RU2197984C1 - Method for treating different forms of pulmonary tuberculosis, resistant to antitubercular chemotherapy, among them - Google Patents

Abstract

FIELD: medicine, phthisiology. SUBSTANCE: immunomodulator Glutoxym is introduced, at least, once daily at 30-60 mg/d, moreover, in case of pulmonary tuberculosis with predominantly exudative type of tissue reaction Glutaxym should be introduced intramuscularly twice daily per 1 ml 3-% solution; at pulmonary tuberculosis with predominantly productive type of tissue reaction Glutoxym is introduced intramuscularly twice daily per 1 ml 1-% solution thrice weekly; at pulmonary tuberculosis at the background of medicinal mycobacterial resistance Glutoxym is introduced twice daily per 1 ml 3-% solution: in the morning - intravenously, in the evening - intramuscularly for 2 mo daily. The invention considerably decreases hepatotoxic action of antitubercular preparations and increases efficiency of antitubercular chemotherapy conducted. EFFECT: higher efficiency of therapy. 5 cl, 6 ex, 7 tbl

Description

 The invention relates to medicine, namely to phthisiology, can be used in medical practice in the complex treatment of patients with various forms of pulmonary tuberculosis.

 A new tuberculosis epidemic has become a global emergency. Tuberculosis has returned to all countries of the world with drug-resistant, slightly curable forms. Significantly increased the number of patients with caseous pneumonia, generalized forms of tuberculosis. More than half of patients have an acute course of tuberculosis with hectic fever, severe inflammatory changes in the blood, and hypoalbuminemia. The intensity of bacterial excretion and the resistance of mycobacteria to the main anti-TB drugs increased.

 The drug resistance of mycobacterium tuberculosis is becoming an increasingly serious obstacle to achieving an effect in the treatment of patients, makes etiotropic therapy ineffective, and is the most common cause of the progression of a specific process that leads to death.

 Under these conditions, the role of drugs that help restore and increase the body's own defenses (specific and non-specific immunological resistance), as well as improve the tolerability of anti-TB drugs and eliminate their hepato-, oto-, neuro-, cardio- and nephrotoxic side effects, significantly increases.

 Currently, chemotherapy is the main method for treating pulmonary tuberculosis, however, more than 50% of patients are resistant to standard therapy, which requires the appointment of expensive reserve drugs that have poor tolerance and are not always available at a TB institution.

 Immunomodulating agents previously used in the complex treatment of tuberculosis, such as thymalin [1, 2, 3], T-activin [1, 2, 3], had a limited spectrum of action (stimulation of T-active lymphocytes) and could be used only in patients with exudative type of tissue reaction. The use of tuberculin [4] in patients with a productive tissue reaction under conditions of increasing drug resistance of mycobacteria can lead to an exacerbation of the tuberculosis process. In this type of tissue reaction, preference is given to beta-leukin [5, 6], which in its characteristics fully corresponds to interleukin-1. However, for the treatment of tuberculosis at the present stage, in the context of increasing drug resistance, it is necessary to use a universal remedy applicable to all types of tissue reaction, able to have a differentiated effect on all links of T-cell immunity, potentiate the specific activity of anti-TB drugs, and have cytoprotective effects.

 The known drug Glutoxim, which is approved on 10.09.98 by the Russian Pharmacological Committee for clinical use as a medicine, which is a biological response modifier with immunomodulating properties (registration number 98 \ 279 \ 3).

 Currently, injectable dosage forms are used for intravenous, intramuscular and subcutaneous administration, which are a solution of the active substance - Glutoxim of various degrees of concentration, in an aqueous solution of NaCl, namely 0.5% (VFS 42-3195-98), 1% and 3 % (VFS 42-3408-99).

According to VFS (42-3195-98, 42-3408-99), Glutoxim is a chemically synthesized biologically active compound - hexapeptide with a stabilized disulfide bond bis - (- gamma-L-glutamyl) -L-cystenyl-bis-glycine disodium salt with the total formula (C ₂₀ H ₂₀ N ₆ Na ₂ O ₁₂ S ₂ ).

The drug Glutoxim is a representative of a new class of drugs - thiopoietins [7], which have unique biological and pharmacological effects, which are:
regulation of the escalation of the redox state of cells;
modulation of the 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 effect on normal and infected cells.

