6, pyrazinamide 2,0, ethambutol 1.2 in the day, the course of Glutoxim 3% - 1.0 ml/jet and 3% - 1.0 ml/m in the evening for 2 months. On the background of therapy with the inclusion of Glutoxim 2 months marked relief of symptoms of intoxication, the normalization of clinical blood parameters. Rg from 17.11.00 marked resorption of inflammatory changes, part of the focal groups. Areas of degradation decreased in volume, the walls of their suffered.

The patient continued in the complex therapy and the drug Glutoxim 1% - 1.0 ml 2 times a day three times a week. In the future, continued clinical and radiographic dynamics with normalization of immunological parameters. The patient was discharged after 6 months in a satisfactory condition, bazillion after 2 months, the cavity decay is not determined 3 months after initiation of therapy. On the background of anti-TB therapy for the entire period of hospital stay adverse events for drugs not obtained.

Example 6

Patient C. , born in 1953, he entered the medical Department Spbniif 10.09.00 with complaints of cough with the release of Muco-purulent sputum green-yellow color, shortness of breath with slight physical what was regressional. Poor tolerance of drugs group GINK, rifampicin due to the development of toxic hepatitis. The reason for hospitalization - further progression of tuberculous process, the ineffectiveness of previous therapy. When Rg-survey - 2-sided lesion of the lung tissue to form a cavity in the upper lobe of the left lung, infiltration with the collapse in the upper lobe of the right lung, multiple foci of dropouts in the lower lobe on both sides.

On physical examination, a state of moderate severity, the rhythmic heart sounds, pulse 100 beats in 1 minute, satisfactory filling. HELL 100/70 mm RT. senior Breathing hard, dry rales are heard over the lower lobes on both sides. In the clinical analysis of blood erythrocyte sedimentation rate of 30 mm/h, WBC - 8,8109; p/I 11%;/I 58%; lymphocytes -12%; monocytes - 10%; eosinophils - 9%. Blood biochemical parameters: Alat 1,43 mmol/l, ASAT 0.73 mmol/l, total bilirubin of 19.7 mmol g/L. Immunological indicators: reduction CD4up to 20% 420,5; a sharp decline in CD8to 14.3% and 247,9 cells/mm3the increase of the coefficient CD4/CD8to 1.7. Smear and culture of sputum for the office positive, smear-positive solid, the office is resistant to streptomycin, kanamycin, isoniazid.

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The patient on the background of the treatment: in/drip isoniazid 15 mg/kg of body weight, rifampicin-0.6, pyrazinamide 2,0, ethambutol 1.6 in the day, the course of Glutoxim 3% - 1.0 ml/jet and 3% - 1.0 ml/m in the evening for 2 months. On the background of therapy with the inclusion of Glutoxim, after 1 month marked relief of symptoms of intoxication, normalization of biochemical and significant improvement in clinical blood (Alat - of 0.68 mmol/l, erythrocyte sedimentation rate of 18 mm/h, WBC 8,0109: p/I 5%; C/I for 64%; lymphocytes - 22%; monocytes - 6%; eosinophils - 3%. Showed a significant increase in immunological parameters: CD4from 20% to 34%; CD8from 14.3% to 25%, the normalization coefficient CD4/CD8. Rg from 19.11.00 marked resorption of inflammatory changes, part of the focal groups. Areas of degradation decreased in volume, the walls of their suffered.

The patient continued in the complex therapy and the drug Glutoxim 1% - 1.0 ml 2 times a day three times a week. In the future, continued clinical and radiographic dynamics with normalization of immunological parameters. The patient was discharged after 6 months in a satisfactory condition, bazillion 3 months from start of therapy. On the Holocene. The patient normally for the first time endured products group GINK and rifampicin.

Thus, the purpose of Glutoxim in the complex treatment of tuberculosis provides for prevention of toxic complications and increases the overall effectiveness of therapy in terms of conversion and closing cavernous, with shortening inpatient treatment in an average of 1.5 months.

Sources of information

1. Pavlova, M. C. Complex chemotherapy with the use of immunotropic drugs infiltrative pulmonary tuberculosis in adolescents. Abstract. Diss. K. M. N. - L.,1980.

