EA013052B1 - Medical preparation - Google Patents

Abstract

The invention relates to a medicinal preparation containing an active agent and target additives, wherein the active agent contains (2,4-dihydroxyl-6-methyl-5-pyrimidyl)-(4-pyridin-carbonyl-hydrazinyl) sulphon of formula (III) or the efficient quantity of pharmaceutically acceptable salts and isomers thereof. In addition, the inventive medicinal preparation can contain at least one type of antituberculous remedy such as isoniozid, rephampicine and pyrazinamide. Said preparation can be embodied in the form of pills, capsules, syrup and injections.

Description

The presented invention relates to a medicinal product that can be used in medicine in the complex treatment of microbacterioses (tuberculosis, leprosy, and so on), non-specific lung diseases, chlamydia and herpetic infections that occur against the background of a secondary immunodeficiency state of the body.

Currently, the prior art knows a large number of drugs for the same purpose.

So, for example, the isoniazid preparation (isonicotinic acid hydrazide-GINK) is known (see Mashkovsky M. D., Medicines, vol. 2, Kharkov, Torsing, 1997, pp. 323-333) of the formula ( I)

O — C — ΝΗ-ΝΗ, ά · N

A significant drawback of isoniazid is its high toxicity (L550 is 150 mg / kg), as well as digestive disorders, kidney activity, neuropsychiatric, hematological, allergic manifestations and toxic hepatitis that occur during long-term treatment.

The phenazide preparation is known (see RF patent No. 2080114), which is a chelate complex of the ferrous iron of isoniazid of the formula (II).

Although this drug has less toxicity compared to isoniazid, its level is quite high (L50 ₅₀ is 250-833 mg / kg). In addition, the big disadvantage is that phenazide cannot be used for cardiopulmonary insufficiency and severe forms of coronary heart disease.

The objective of this invention is to develop a new drug that would retain the same healing properties, but had lower (about 50 times less) toxicity, was stable during storage, and also in which side effects would be minimized.

The problem is solved by the proposed drug, which includes the active substance and target additives, the difference of which is that it contains (2,4-

or isomers in an effective amount.

Preferably, the medicament further comprises at least one anti-tuberculosis agent.

Preferably, the drug as an anti-tuberculosis agent may contain isoniazid, refampicin, pyrazinamide.

Preferably, the medicament may be in the form of tablets, combination tablets, capsules, syrup and injections.

Receive (2,4-dihydroxy-6-methyl-5-pyrimidyl) - (4-pyridinecarbonylhydrazinyl) sulfone of formula (III) by a known reaction by reacting 6-methyluracil-5-sulfochloride with isoniazid in dry acetonitrile by boiling with stirring.

The agent according to the invention can be administered in the usual manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally).

The dosage depends on the age, condition and weight of the patient, as well as on the type of administration. According to the invention, the proposed drug contains an active substance in an amount of from 0.1 to 4 g.

The proposed drugs are manufactured in the usual way. Along with the active substance, the drugs may contain conventional excipients adopted in the technology of drug preparation, such as tablet binders, fillers, preservatives, substances sprayed onto tablets, flow regulators, emollients, wetting agents, dispersants, emulsifiers, solvents, prolongators actions, antioxidants and / or propellants (see N. Zisksg s1 a1 .: RNag-tahsShysNs Tse1to1oshch. T1ists-Usg1ad. §1i11dagb, 1991).

In addition, the proposed drugs instead of individual active substances may contain combinations of various active substances in order to use together the qualities of individual

- 1 013052 active substances when used, or also because the individual active substances in combination have synergism, that is, they result in a super-additive strengthening of the action.

Clinical trials

Clinical trials have been conducted on patients with respiratory tuberculosis, in the treatment of exacerbations of chronic purulent-obstructive bronchitis, in the treatment of patients with pneumonia, as well as in patients with inflammatory diseases of the respiratory tract caused by intracellular pathogens (chlamydia).

1. Clinical trials in patients with respiratory tuberculosis

Under observation were 62 patients with various forms of pulmonary tuberculosis. The control group consisted of 20 patients with respiratory tuberculosis similar in gender, age, clinical laboratory and radiological characteristics of the process with the study group. The vast majority of patients in the study group (55 people - 88.8%) were men, women made up only 11.2% (7 people). The age composition of patients ranged from 18 to 70 years. All patients had newly diagnosed forms of tuberculosis. The most common clinical forms were infiltrative tuberculosis, tuberculous pleurisy, caseous pneumonia. In the majority of patients observed, the tuberculosis process was widespread. Decay cavities were determined in 93.5% of cases, most often they were multiple or with caverns larger than 4 cm in diameter. Bacterial excretion was determined in 42 people (67.7%), which in 53.2% of cases was massive. One patient showed drug resistance to all anti-TB drugs. Patients at admission revealed an intoxication syndrome, which in 42.0% of cases was pronounced (fever, inflammatory changes in the blood, weight loss). An immunological examination conducted by the patient included an assessment of the subpopulation composition of lymphocytes using monoclonal antibodies to CE3 '. SE4 '. SE8 '. SE16 '. SE20 '. SE25 'and determination of the concentration of immunoglobulins by the method of radial immunodiffusion according to Mancini. The functional activity of T cells was determined in RBTL on FTA and RTML with PHA and III1D. The specific humoral and cellular response was evaluated by the level of anti-tuberculosis antibodies in serological reactions (RPK, RIGA, ELISA) and in RBTL with PPD. A study of the immune status of patients with tuberculosis showed that almost all of them had some kind of immunity violation. In most of them, the process proceeded against the background of a reduced absolute or relative number of lymphocytes, initially low rates and deficiency of T-helpers and T-suppressors. Higher baseline EC values (CE16 ⁺ ) were noted, which, apparently, compensates for the lack of T-lymphocytes. In 40 patients (70.0%), immunoglobulins were reduced, especially classes A and O.