 Being an analogue of key cellular metabolites, the active substance of the drug Glutoxim has high bioavailability, as a result of which, when introduced into biological media, it instantly translocates into target cells, triggering a cascade mechanism of biochemical reactions of metabolic regulation, proliferation and differentiation of cells, which forms a wide range of immunomodulating and cytoprotective effects of the drug . To date, quite a lot of experience has been gained with the use of the drug Glutoxim in clinical medicine, confirming its biological and pharmacological effects.

 The problem to which the claimed invention is directed is to create a method for treating patients with various forms of pulmonary tuberculosis by administering Glutoxim against a background of complex specific therapy to achieve a therapeutic effect due to the regulatory effect of the drug on the pathogenetic mechanisms of the development and course of this disease, as well as the prevention of complications.

 This application is for the first time shown and substantiated that the use of Glutoxim in clinical practice in the complex treatment of patients with pulmonary tuberculosis allows for a fundamentally new level to carry out immunological and cytoprotective support for antituberculous chemotherapy.

 According to the claimed invention, a method of treating various forms of pulmonary tuberculosis is that against the background of complex specific therapy, Glutoxim is administered at least once a day at a dose of 20 to 60 mg per day (depending on the nature of the course and severity of the disease) during the period necessary to achieve a therapeutic effect.

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

 According to the claimed invention, for pulmonary tuberculosis with a predominantly productive type of tissue reaction, Glutoxim is administered 3 times a week intramuscularly in a dose of 1 ml of 1% solution.

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

 According to the invention, in acute progressive forms of tuberculosis, Glutoxim is administered intramuscularly or subcutaneously once 3 times a week in 1 ml of a 3% solution.

In this case, the active substance of the drug Glutoxim is a chemically synthesized biologically active compound - hexapeptide with a stabilized disulfide bond bis (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt with the total formula - (C ₂₀ H ₃₀ N ₆ Na ₂ O ₁₂ S ₂ ).

 In clinical conditions, the method is as follows.

 Against the background of the use of specific anti-TB drugs, Glutoxim is prescribed intravenously and / or intramuscularly according to the following scheme.

 In patients with pulmonary tuberculosis with a predominantly exudative type of tissue reaction, Glutoxim is prescribed in the first two months of chemotherapy in the form of a 3% solution of 1 ml 2 times a day intravenously or intramuscularly in a daily dose of 60 mg daily. When treating a patient in a day hospital, it is allowed to administer the drug 5 days a week (except Saturday, Sunday).

 With a productive type of specific inflammation, a 1% Glutoxim solution is administered intramuscularly 2 times a day, 3 times a week at a dose of 20 mg per day.

 In cases of developed drug resistance of mycobacteria to anti-TB drugs, a 3% Glutoxim solution is prescribed daily 2 times a day, 1 ml intravenously in the morning and 1 ml intramuscularly in the evening for a period of at least 2 months.

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

The introduction of the drug Glutoxim in patients with pulmonary tuberculosis, including with drug resistance of mycobacteria, provides:
1. Regulation of immunity. It is known that the nature of the immune response depends on the dominant participation of clones of CD4 + T-lymphocytes - type 1 helpers (Th1) and type 2 helpers (Th2), which differ in the cytokines they produce and in the activation of the immune response in the cellular or humoral type [8]. Activation by the Glutoxim Th1 drug producing interferon gamma, interleukin 2, tumor necrosis factor alpha and beta, leads to stimulation of the function of T-lymphocytes and resident macrophages, i.e. to the development of an immune response according to the cellular type, which plays a decisive role in protecting the body from tuberculosis. The function of the pleiotropic cytokine IL-12 is also important. Launching its products, Glutoxim regulates the ratio of Th1 / Th2 in the direction of increasing T-cell immunity. Differentially acting on the macrophage immunity, Glutoxim, on the one hand, promotes the activation, proliferation and differentiation of functionally capable resident macrophages of the lungs, on the other hand, causes apoptosis of macrophages infected with mycobacterium tuberculosis (see example 1). The drug Glutoxim inhibits the system of the P-glycoprotein complex (product of the MDR gene), which prevents the development of drug resistance of tuberculosis mycobacteria.

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

 3. Prevention of toxic-allergic complications of anti-tuberculosis chemotherapy (see examples 3, 6).

 4. Rapid restoration of the quality of life of patients (see examples 4,5).

5. Improving the effectiveness of treatment according to the main criteria for the cure of tuberculosis (see examples 4, 5, 6)
The invention is illustrated by examples that clearly demonstrate the identified properties of Glutoxim in experimental models (examples 1, 2, 3).