2. Snoring B. E. Peculiarities of the immune status of patients with pulmonary tuberculosis and its role in the diagnosis, prediction of flow and immune therapy. Abstract: Diss. D. M. N. - St. Petersburg, 1996.

3. Ivanov, L. A. Modern methods of correction etiopathogenetic treatment of destructive forms of pulmonary tuberculosis. Abstract. Diss. D. M. N., St. Petersburg, 1995.

4. Pavlova, M. C. Features of the course and treatment of respiratory TB in adolescents in modern epidemiological situation: author. Diss. D. M. N. - St. Petersburg, 2000.

5. Ivanov, L. A. , Pavlova, M. C., Vinogradova T. I., Archakov, L. I., Simbirtsev A. C. Application of rIL1 (Beth is: Sat. summary. - M., 2001.

6. Archakov, L. I. Complex therapy of patients with infiltrative tuberculosis of the lungs with the use of recombinant interleukins. Abstract. Diss. K. M. N., St. Petersburg, 2001.

7. RF patent 2089179 "Stimulator of endogenous production of cytokines and hemopoietic factors and how to use it", B 25 from 10.09.97.

8. Fan XG, Li CZ et al. Circulating Th1 and Th2 cytokines in patients with hepatitis With virus infections. Mediators Innamm. 1998, 7: 295-297.

1. Method for the treatment of various forms of pulmonary tuberculosis, characterized in that on the background of anti-TB treatment at least once a day enter the immunomodulator Glutoxim in a dose of from 20 to 60 mg per day.

2. The method according to p. 1, in which the active substance of Glutoxim is a chemically synthesized biologically active compound is a Hexapeptide with stabilized by a disulfide bond bis-(gamma-L-glutamyl)-L-cysteinyl-bis-glycine disodium salt, with a total formula - (C20H32O16H6S2).

3. The method according to p. 1, characterized in that when tuberculosis predominantly exudative type of tissue reaction Glutoxim intramuscularly 2 times daily 1 ml of 3% solution.

4. The method according to p. 1, distinguished by intramuscular injection, 2 times a day, 1 ml of 1% solution of 3 times per week.

5. The method according to p. 1, characterized in that in the light of tuberculosis in the background of drug resistance of mycobacteria to Glutoxim administered 2 times daily 1 ml of 3% solution: in the morning, intravenously, in the evening intramuscularly for 2 months daily.

 

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The invention relates to medicine, namely to psychiatry

The invention relates to the derivatives of dolastatin 15 General formula (I) a-b-D-E-F(G)r-(K)s-L, where a, b, D, E, F, G and K are remnants-amino acids and s and r are each independently 0 or 1

The invention relates to compounds of the formula X1-Leu-His-Lys(R1)-Leu-Gln-Thr-Tyr(R2)-Pro-Y, where X1- H-, A1O-CO-, H-Lys(R3)-Leu-Ser-Gln-Glu(B4)-, A1O-CO-Lys(R3)-Leu-Ser-Gln-Glu(B4)-; Y is-OH, -Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2;1there is tert-butyl; R1- protective group of the formula IN the1O-CO - Epsilon-amino group of the Lys residue, R2- protective group of the formula IN the2About-WITH - hydroxyl group of residue Taut, R3- protective group of the formula IN the3O-CO - Epsilon-amino group of the Lys residue IN4- protective group for the gamma-carboxyl group of Glu residue, and1IN2IN3and4may be the same or different and are selected from the range: 2-alkylsulfonates, 2-phenylsulfonyl, 2-(substituted aryl)sulfonylated

The invention relates to medicine, in particular to immunology and Nephrology

The invention relates to medicine and the pharmaceutical industry in creating new medicines for the treatment of bronchopulmonary diseases infectious and inflammatory nature, accompanied asthmatic component

The invention relates to liposomes, including new peptide antigens that are involved in the regulation of human immunity against hepatitis b virus, more specifically to the group of peptides corresponding to epitopes of antigens derived from beam HBV X

The invention relates to medicine, in particular to the medical industry, and can be used for treating immunodeficiencies involving violation of the process of differentiation of T-lymphocytes

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

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