Chemotherapy was carried out on patients according to the traditional scheme using 4 anti-tuberculosis drugs (refampicin, pyrazinamide, streptomycin or ethambutol, instead of isoniazid, the patient in the study group was prescribed the drug according to the invention at 800 mg per day). Other drugs with immunomodulatory effects were not used.

Research results

The effectiveness of complex chemotherapy was evaluated after 1, 2, 4 and 6 months of treatment. A positive treatment result in the immediate follow-up period (1-2 months) was observed in 58 (93.5%) patients in the study group and in 12 (60.0%) in the control group. Detoxification occurred in 42 (67.7%) patients in the study group after 1 month and after 2 months in another 17 (27.4%) people, in the control group 45.0 and 25.0%, respectively. The intensity of bacterial excretion decreased in 19 (30.6%) in the study group and in 4 (20.0%) people in the control group. Positive radiological dynamics of the process was revealed after 1 month in 51.8% of observations and after another 2 months in 42.5% in the study group, and in the control group in 35.0 and 30.0%, respectively. It was manifested by the resorption of infiltration and part of the foci, a significant decrease in the size of the decay cavities. The most significant radiological changes were noted in patients with a pronounced exudative reaction and persistent changes in the immune status.

Among patients who completed a 4-month course of chemotherapy, sputum negation occurred in 95% in the study group and in 80% in the control group. In 51.6% of cases in the study group and in 40.0% in the control group, decay cavities were closed. After 6 months of treatment, only 1 patient in the study group and 2 patients in the control group maintained bacterial excretion and lung decay cavities.

Patient tolerance of the agent according to the invention was satisfactory, in 3 patients in the study group there was an adverse reaction in the form of a skin rash, no other adverse reactions were noted. At the same time, in 2 patients in the group where the agent according to the invention was used, with clinical signs of persistent chronic hepatitis, increased levels of bilirubin and transaminases in blood serum, laboratory parameters returned to normal after 1 month of chemotherapy.

After a course of chemotherapy with the agent according to the invention for 1-2 months, an analysis of immunological changes revealed a multidirectional change in immunity indicators. In the study group, there are tendencies toward an increase in the content of CE4 '. With an initially reduced content of SE8 '

- 2 013 052 of their number was not observed. At initially high EC values (SI16 ⁺ ), the dynamics of their normalization was noted. A positive effect on the functioning of the B-system, an increase in initially reduced immunoglobulin levels was revealed. In 44.0% of cases, an increase in the level of 1d C and A was noted. In the control group, at the first stages of treatment, some signs of immunosuppression were noted, as a result of the action of anti-TB drugs: a decrease in the number of E and B lymphocytes, especially due to T-suppressors. However, after 6 months of chemotherapy, differences in the immune status of patients in the study and control groups were not significant. The immunomodulatory effect of the agent according to the invention is manifested in the initial stages of treatment of tuberculosis (see tables. 1 and 2).

Evaluation of the treatment results showed the promise of using the agent according to the invention in the complex treatment of patients with severe immune status disorders, common and destructive forms of pulmonary tuberculosis. The tool according to the invention is also effective in the presence of severe concomitant diseases, when isoniazid is contraindicated or causes fatal adverse reactions.

Table 1. The dynamics of immunological parameters in patients with pulmonary tuberculosis when using the funds according to the invention (M ± m)

Indicators Terms of treatment White blood cells 10¾ before treatment 2 months later in 6 months T lymphocytes% before treatment 2 months later in 6 months СО4 ⁺ - lymphocytes% before treatment 2 months later in 6 months СО8 ⁺ - lymphocytes% before treatment 2 months later in 6 months SI4 ⁴ · / οϋδ * before treatment 2 months later in 6 months B-lymphocytes% before treatment 2 months later in 6 months СО ⁺ 16 - ΝΚ before treatment 2 months later in 6 months

Observation groups studied n = 62 control n = 20 10.9 ± 0.309 * 9,810.04 * 7.01 ± 0.274 * 8,010,021 * B, 61 ± 0.21 * 7.0210.281 * 27.58 ± 1.02 26.7411.1 * 31.0 ± 1.03 28.011 g 32.59 ± 0.105 * 24,210,120 * 42.15 ± 0.024 * 39.6211.49 44.29 + 3.09 34.4810.88 * 46.68 ± 1.408 41.83 + 1.292 26.96 + 1.3 28.5710.012 * 28.57 ± 0.32 * 26,211,8 27.0810.87 * 28.01 ± 0.22 * 1.49 ± 0.002 * 1.32 + 1.133 1.5 ± 0.130 * 1.4311.023 * 2.0 ± 0.125 * 1.9310.092 * 11.2 ± 0.068 * 18,610,346 * 27.08 ± 0.292 * 12,210,335 * 30.7210.873 29.82 + 1.048 35.6 + 1.2 25,810.94 * 20,810.77 * 22.7 + 1.45 16.7310.94 * 18.0211.21

Note: * the difference is significant (p less than 0.05) in relation to the norm

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Table 2. The dynamics of immunological parameters in patients with pulmonary tuberculosis when using the funds according to the invention (M ± m)