 Example 1. The effect of Glutoxim on the growth of drug-resistant mycobacterium tuberculosis in the cell and extracellular medium in the lung tissue culture of mice.

 The effect of Glutoxim on the growth of drug-resistant mycobacteria tuberculosis (hereinafter referred to as LR MBT) in the presence of anti-TB drugs to which mycobacteria are resistant (isoniazid and rifampicin) was studied. The lung tissue of mice was cultured by a modified method of explantation in silicone perfusion chambers. Pieces of lung tissue (explants) were placed on the coverslip of the chambers and fixed to the glass using rabbit blood plasma. Medium 199 was introduced into the chambers. Within 5-6 days of cultivation, an extensive area of eviction and growth of cellular elements formed around the explants, among which macrophages and fibroblasts predominated. A fibroblastic shaft appeared along the perimeter of the explants, which exfoliated, forming a ring-shaped structure filled with various mobile cellular elements of the lung tissue. Large and small macrophages also prevailed here.

 Drug-resistant mycobacteria (hereinafter referred to as LR MBT) were obtained from patients with tuberculosis. Resistance to isoniazid was 1 μg / ml, to rifampicin - 50 μg / ml. A suspension of LR MBT in medium 199 was obtained without quantitative dosing of microbial bodies (the same volume of a suspension of LR MBT).

 In the first series of experiments, the effect of Glutoxim alone on the growth of LR MVT was studied. Glutoxim from ampoules with 1 ml of a 3% drug solution was diluted to a final concentration of 1 μg / ml in medium 199 containing 10% serum of cattle and a suspension of LR of MBT. In the control variant, the same nutrient medium was used with an equal content of the suspension of LR of the MBT without Glutoxim.

 In the second series of experiments, the effect of Glutoxim on the growth of LR of MBT in the presence of isoniazid or rifampicin was studied. Isoniazid was diluted in medium 199, containing the same components as in the first series, to a concentration of 1 μg / ml, rifampicin to a concentration of 50 μg / ml, glutoxim to a concentration of 1 μg / ml. 5 groups of chambers were allocated: 1. Control without drugs; 2. Chambers containing one isoniazid; 3. Cameras with one rifampicin; 4. Chambers containing isoniazid + glutoxim; 5. Cameras containing rifampicin + glutoxim.

 The growth of microcolonies of LR MBT and the growth of cellular elements in the eviction zone (VNU) and beyond (VNU) were observed in phase contrast using an inverted microscope. Microcolonies of the LR of the MBT, which are characteristic morphological formations known as braids, were counted in 100 fields of view with an increase of 2 • 10 • 40. At the same time, the state of cellular elements was assessed: their viability, mobility, phagocytic activity, and the state of internal structures (nuclei, granules, endo- and ectoplasmas).

 In the first series of experiments, LR microcolonies of MBT appeared in the form of small “braids” 3-4 days after inoculation of the microbial suspension both in control (without Glutoxim) and in experimental chambers in a large number outside the zone of eviction and growth of cellular elements and in a small amount within this zone. In the next 3-5 days, their number and size increased. Table 1 presents the growth dynamics of microcolonies of LR MBT under the action of the drug Glutoxim. From table 1 it is seen that when using Glutoxim alone at a concentration of 1 μg / ml in the area of eviction and growth of cell elements, the number of grown microcolonies of LR MBT was significantly less than beyond, which is confirmed by the high degree of statistical significance of the differences. In the control chambers, the number of microcolonies of LR MBT within the cell array did not statistically differ from that outside it.

 In the control chambers, most of the cellular elements lost signs of viability: macrophages were immobile, did not form pseudopodia, large shapeless inclusions were detected in their cytoplasm. Out of many macrophages, there were outgrowths of the “braid” of MBT microcolonies. Fibroblasts were deformed, granular structures in them were lumpy, and nuclei were not visually detected.

 In cells with Glutoxim, signs of degradation of cellular elements were also observed, but they were not so pronounced. Some macrophage mobility remained, their cytoplasm seemed more structural. Some macrophages formed pseudopodia, which indicated the continuation of the phagocytosis process. Some fibroblasts were deformed, but part retained a typical spindle-shaped shape with the correct arrangement of granules and a clearly visible nucleus.