Indicators Terms of treatment Observation groups studied n = 62 control n = 20 T-lymphocytes (norm 33.1 + 0.953) before treatment 27.58 ± 1.2 ‘ 26.74 ± 1.1 * 2 months later 3Ϊ, 0 ± ί, 3 * 28.0 + 1.1 in 6 months 32.59 + 0.105 * 24.2 ± 0.1205 * 1®A (norm 1.9 ± 0.21) before treatment 2.0 ± 0.22 1.9 ± 0.17 * 2 months later 2.38 ± 0.19 * 1.8 ± 0.06 * in 6 months 2.21 ± 0.18 1.9 + 0.21 * 1M (norm 1.35 + 0.243) before treatment 1.32 ± 0.158 * 1.29 ± 0.115 * 2 months later 1.68 ± 0.272 * 1.24 ± 0.218 * in 6 months 1.42 ± 0.085 * 1.38 ± 0.036 * 1 ₈ e (norm 10.5 ± 0.9) before treatment 9.9 + 0.10 * 9.8 ± 0.21 * 2 months later 11.0 ± 0.204 * 10.2 ± 0.06 * in 6 months 10.98 ± 1.02 10.58 ± 0.3 * E-ROCK% (norm 63.9 ± 1.2) before treatment 42.2 ± 0.9 * 36.0 ± 0.86 2 months later 49,811,4 47.2 ± 0.08 * in 6 months 49.6 ± 1.2 46.3 ± 0.5 * RBTL with PHA% (norm 59.2 ± 2.1) before treatment 46.0 ± 0.82 * 46.6 ± 0.908 * 2 months later 47.2 ± 1.2 46.2 + 1.3 in 6 months 47.1 ± 1.123 46.6 ± 0.603 * Ea-ROCK% (norm 18.4 ± 3.2) before treatment 14.8 ± 0.37 * 14.0 ± 1.04 2 months later 18.2 ± 2.1 13.1 ± 0.9 * in 6 months 17.6 ± 0.35 * 14.2 ± 1.18

Note: * the difference is significant (p <0.05) in relation to the norm

2. Clinical trials for the treatment of exacerbations of chronic purulent-obstructive bronchitis (HCG)

During clinical trials, 28 patients with chronic obstructive hypertension were examined. 14 patients received the drug according to the invention and 14 patients received a placebo. The effectiveness of the treatment was evaluated based on the reduction of the main symptoms of the disease (cough, shortness of breath, changes in the nature of sputum) in points on a four-point scale depending on the severity of clinical symptoms, as well as the disappearance of fever and wheezing (in days).

Cough, shortness of breath: 3 points - symptoms constantly; 2 points - more than two times; 1 point - once; 0 - no symptoms.

Sputum: 3 - purulent; 2 - mucopurulent; 1 - mucosa; 0 - no sputum. The degree of inflammation activity was evaluated according to laboratory data.

The active inflammatory process was considered with an increase in leukocytes, an increase in ESR, the presence of a half-shift, CRP in the blood serum.

The study was carried out before treatment and was repeated on days 7, 14 of therapy.

Bacteriological examination of sputum showed that the main causative agents of HCB were pneumococcus, Klebsiella pneumonia, staphylococcus, which were determined in associations.

All patients underwent a study of bronchial obstruction (FEV1) before treatment and on the 14th day of therapy on the Iotesteya apparatus.

The treatment regimen was as follows:

1. The selection of antibiotic therapy empirically.

2. Administration of the agent of the invention and placebo in 200 mg capsules twice daily for 14 days.

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Table 3. The dynamics of the clinical manifestations of HCG under the influence of taking the agent according to the invention and placebo (M ± p)

Symptoms of the disease Patient groups Study Dates Before treatment 7 days 14 days Cough tool for invention. 2.29 ± 0.47 1.43 ± 0.51 * 0.64 + 0.49 * ^L Placebo 2.99 ± 0.47 2.0 ± 0.39 1.36 ± 0, ’63 * Shortness of breath tool for invention ' 1.85 + 0.77 0.78 ± 0.57 * 0.5 ± 0.65 * ^ll Placebo 2.0 ± 0.68 1.36 ± 0.84 Ϊ, ‘0 + 0.78 * Sputum tool for invention 2.07 ± 0.92 1.0 ± 0.55 * 0.14 + 0.36 * ^lll Placebo 2.14 + 0.77 1.86 + 0.95 0.86 ± 0.66 *

Note: P <0.01;' ^{,, ml} when compared with the results in the placebo group at the end of therapy;

* when comparing with data before treatment.

There was a significant reduction in clinical symptoms (Table 3) in patients receiving the agent of the invention, compared with baseline and placebo.

The wheezing during treatment with the agent of the invention disappeared on day 7, and when taking a placebo, on day 10.

Body temperature returned to normal in the group of patients receiving the agent of the invention on day 3, and placebo on day 5 of therapy.

When assessing bronchial patency, a significant increase in FEV1 was observed in comparison with baseline data and placebo by the end of therapy (Table 4)

Table 4. The dynamics of bronchial patency under the influence of taking the means according to the invention and placebo (M ± p)

Indicators (% of the proper value) Patient groups Duration of observation Before treatment 14 days FEV1 tool for invention 61.3 + 2.61 72.15 ± 2.78 * ^L Placebo 61.7 + 2.25 66.31 ± 2.46

Note: P <0.01, 'when compared with the results in the placebo group at the end of therapy;

* when comparing with data before treatment.

The degree of inflammation activity decreased to a greater extent in the group of patients receiving the agent according to the invention (Table 5).

Table 5. The dynamics of the frequency of changes in inflammatory laboratory tests of patients with CBH under the influence of taking the agent according to the invention and placebo

Indicators Patient groups Study Dates Before treatment In 7 days Abs. % Abs. % Leukocytosis tool for invention 8 57.0 0 0 Placebo nine 64.3 6 42.9 ESR increase tool for invention eleven 78.6 5 45.5 Placebo 12 85.7 8 57.1 P / N shift agent according to the invention 5 35.7 2 14.3 Placebo 5 35.7 3 21,4 CRP tool for invention 6 42.9 0 0 Placebo 5 35.7 3 21,4

Receiving the funds according to the invention did not cause intolerance

3. Clinical trials in the treatment of pneumonia patients

The study included 20 inpatients with pneumonia aged 16 to 65 years. The distribution by groups was as follows:

the group receiving the drug according to the invention (main) - 10 people (6 men and 4 women). The average age is 43.7 ± 3.61.

the placebo group (control) - 10 people (6 men and 4 women). The average age is 43.8 ± 4.49.

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In all patients on the basis of clinical diagnostic criteria, community-acquired pneumonia was detected. The clinical course of pneumonia is presented as follows: The course of pneumonia

The main group:

Typical - 7 patients

Atypical - 3 patients

Control group:

Typical - 7 patients

Atypical - 3 patients

X-ray changes were characterized by infiltration of the pulmonary fields of the focal, including confluent nature (in three patients of the main and three patients of the control group) and in one case (main group) of an interstitial nature.

The localization of pneumonia according to x-ray examination is reflected as follows:

Localization of pneumonia Main group Right Left Upper lobe 3 - Lower lobe 2 4 Average share one - Control group Upper lobe 2 one Lower lobe 4 3 Average share - -

The study included patients with pneumonia of mild and moderate course.

All patients were introduced into the study no later than 7 days after the onset of the disease. The average hospital stay before the study was 4 days.

All patients were prescribed antibiotics in medium therapeutic dosages, patients with a typical course - semi-synthetic penicillins and cephalosporins of Ι-ΙΙ generations, with atypical - macrolide antibiotics. Two patients of the main group and one control group additionally received cardiovascular drugs.

The main concomitant diseases identified in the therapeutic groups are presented as follows:

Concomitant pathology in patients with pneumonia

The main group:

Chronic bronchitis -3

Bronchial asthma -1

Cardiovascular Disease - 2

Control group:

Chronic bronchitis -3

Bronchial asthma -2

Cardiovascular disease -1

Tuberculosis (not active) -1

A prerequisite for participation in a clinical trial was the informed written consent of the patient.

The study did not include patients with a history of allergic reactions to isoniazid group drugs, serious liver or kidney dysfunction, terminal stage of the disease, pregnancy or risk of pregnancy, severe neuropsychiatric diseases, as well as patients who participated in a clinical study over the past 30 days .

Static analysis showed the absence of significant differences in the studied indicators between groups.

Research methods

Within 21 days, patients underwent a course of treatment with the agent according to the invention in a dose of 0.2 x 2 times a day or placebo. The randomization of therapeutic groups was carried out according to the table of random numbers using the balancing number method.

Each patient underwent a complete clinical and radiological examination, initially and on

- 6 013052 days from the start of the study.

Criteria for evaluating the effectiveness included: changes in the nature and frequency of coughing, the amount of sputum, the severity of sweating, headaches and muscle pains, weakness, the dynamics of radiological changes (complete, incomplete, absent), the frequency of occurrence of episodes of acute superinfection during treatment.

The assessment was carried out by the attending physician, as well as independently by the patient while keeping a diary. Each criterion was evaluated by patients quantitatively in scores from 0 to 4. Based on the analysis of the diary of lobar and objective indicators, the overall treatment result was determined by day 10:

"Excellent" - almost complete disappearance of symptoms; "good" - most symptoms have disappeared, but some of them remain at a minimum level; "unsatisfactory" - most manifestations of the disease remain unchanged or worsen

Clinical findings

Positive dynamics of clinical and radiological symptoms was noted in most patients of both the main and control groups. However, it was more pronounced in patients of the main group. So, by the tenth day, only 4 patients of the main and 7 patients of the control group had a rare cough. Patients of the main group at this time allocated a smaller amount of sputum. The dynamics of symptoms of intoxication (weakness, myalgia, sweating) turned out to be more pronounced in the main group of patients. The severity of the condition on day 10 was estimated at 36.2 + 3.4 points in the main and 47.3 + 4.8 points in the control group. The absence of positive radiological dynamics was noted in 2 patients of the control group, in 1 of the patients of this group an episode of respiratory superinfection (ARVI) was noted. In patients of both groups, by the 10th day of treatment, there was a decrease in the number of white blood cells in the blood and normalization of ESR.

Dynamics of changes in the main biochemical parameters of blood (ALT, bilirubin, creatinine), as well as pathological changes in urine both before and during treatment were not detected.

Table 6. The dynamics of the main clinical indicators

Originally 10 days The group of means according to the invention Cough (+) 10 people 4 people Sputum (ml) 25 + 6.67 4,5 + 2,29 Weakness (points) 2.6 + 0.25 0.4 + 0.22 Myalgia (points) 2.1 + 0.25 - Sweating (points) 2.7 + 0.15 - Placebo group Cough (+) 10 people 7 people Sputum (ml) 17 + 9.67 8.5 + 5.1 Weakness (points) 2.6 + 0.16 0.7 + 0.26 Myalgia (points) 1.8 + 0.42. 0.5 + 0.27 Sweating (points) 2.8 + 0.13 0.5 + 0.22

Comprehensive assessment of the clinical effectiveness of the agent according to the invention

The group of means according to the invention

Excellent result6

Good result4

Unsatisfactory Placebo Group

Excellent result2

Good result5

Poor 3

Severe side effects when taking the funds according to the invention, requiring its cancellation or dose reduction, was not observed in any patient.

3. Clinical trials in the treatment of patients with inflammatory diseases of the respiratory tract caused by intracellular pathogens (chlamydia)

The first group (main) - 12 people received 400 mg of the drug according to the invention daily; the second group is 8 placebo people.

All patients included in the study were prescribed monotherapy. Treatment continued for 21 days. Patients received 1 capsule of the drug according to the invention - 0.2 twice a day. Patients included in the placebo group were given identical appearance capsules with an indifferent filler in similar dosages.

Clinical, laboratory, immunological and instrumental examination was carried out before the start of treatment, on the 7th day from the start of taking the funds according to the invention and immediately after the end of the course.

Research methods, ethical standards, selection criteria and exclusion of patients from the study, as well as other mandatory criteria of the study protocol, are carried out in accordance with the approved “Clinical Trials Protocol”.

All patients included in this study were under follow-up at 7 hospitalizations. When evaluating the effectiveness of the agent according to the invention, a set of traditional clinical laboratory and instrumental parameters was used, performed according to the clinical observation program of this category of patients (Table 7).

Table 7

Signs Clinical groups I group P group Average age 32 36 Men 3 5 Women nine 3 The average duration of the disease 2.5 years 2.3 years

All patients included in the study and study groups were comparable among themselves according to the main criteria characterizing the patients and the duration of the disease. Based on the data from a detailed clinical examination of patients, concomitant diseases that are in the phase of persistent drug remission or are not included in the Criteria for Exclusion of Patients from Studies were analyzed.