 Thus, Glutoxim in the absence of anti-tuberculosis drugs contributed to a more efficient phagocytosis of MBT in the cell culture medium of lung tissue and reduced the damage to cellular elements caused by infection.

 In the second series of experiments, the administration of Glutoxim in combination with anti-tuberculosis drugs: isoniazid or rifampicin led to significant changes in the number of drug-resistant microbial population in the area of eviction and growth of cellular elements compared to that outside it. Table 2 shows the effect of Glutoxim on the growth of LR microcolonies in the presence of major anti-TB drugs.

 Glutoxim had a significant effect on the growth of LR of MBT in the cell medium both in the presence of isoniazid and rifampicin. The number of microcolonies here was 10 times less with the combination of glutoxim with isoniazid and 5 times less when combined with rifampicin compared to that in the extracellular medium. When comparing these data with the data obtained in the first series of experiments, one gets the impression that Glutoxim increased the antituberculous activity of rifampicin and isoniazid. This is due to a significant weakening of the vitality of the LR MVT upon activation of the phagocytic ability of macrophages, as a result of which the effect of anti-TB drugs becomes more pronounced.

 Characteristic was the complete preservation of the viability of the cellular elements of the lung tissue with the combination of Glutoxim with isoniazid or rifampicin. Macrophages were motile, and there were no morphological signs of degradation. Fibroblasts had a characteristic oblong shape, an oval nucleus with nucleoli, a perinuclear arrangement of granules was noted in them.

 In control chambers without preparations, with isoniazid alone or with rifampicin alone, the cell elements underwent significant degradation and were not viable. There was a spit "braid" of the LR MVT from macrophages. Outside the cell array, in all cases, abundant growth of microcolonies of LR MVT was observed.

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

 Example 2. The effectiveness of the treatment and the state of the immune status when glutoxim is included in the complex chemotherapy of experimental tuberculosis in mice.

 The study was conducted on 180 white, outbred mice - males, from which intact (n = 20) and infected untreated (control culture n = 20) were isolated. The remaining 140 animals comprised two treatment control groups and 4 groups with the inclusion of glutoxim in complex anti-tuberculosis therapy. To simulate experimental tuberculosis in mice, a suspension of M. bovis 8 culture was used, which was injected into the tail lateral vein at a dose of 0.1 mg / 0.2 ml per mouse. Treatment of animals began on the 10th day from the moment of infection (upon detection of single foci of productive specific inflammation in the lungs) and continued for 8 weeks. Glutoxim was administered at doses of 20 and 40 mg / kg, subcutaneously against the background of two (isoniazid + rifampicin) and three (isoniazid + rifampicin + pyrazinamide) tuberculostatics. Anti-TB drugs were prescribed in therapeutic doses: isoniazid (N) 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 as an aqueous suspension were administered per os daily, 5 days a week. In order to dynamically monitor the results of treatment, animals were taken from the experiment with a frequency of 4 and 8 weeks by decapitation. The effectiveness of treatment was evaluated by indicators of the severity of the course of tuberculosis infection: the dynamics of the body weight of animals, the mass coefficients of the internal organs (lungs, liver, spleen); lung lesion indices; inoculation of mycobacteria from the spleen (the number of colony forming units - CFU). In immunological studies, the macrophage immunity link has been studied. His tension was assessed by the reaction of changes in the intensity of recovery of nitrotetrazolium blue - (hereinafter HCT - test) - spontaneous and induced by zymosan.

 The use of Glutoxim in combination with (H + R) and (H + R + Z) makes a significant improvement in the treatment of experimental mouse tuberculosis. In this case, the therapeutic effect is dose-dependent in nature and is most pronounced when using the drug at a dose of 40 mg / kg. It should be noted that the appointment of Glutoxim in combination with anti-TB drugs contributed to a significant decrease in the growth rate of the pathogen in crops from the spleen (1.7 - 1.9 times compared with the corresponding control).

 Table 3 shows the effect of Glutoxim on the effectiveness of chemotherapy in experimental mouse tuberculosis (4 weeks of therapy).

 Table 4 shows the effect of Glutoxim on the effectiveness of chemotherapy in experimental mouse tuberculosis (8 weeks of therapy).

 Under the influence of Glutoxim, a decrease in the prevalence of specific lung lesion was recorded, which was confirmed by a significant decrease in the lesion index of this organ by 22-35%. Mice treated with glutoxim in combination with anti-tuberculosis drugs (H + R) or (H + R + Z) showed a steady decrease in liver mass ratios.

 Table 5 presents the dynamics of the functional activity of peritoneal macrophages, which is determined by the value of the average cytochemical coefficient (hereinafter - SCC, conventional units) during complex therapy for 4 and 8 weeks. In this case, the SCK coefficient is calculated by the ratio of the number of cells with the included formazan granules (in the HCT reduction reaction - nitro-blue tetrazolium) to the total number of counted cells, according to the procedure, not more than 100.

 Glutoxim stimulated macrophage functional capacity by 1.5-2 times compared with control groups, as evidenced by the dynamics of the SCK coefficient (see table 5).

 The data obtained indicate that the use of Glutoxim increases the effectiveness of the complex therapy of acutely progressing generalized tuberculosis in mice.

 Example 3. Glutoxim correction of the hepatotoxic effect of anti-TB drugs in experimental studies.

 The study was conducted on 30 white, outbred rats - males, weighing 240-300 g. Liver damage was caused by the introduction of anti-TB drugs (Slivka Yu. I., 1989): isoniazid 50 mg / kg, subcutaneous, rifampicin 250 mg / kg orally, pyrazinamide 45 mg / kg orally. Glutoxim was administered subcutaneously at doses of 20 and 40 mg / kg. The course of administration of all drugs was 14 days. Animals were removed from the experiment by decapitation. The functional state of the liver was evaluated by the activity of indicator enzymes in the blood serum (AlAT, AsAT, bilirubin).

 A histological examination of rat liver preparations stained with hematoxylin and eosin was performed; the severity of dystrophic changes and the state of the microvasculature of the liver were taken into account.

 Table 6 presents the biochemical parameters of rat serum. Tuberculostatics caused marked changes in the functional state of the liver (see table 6).

 The toxic effect of anti-tuberculosis drugs on the liver was manifested by a significant increase in the activity of transaminases: AlAT 1.22 ± 0.12 mmol / h. l and AsAT 1.64 ± 0.07 versus 0.93 ± 0.1 and 1.3 ± 0.12 in intact animals (p <0.1 and 0.05, respectively); serum bilirubin level increased 7.98 times compared with the established norm.

 Histological studies have shown that under the influence of anti-TB drugs, the liver structure is disturbed. Hepatocytes located in the central departments of the hepatic lobules increase sharply in volume, round up, narrowing the lumen of the corresponding sinusoids, and undergo protein and fatty degeneration. Portal and intralobular inflammatory infiltrates were detected. Portal and intralobular inflammatory infiltrates were detected. Table 7 presents the morphological characteristics of rat liver. Significant changes were found in the vascular system of the liver (see table 7), this is indicated by a significant decrease in the coefficient of effective vascularization (CEV) - 0.25 ± 0.08 versus 1.11 ± 0.4 in intact rats.

 When using Glutoxim, a significant decrease in the hepatotoxic effect of anti-TB drugs was observed. The most pronounced hepatoprotective effect of glutoxim was at a dose of 40 mg / kg. So, the level of aminotransferases did not statistically differ from that in the intact group; serum bilirubin level was 1.5 times lower compared to the control. In a morphological study of rat liver preparations protected with glutoxim at a dose of 40 mg / kg, a tendency toward normalization of the liver structure, as well as an improvement in its hemodynamics, was noted. At the same time, CEV in both the central and peripheral parts of the lobules did not statistically differ from the corresponding indicators in the intact group and exceeded the digital data of control animals by 3.8–4.5 times (see table 7).

 Thus, experimental studies conducted on rats with liver damage with anti-TB drugs showed that Glutoxim has a pronounced hepatoprotective effect, contributes to the correction of structural and metabolic disorders that occur in the liver.

 The invention is illustrated by examples 4, 5 and 6, demonstrating the results of the clinical use of Glutoxim in a limited group of patients, demonstrating its pharmacological properties and confirming the possibility of achieving a therapeutic effect.

 Example 4

 Patient I., born in 1953, was admitted to the clinic on September 5, 2000 with complaints of weakness, fatigue, high fever, chest pain, shortness of breath during physical exertion, sweating. From the anamnesis it is known that he fell ill acutely. An examination in the clinic revealed a pathology in the lungs, regarded as specific, and the patient was hospitalized in the I therapeutic department of the Research Institute of FP.