The criteria for inclusion in this study were:

the presence of chronic recurrent infections of the respiratory tract (chronic pharyngitis, pharyngotracheitis, chronic recurrent laryngitis, chronic bronchitis);

the presence of a positive reaction for CIash1y1a 1gasyosh118 on smears from the throat by polymerase chain reaction (PCR).

Exclusion Criteria:

the presence of acute viral infections and other conditions that alter the parameters of the immune, interferon status, phagocyte system;

the need to take medications (about the underlying or concomitant diseases), which can affect the indicators of immune, interferon status and activity of phagocytes.

The observed patients included in this study had signs of chronic inflammation of the respiratory tract, in the form of recurrent pharyngitis, tracheitis, and in some cases of recurrent laryngitis. Almost all patients had a history of frequent repeated courses of antibiotic therapy.

Immunological and virological examination was carried out in dynamics before treatment, after 1 week and 3 weeks from the start of treatment.

The study of the immune status included the identification of 6 subpopulations of lymphocytes: ί.Ό3 +. ί.Ό4 +. SE8 +, SE72 +, SE16 +, ΌΚ +, immunoregulatory index (IRI), immunoglobulins of classes A, M, C, circulating immune complexes (CEC), functional activity of antibodies (antibody avidity). The study of interferon status included determining the level of serum interferon (IFN), the ability to produce IFN-α (under the influence of the Newcastles disease virus), as well as the ability to produce IFN-γ under the influence of PHA and ConA. The state of the phagocyte system was evaluated in the original chemiluminescent test by the spontaneous activity of neutrophils, as well as by the ability to activate (CL coefficient) when incubated with 3 dilutions of the substance of the invention and two immunotropic drugs (thymogen and cycloferon).

The detection of CIash1y1a GigasyotaSh was carried out using polymerase chain reaction (PCR). Epithelial cells from the pharynx, saliva, white blood cells and peripheral blood lymphocytes served as a material for DNA isolation. Diagnostic kits manufactured by Litef NPF were used in the work.

Examination of patients with CPX revealed changes in the immune system and interferonogenesis. So, the level of 1dA in blood serum was significantly increased, in half of the patients the level of 1dM was increased, the level of 1dC was reduced, in most patients of both groups the production of low-grade, i.e. functionally defective antibodies prevailed, the content of B-lymphocytes was reduced.

In the subpopulations of lymphocytes as a whole, there was a tendency to a decrease in the content of common T-lymphocytes, T-helpers, T-suppressors.

Marked changes were detected in patients with CPX and in the interferon system. So, in most patients, the level of interferon in the blood serum was increased and the ability to virus was reduced

- 8 013052 induced IFN-alpha production.

The state of humoral immunity in patients with chronic respiratory chlamydia during treatment with the agent according to the invention is presented in table. 8.

Table 8. The content of immunoglobulins of classes A, M, C and circulating immune complexes (CEC) before and during treatment with the agent of the invention in patients with chronic respiratory chlamydia (n = 20)

Pok-l 1dA (mg%) 1dM (mg%) 1dS (mg%) CEC (c.u.) Norm 100-250 80-200 900-2000 45-85 donors 153.3 + 5.4 112.6 ± 4.3 1450.2 + 32.1 65.4 ± 2.9 Experience, group Group Comp. Experience, group Group Comp. Experience, group Group Comp. Opgg Group Group r comp. Exodus 250.2 +/- 24.06 * 242.6 + / 22.89 ’ 145.5 +/- 18.46 194.25 + / -33.18 * 1213 +/- 96.8 1286.25 +/- 70.48 65.73 +/- 8.38 69.38 +/- 5.01 7 days 250.7 +/- 22.63 * 269.9 +/- 16.71 * 149.2 +/- 20.08 211.13 + / -28.8 * 1270.0 + / -95.22 1270.0 + / -62.42 64.6 +/- 4.73 66.63 +/- 7.45 21 days 244.9 +/- 25.23 * 258.9 + / 17.89 ’ 167.4 + / 16.63 216.38 + / -30.17 * 1319 +/- 80.63 1221.25 +/- 57.89 69.8 +/- 4.07 81.38 +/- 5.68

* - significance of differences compared with indicators of the group of healthy donors.

The study of avidity of antibodies to patients with CPX at the starting point showed a decrease in the production of highly avid, that is, functionally complete antibodies in most patients of the experimental and control groups. Among the patients in the control group, no significant positive changes in these indicators were observed, the predominance of the synthesis of functionally defective antibodies remained (see Table 9).

Table 9. The indicators of avidity of antibodies in patients with chronic respiratory chlamydia in dynamics during treatment with the agent according to the invention in the main group (n = 12) and the comparison group (n = 8)

Total antibody titer (X-AG) % low avid antibodies (X-AG) Main group R rupa comparison Main group Comparison group Exodus 72.73 +/- 11.49 * 76.0 +/- 12 * 60.7 +/- 9.37 * 64.88 +/- 9.3 * On the 7th day 66.91 +/- 6.76 * 72.0 +/- 8 * 51.18 +/- 0.47 * 76.63 +/- 1.62 * For 21 days 48.0 +/- 5.71 *** 84.0 +/- 13.44 *, *** 4.6 +/- 4.5 *** 75.00 +/- 0 *** Donors 43.4 +/- 2.0 16.7 +/- 3.2 norm 32-64 0-25%

*** - significant difference with baseline indicators, p <0.05 * - significance of differences compared with the indicators of the group of healthy donors.

The state of cellular immunity in patients with chronic respiratory chlamydia during treatment with the agent of the invention

As mentioned above, in some patients, a moderate decrease in T-helpers (004+), T-suppressors (CE8 +), the total number of T-lymphocytes (CE3 +) was closer to the lower limit of the norm. On average, the changes in these indicators in groups were unreliable, which is apparently due to a small number of observations (Tables 10 and 11).