An objective examination of the state of moderate severity. Heart sounds are rhythmic, the pulse is 108 beats in 1 minute, satisfactory filling. HELL 85/40 mm RT. Art. In the lungs, breathing is weakened, moist finely bubbling rales are heard over the upper lobe of the right lung, BH-30 in 1 minute. In a clinical blood test dated September 6, 2000 - ESR is accelerated to 63 mm / hour, Hg 100 g / l, white blood cells 10.0 • 10 ⁶ ; PO Box 28%, PO Box 61.5%; lymphocytes 2.5%; monocytes 5%, basophils 0.5%. Blood biochemistry: albumin is reduced to 28.2 g / l, fibrinogen is increased to 9 g / l, urea is increased to 16.5 mmol / l; total bilirubin increased to 41 μmol / l; ALT 1.2 mmol / L. Serological reactions with tuberculosis antigen: PKK - 57 cu; RPG - 43.0 cu, that is, there is a hyperproduction of antibodies. Immunology: the number of T-lymphocytes and their subpopulations (CDs, CD4, CDs) is reduced: to 46.5% and 656 cells / mm ³ , respectively; 25% and 352.7 cells / mm ³ ; 19% and 268 cells / mm ³ .

On the survey roentgenogram (hereinafter - Rg) and tomogram (hereinafter - TMG) from 09/08/00: infiltrative-atelectatic compaction at the base of the upper lobe of the right lung, combined with caseous-necrotic inhomogeneous foci, grouped lesions in the surrounding tissue. In the middle lobe, a roundish infiltrate of 6.0 • 4.0 cm. In C _6, total infiltration, sites of melting of caseosis, in C ₁₀ groups of exudative foci. The left lung is emphysema, in the lower lobe there are multiple foci of different sizes. By means of bacterioscopy and culture, MBT (hereinafter referred to as mycobacterium tuberculosis) with LU (hereinafter referred to as drug resistance) to streptomycin and isoniazid were detected.

Clinical diagnosis: "Infiltrative tuberculosis of the right lung in the decay phase with screenings in C ₆ , C _{10 of the} left lung, Office (+)."

 To the patient against the background of complex specific therapy: isoniazid iv drip; rifampicin, pyrazinamide, ethambutol Glutoxim was administered for 6 months (2 months iv 3% - 1.0 ml in the morning and 3% - 1.0 ml in the evening, subsequent 4 months 1% - 1.0 ml in / m 2 times a day 3 times a week).

 Against the background of the therapy, after 2 months, the relief of symptoms of intoxication was established, the improvement of blood hematological parameters: a decrease in ESR to 16 mm / h; normalization of leukocytes and p / I neutrophils; an increase in lymphocytes from 2.5% to 31%. Normalization of biochemical parameters began already after 2 weeks from the start of Glutoxim therapy: bilirubin - 12.2 mmol / l, ALT - 0.12 mmol / l, urea - up to 4.4 mmol / l. The subpopulations of T-lymphocytes and the humoral response did not statistically significantly differ in comparison with the initial data, i.e. remained reduced.

 Rg and TMG from November 2000 registered pronounced positive dynamics: resolution of the infiltrative-atelectatic component, resorption of inflammatory changes, parts of focal formations, reduction and closure of some decay cavities. The patient continued therapy in the same volume with further improvement.

 Discharged after 6 months in satisfactory condition, abacillated since September 2000 (after 1 month of therapy), decay cavities are not determined after 3 months from the start of treatment.

 After normalization of biochemical parameters after 2 weeks from the start of Glutoxim therapy, no toxico-allergic manifestations were obtained throughout the entire massive anti-tuberculosis therapy, which indicates the effectiveness of using Glutoxim as a support drug, basic anti-tuberculosis therapy.

Example 5
Patient E., born in 1960, was admitted to the therapeutic department of SPbNIIF on September 12, 00, complaining of a cough with white mucous discharge, shortness of breath during physical exertion, sweating, weight loss. From the anamnesis: the disease was detected when contacting the clinic. When Rg-examination - 2-sided lesion of the lung tissue. Nonspecific therapy without effect. After consulting a TB specialist, the patient was hospitalized in the therapeutic department of SPbNIIF.