Table 10. Indicators (%) of the T-link of immunity in patients with chronic respiratory chlamydia in dynamics during treatment with the agent of the invention in the main group

Index Οϋ5 +,% CO2 +,% СО8 +,% IRI СО72 +,% Οϋ16 +,% Donors 81.6 +/- 2.1 44.3 +/- 1.8 28.4 +/- 2.3 1.56 +/- 0.2 5.3 +/- 2.0 11.2 +/- 1.5 Norm 74-88% 40-50% 24-34% 1.3-2.6% 3-7% 8-14% Before treatment 74.18 +/- 2,57 39.36 +/- 3.09 25.73 +/- 2.42 1.61 +/- 0.17 3 +/- 0.69 12.73 +/- 1,62 After 7 days 76.64 +/- 1.71 42.82 +/- 2,35 25.91 +/- 2.22 1,753 +/- 0.17 3,273 +/- 0.51 11.82 +/- 1,52 After 21 days 74.82 +/- 1.8 43.82 +/- 1.99 26.09 +/- 1.32 1,741 +/- 0.16 2,182 +/- 0.49 15.09 +/- 1.72

- 9 013052

Table 11. Indicators (relative) of immunity T-link in dynamics in patients with chronic respiratory chlamydia of the comparison group who did not receive the agent according to the invention (n = 8)

Show- tel CO5 +,% CO2 +,% SE8 +,% At Οϋ72 +,% Οϋ16 +,% Donors 81.6 +/- 2.1 44.3 +/- 1.8 28.4 +/- 2.3 1.56 +/- 0.2 5.3 +/- 2.0 11.2 +/- 1.5 Norm 74-88% 40-50% 24-34% 1.3-2.6% 3-7% 8-14% Before treatment 72.9 +/- 38.13 +/- 22.75 +/- 1.87 +/- 2.63 +/- 14.13 +/- NII 2.74 2.72 2,169 0.33 0.59 1.84 After 72.0 +/- 36.13 +/- 22.25 +/- 1.75 +/- 2.63 +/- 12.75 +/- 7 days 1.67 * 1,076 * 2.71 0.16 0.42 1.87 After 68.25 +/- 36.38 +/- 24.25 +/- 1,60 +/- 2.38 +/- 13.13 +/- 21 days 1.42 * 0.92 * 2,562 0.14 0.42 1.94

* -authentication difference] compared with the performance of a group of healthy donors.

The state of interferon status in patients with chronic respiratory chlamydia during treatment with the agent according to the invention

As already mentioned, an increase in serum interferon and a decrease in the ability to virus-induced production of IFN-alpha were found in most patients with XRX. Against the background of taking the agent according to the invention in patients of the main group, the content of serum IFN remained at the same level both after one and three weeks of treatment, while in the comparison group in some patients the level of serum IFN increased significantly during the observation (table . 12).

Table 12. Dynamics of indicators of interferon status in patients with chronic respiratory chlamydia while taking the means of the invention in the main group and in the comparison group

Serum IFN (IU / ml) IFN-alpha (IU / ml) IFN gamma (IU / ml) DOS column (n = 12) Gr. Compare. (n = 8) Main gr. (n = 12), .. Gr. Compare. (n = 8) Main gr. (n = 12) Gr. Compare. (n = 8) Exodus 8.7 +/- 2.91 8.75 +/- 3.05 98.9 + / 18.41 * 152 +/- 20.73 90.2 +/- 14.19 93 +/- 9.06 1st week 8.4 +/- 1.66 17.75 +/- 5.31 * 110.5 +/- 41.64 114 +/- 22.51 52.7 +/- 9.07 70 +/- 14.16 3rd week 7.6 +/- 1.74 18.0 +/- 3.21 * 132.4 +/- 20.25 100 +/- 11.21 * 73.5 +/- 11.36 80.0 +/- 10.77 Donors 3.1 +/- 0.06 148.5 +/- 9.3 79.3 +/- 4.5 norm 54 128-640 32-256

* -significance of differences compared with indicators of the group of healthy donors.

The functional activity of neutrophils in patients with chronic respiratory chlamydia while taking the funds according to the invention

When studying the functional ability of neutrophils by the CL test, there were no significant deviations from normal limits in most patients.

It is important to note that when using the agent according to the invention for 21 days an adequate neutrophil response was maintained in the ίη νίίτο test both to repeated stimulation with the agent according to the invention and to the effects of other immunocorrections (thymogen, cycloferon), thus, during the treatment, tolerance did not occur blood cells to the stimulating effect of the agent according to the invention, and their hyporeactivity to the action of other immunocorrectors (table. 13).

Table 13. The indicator of the functional activity of Kl neutrophils (chemiluminescence coefficient) before and during treatment with the agent according to the invention (n = 12)

means according to the invention 1: 100 Timogen 1: 100 Cycloferon 1: 100 30 min. 60 min 30 min. 60 min 30 min. 60 min Until le 1.10 +/- 1.06 +/- 1.13 +/- Ϊ.16 +/- 1.05 +/- 0.99 +/- of the 0.019 0.018 0.056 0,083 0,03 0,033 After 1 1.05 +/- 1.01 +/- 1.11 +/- 1.10 +/- 1.02 +/- 0.95 +/- weeks 0,036 0,085 0,049 0,079 0,034 0,038 After 3 1.08 +/- 1.04 +/- 1.14 +/- 1.21 +/- 1.08 +/- 1.03 +/- weeks 0.018 0.02 0,027 0.05 0.015 0.019

The results of PCR diagnosis of chronic respiratory chlamydial infection during therapy with the agent according to the invention

The use of the agent according to the invention as monotherapy for three weeks in patients with chronic respiratory chlamydia in 9 out of 12 cases led to the suppression of chlamydial infection,

- 10 013052 including in the presence of resistance to antichlamydia antibiotics. In the comparison group among patients receiving placebo, there were no cases of suppression of chronic chlamydial infection during the observation period (Table 14).