With an objective examination, the condition is moderate, heart sounds are rhythmic, the pulse is 86 beats in 1 min, satisfactory filling. HELL 140/100 mm RT. Art. Hard breathing, wheezing is not heard. In the clinical analysis of blood ESR up to 32 mm / h, white blood cells - 9.8 • 10 ⁶ ; PO Box 10%; s / i 50%; lymphocytes - 16%; monocytes - 9%; eosinophils - 6%. Blood biochemical parameters are within normal limits. Immunological indicators: decrease in CD ₄ to 22% 444.5; a sharp decrease in CD ₈ to 11.6% and 234.9 cells / mm ³ increase in the coefficient of CD ₄ / CD ₈ to 1.9. Overproduction of RPK antibodies up to 90 cu is detected; RGL 50 cu; IFA 2.283 cu Survey Rg from 08.21.00 (from another institution): in the upper lobes of both lungs, against the background of inflammatory changes, many polymorphic lesions are revealed, which, merging, form infiltrates, among which thin-walled caverns from 4.0 to 2.0 cm in diameter. Apical pleura thickened. Bacterioscopy and sputum culture at MBT are positive, MBT are resistant to kanamycin and ethionamide.

 Clinical diagnosis: Disseminated tuberculosis of the upper lobes of both lungs in the phase of infiltration and decay, MBT (+).

 The patient on the background of complex therapy: iv drip isoniazid 15 mg / kg body weight, rifampicin 0.6, pyrazinamide 2.0, ethambutol 1.2 per day, a course of glutoxim 3% - 1.0 ml iv in a jet and 3% - 1.0 ml im in the evening for 2 months. Against the background of ongoing therapy with the inclusion of Glutoxim, 2 months later, relief of symptoms of intoxication and normalization of clinical blood parameters are noted. Rg from 11/17/00 there is a resorption of inflammatory changes, part of the focal formations. Destruction sites decreased in volume, their walls were thinned.

 The patient continued with complex therapy and the administration of the drug Glutoxim 1% - 1.0 ml 2 times a day three times a week. In the future, positive clinical and radiological dynamics remained with the normalization of immunological parameters. The patient was discharged after 6 months in satisfactory condition, abacillated after 2 months, decay cavities are not determined after 3 months from the start of therapy. Against the background of anti-tuberculosis therapy for the entire period of stay in the hospital, side effects on drugs were not received.

Example 6
Patient V., born in 1953, was admitted to the therapeutic department of SPbNIIF on September 10, 00, complaining of a cough with mucus-purulent sputum of green-yellow color, shortness of breath with little physical exertion, sweating, weight loss. From the anamnesis: tuberculosis was detected in 1998. It was treated irregularly. The process has progressed. Poor tolerance of GINC drugs, rifampicin due to the development of toxic hepatitis. The reason for hospitalization is the further progression of the tuberculosis process, the inefficiency of previous therapy. An Rg examination revealed a 2-sided lesion of the lung tissue with a cavity formed in the upper lobe of the left lung, an infiltrate with disintegration in the upper lobe of the right lung, multiple foci of screening in the lower lobes on both sides.

With an objective examination, the condition is moderate, heart sounds are rhythmic, the pulse is 100 beats in 1 min, satisfactory filling. HELL 100/70 mm RT. Art. Hard breathing, dry rales are heard over the lower lobes on both sides. In the clinical analysis of blood ESR - 30 mm / h, white blood cells - 8.8 • 10 ⁹ ; PO Box 11%; s / s 58%; lymphocytes -12%; monocytes - 10%; eosinophils - 9%. Blood biochemical parameters: AlaT 1.43 mmol / L, AcaT 0.73 mmol / L, total bilirubin 19.7 mmol g / L. Immunological indicators: decrease in CD ₄ to 20% 420.5; a sharp decrease in CD ₈ to 14.3% and 247.9 cells / mm ³ increase in the coefficient of CD ₄ / CD ₈ to 1.7. Bacterioscopy and sputum culture on MBT are positive, massive bacterial excretion, MBT are resistant to streptomycin, kanamycin, isoniazid.

 Clinical diagnosis: Fibrous-cavernous pulmonary tuberculosis in the phase of infiltration and contamination, MBT (+).