Table 14. Indicators in patients with chronic respiratory chlamydia in dynamics during treatment with the agent according to the invention in the main group (n = 12) and the comparison group (n = 8)

Clinical groups Exodus 1st week 3rd week Discovery. Not found. DETECTED Not found. Discovery. Not found. Main group 12 0 6 6 3 nine Comparison group 8 0 7 one 8 0

For comparison, the following are data on phenazide treatment given in table. 15-17.

Table 15. The effectiveness of phenazide in the treatment of patients with primary pulmonary tuberculosis

A drug Number of patients Of which With BC + Termination of bacteriological isolation, months, (%) Closing of decay cavities, month, (%) one 2 3 3 phenazide thirty fifteen 20.0 33.3 13.3 25.0 (7 of 28) Total: 66.6

Table 16. The frequency of cessation of bacterial excretion after 3 months of phenazide use in the treatment of patients with destructive pulmonary tuberculosis

number Of these with BC (-) Of these with BC (+) sick In 3 months In 3 months Abs. thirty 21 nine % one hundred 70.0 30,0

Table 17. Frequency of cavern closure after 3 months of phenazide use in the treatment of patients with destructive pulmonary tuberculosis

Number of patients Cavern closures After 3 months Caverns After 3 months Abs. thirty 6 24 % one hundred 20,0 80.0

The biological activity of the substance according to the invention

Evaluation of the anti-tuberculosis activity of η νίΐΓΟ substance according to the invention

Evaluation criteria were the levels of minimal inhibitory and bactericidal concentrations (MIC, MBC). The determination of IPC, MBC was carried out by the standard method of serial dilutions in accordance with the requirements of the Pharmacological Committee (Guide to the experimental (preclinical) study of new medicinal substances, M., 2000).

Test culture: Η37Κν is a laboratory strain of M. tuberculosum, highly virulent, sensitive to anti-tuberculosis drugs.

To prepare a matrix solution of the substance of the invention, 10 mg of powder was weighed and 1 ml of dimexide was added. Incomplete dissolution of the substance occurred (fine suspension). For the preparation of working solutions, Shkolnikova's medium was used as a diluent.

To determine the MPC and MBC, a test culture was grown for 2 weeks in the Shkolnikova liquid nutrient medium with the addition of various concentrations of the substance of the invention in a wide range (128; 64; 32; 16; 8; 4; 2; 1; 0.5; 0 , 25; 0.125; 0.06 μg / ml).

Then smears were prepared and stained according to Ziehl-Nielsen. In smears, the number of microbacteria was counted, and on the basis of the obtained results, the IPC of the substance according to the invention was determined, in which their growth was suppressed.

The viability of the office after exposure to the substance according to the invention was evaluated by their ability to grow on Levenshtein-Jensen medium (after removing the substance according to the invention by washing with saline). MBC of the substance of the invention was determined by the lack of culture growth.

As a result of the studies, it was found that the IPC of the substance according to the invention ranged from 8 to 16 μg / ml; MBK - 16-32 μg / ml. This range of values is probably due to the low solubility of the substance according to the invention.

The study of the anti-leprosy activity of a substance according to the invention - (2,4-dihydroxy-6-methyl-5pyrimidyl) - (4-pyridinecarbonylhydrazinyl) sulfone and its soluble form

- 11 013052

The anti-leprosy activity of the substance of the invention and its soluble form was studied using the classical Shepard method. According to this method, mice infected in the sole of the paw of the foot of 5,000 mycobacteria isolated from the leprooma of a patient or transplanted laboratory strain were treated with the test substance of the invention for several months. The substance according to the invention was administered intragastrically through a probe in 0.5 ml of starch suspension or subcutaneously in 0.2 ml of physiological saline 5 times a week. At the end of the experiment, the animals were killed, the paw tissue was triturated and a quantitative bacterioscopic analysis was performed. The results of the experiment were judged by the number of mycobacteria that multiplied in the paw after infection. In the study of the anti-leprosy activity of the substance according to the invention and its soluble form, 6 experiments were carried out in which 450 linear mice of the VAGV / C line, P ₁ (A x C ₅₇ BT), RDSVA x C ₅₇ VD were used. Activity data are presented in table. eighteen.

Table 18. Anti-leprosy activity of a substance according to the invention and soluble leform

Mouse genotype VA1V / S P (A x C ₅₇ B1 / 6) EDSVAh With _B7 B1 / 6) Drugs administered at a dose of 100 mcg / mouse 5 times per week The number of mycobacteria leprosy in the foot x 10 ^b The control 8.6 + 0.74 0.085 ± 0.074 0.076 ± 0.008 DDS 4.24 ± 0.62 ^x 0.042 ± 0.007 The substance according to the invention - - - Soluble Lectform of a Substance of the Invention Reg. Soluble leform form of the substance according to the invention sc

* X - values significantly different from the control (p <0.01).

Animals (mice hybrids (CBA x C ₅₇ VR6) _s p infected with Mycobacterium leprae taken from the patient type lepromatous leprosy, were divided into 5 groups:

the group (control) received 0.5 ml of starch suspension, the group received 100 μg / mouse DDS 3 times a week, the group received 100 μg / mouse of the substance according to the invention 3 times a week, the group was treated with a soluble leformol of the substance according to the invention in a dose of 100 μg / mouse in the same mode, the group received a soluble leform form of the substance according to the invention at a dose of 100 μg / mouse sc 3 times a week.

The substance of the invention was introduced into the stomach with a probe in 0.5 ml of starch suspension. The substance according to the invention (soluble leform of the substance according to the invention), administered at 500 μg / mouse 2 times a week subcutaneously, had a bactericidal effect (see table. 19).