The patient on the background of complex therapy: iv drip isoniazid 15 mg / kg body weight, rifampicin 0.6, pyrazinamide 2.0, ethambutol 1.6 per day, a course of Glutoxim 3% - 1.0 ml iv in a stream and 3% - 1.0 ml im in the evening for 2 months. Against the background of the ongoing therapy with the inclusion of Glutoxim, within 1 month, relief of symptoms of intoxication, normalization of biochemical symptoms and a significant improvement in the clinical indicators of blood are noted (AlaT - 0.68 mmol / L, ESR 18 mm / h, white blood cells 8.0 • 10 ⁹ : p I am 5%; s / I 64%; lymphocytes - 22%; monocytes - 6%; eosinophils - 3%. A significant increase in immunological parameters was noted: CD ₄ from 20% to 34%; CD ₈ from 14.3% to 25 %, normalization coefficient CD ₄ / CD _8. Rg on 19/11/00 resorption inflammatory changes noted, parts focal groups. Land degradation umenshilis in volume, their walls are thinned.

 The patient continued with complex therapy and the administration of the drug Glutoxim 1% - 1.0 ml 2 times a day three times a week. In the future, positive clinical and radiological dynamics remained with the normalization of immunological parameters. The patient was discharged after 6 months in satisfactory condition, abacillated 3 months after the start of therapy. Against the background of anti-tuberculosis therapy for the entire period of stay in the hospital, side effects on drugs were not received. For the first time, a patient normally tolerated GINC and rifampicin preparations.

 Thus, the appointment of Glutoxim in the complex treatment of tuberculosis provides the prevention of toxic complications and increases the overall effectiveness of therapy in terms of abacillation and closure of decay cavities, with a reduction in the duration of inpatient treatment by an average of 1.5 months.

Sources of information
1. Pavlova M. Century. Complex chemotherapy using immunotropic drugs with infiltrative pulmonary tuberculosis in adolescents. Abstract. diss. Ph.D. - L., 1980.

 2. Knoring B. E. Features of the immune status of patients with pulmonary tuberculosis and its role in the diagnosis, prognosis of the course and immunocorrection of therapy. Abstract: Diss. doctor of medical sciences - St. Petersburg, 1996.

 3. Ivanova L. A. Modern methods of correction of etiopathogenetic therapy of destructive forms of pulmonary tuberculosis. Abstract. diss. doctor of medical sciences - St. Petersburg, 1995.

 4. Pavlova M. V. Features of the course and treatment of respiratory tuberculosis in adolescents in modern epidemiological conditions: Abstract. diss. doctor of medical sciences - St. Petersburg, 2000.

 5. Ivanova L. A., Pavlova M. V., Vinogradova T. I., Archakova L. I., Simbirtsev A. S. Using rIL1β (beta-leukin) in the treatment of patients with infiltrative pulmonary tuberculosis // 11 Nat. congress on respiratory diseases: Sat. summary. - M., 2001.

 6. Archakova L.I. Complex therapy of patients with infiltrative pulmonary tuberculosis using recombinant interleukins. Abstract. diss. Ph.D. - St. Petersburg, 2001.

 7. RF patent 2089179 "Stimulator of the endogenous production of cytokines and hematopoietic factors and the method of its use", BI 25 from 09/10/97.

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

Claims (5)

 1. A method of treating various forms of pulmonary tuberculosis, characterized in that against the background of anti-tuberculosis chemotherapy, at least once a day, a Glutoxim immunomodulator is administered at a dose of 20 to 60 mg per day. 2. The method according to claim 1, in which the active substance Glutoxim is a chemically synthesized biologically active compound - hexapeptide with a stabilized disulfide bond bis- (gamma-L-glutamyl) -L-cysteinyl-bis-glycine disodium salt with the total formula - ( C ₂₀ H ₃₂ O ₁₆ H ₆ S ₂ ).  3. The method according to claim 1, characterized in that in pulmonary tuberculosis with a predominantly exudative type of tissue reaction, Glutoxim is administered intramuscularly 2 times a day, 1 ml of a 3% solution.  4. The method according to claim 1, characterized in that in pulmonary tuberculosis with a predominantly productive type of tissue reaction, Glutoxim is administered intramuscularly 2 times a day, 1 ml of 1% solution 3 times a week.  5. The method according to claim 1, characterized in that for pulmonary tuberculosis against the background of drug resistance of mycobacteria Glutoxim is administered 2 times a day, 1 ml of 3% solution: in the morning - intravenously, in the evening - intramuscularly for 2 months daily.

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