Table 19. Anti-leprosy activity of DDS, the substance according to the invention and soluble leforms, depending on the mode

Μg / mouse dose 100 mcg / mouse 500 mcg / mouse 3 times a week 2 times per week Preparations

The number of mycobacteria leprosy in the foot x 10 ^{& -}

The control 0.45 ± 0.06 0.34 + 0.03 DDS 0.21 ± 0.03 0.098 + 0.011 substance according to the invention 0.09 ± 0.007 0.042 + 0.007 Soluble Lectform of a Substance of the Invention Reg. 0.06 + 0.007 0.036 ± 0.005 Soluble leform form of the substance according to the invention sc - -

The anti-leprosy activity of the soluble form of the substance according to the invention of its soluble form was studied in comparison with DDS, an insoluble form of the substance according to the invention. In the experiment, P | mice (CBA x C ₅₇ BP6) were used, infected with mycobacteria of the leprosy taken from the leprooma of the patient with the lepromatous leprosy type.

Infected mice were divided into groups:

group - control (mice were injected with 0.5 ml of starch suspension daily, except weekends);

Groups 2, 3, 4 received respectively 100 μg of DDS, a substance according to the invention or a soluble leform of a substance according to the invention in 0.5 ml of a starch suspension 5 times a week;

Groups 5, 6, and 7 received, respectively, 50, 100, 200 μg of the soluble form of the substance according to

- 12 013052 subcutaneously in 0.2 ml of physiological saline 5 times a week;

Groups 8, 9, 10 received, respectively, 5 times a week, 50, 100, 200 μg of the soluble form of the substance of the invention subcutaneously in 0.2 ml of physiological saline, but treatment was started a month after infection.

The results are shown in table. twenty.

Table 20. Anti-leprosy activity of the soluble form of the substance according to the invention, depending on the dose and mode of administration

Dose The number of mycobacteria leprosy in the foot x 10® R Preparations The control 0.48 * 0.04 DDS 100 mcg, by mouth 0.11 * 0.02 ^x <0.01 a substance according to the invention 100 mcg, inside 0.13 * 0.01 ^x <0.01 Soluble Lectform of a Substance of the Invention 100 μg, Orally 0.09 Soluble Lectform of a Substance of the Invention 50 μg Subcutaneously 0.22 * 0.02 ^x <0.01 Soluble Lectform of a Substance of the Invention 100 μg Subcutaneously - Soluble leform form of the substance of the invention 50 mcg subcutaneously, treatment started 1 month after infection 0.27 * 0.03 ^x <0.01 Soluble leform form of the substance of the invention 200 mcg subcutaneously, treatment started 1 month after infection

The study of the immunomodulatory effect on the proliferative activity of a substance according to the invention

Tests were conducted on the effect of the substance of the invention on the proliferative activity of peripheral blood lymphocytes in patients with tuberculosis 3 months after the start of treatment.

The proliferative activity of peripheral blood mononuclear cells was determined for various mitogens in 151 patients with tuberculosis, including 137 adults and 14 children. Moreover, the initial examination 22, re-examination 11, the third examination 4.

As a control group, a group of healthy blood donors was recruited (n = 19). In addition to proliferative tests for various mitogens, peripheral blood mononuclear cells were activated with a polyclonal activator (PHA), tuberculin with Isodinafon to further study the synthesis of IFN-γ in culture supernatants. The studied patients collected serum to determine the classes and subclasses of immunoglobulins. The data are given in table. 21.

The substance according to the invention has an immunomodulatory effect on the proliferative activity of lymphocytes. A decrease in lymphocyte proliferation after a course of treatment was established only in response to a suboptimal dose of CSF. However, the analysis of the proliferative response in each individual patient indicates the stimulation of reduced lymphocyte function and suppression of increased function, which confirms the immunomodulating effect of the substance according to the invention.

Table 21. Proliferative activity of peripheral blood mononuclear cells of patients undergoing treatment with a substance according to the invention

R groups of patients spont Inclusion of Ί-thymidine (cpm) by lymphoid cells cultured for 3 days PHA10.0 mcg / mp IP PHA 1.0 μg / ml IP RUUMYU.O μg / ml IP ΡΆ / Μ 1.0 mcg / ml IP Donors 150 7598.9 57.6 1955.8 15.8 3358.5 24.9 3373.8 26.1 n = 19 ± 19.0 ± 845.8 ± 7.8 ± 617.5 ± 6.2 ± 393.1 ± 3.2 ± 3.7 ± 3.0 Pvrvich- 191.2 10,839.6 76.3 5226.5 34,4 3626.5 25.5 9447.9 28.1 new examination ± 41.1 ± 1244.9 ± 6.7 ± 943.4 ± 4.7 ± 436.4 ± 3.3 ± 516.1 ± 3.6 Repeat 124.5 12510 118.8 5428.5 52.6 3317.5 32.6 3518.6 34.3 new examination ± 19.7 ± 2215.8 ± 21.2 ± 2240.2 ± 17 4 ± 448.1 ± 5,4 ± 501.6 ± 5.7

- 13 013052

Patient groups Inclusion of N-thymidine (cpm) by lymphoid cells cultured for 3 days spont 1_RZ 20.0 μg / ml IP 1P5 10.0 μg / ml IP Tuberculin IP Tub-n + isodinafon μg / ml IP Donors 150 126.3 0.91 124.8 0.91 241.1 1.7 257.2 1.95 ± n = 19 ± 19.0 ± 12.8 ± 0.09 ± 18.3 ± 0.13 ± 53.2 ± 0.4 ± 88.1 0.76 Primary 191.2 234.4 175 448.2 2,3 635.1 3,5 402.1 2.8 ± new examination ± 41.1 ± 102.6 ± 0.87 ± 234 ± 0.98 ± 263.8 ± 1,1 ± 119.2 0.94 Repeat 124.5 443.8 4.2 304.6 2.7 277.9 2.6 279.6 3.7 ± new examination ± 19.7 ± 95.6 ± 1.2 ± 66.9 ± 0.6 ± 75.5 ± 0.9 ± 75.7 1,6

The method of obtaining the active substance of the drug and the method of obtaining the forms of the drug are illustrated by the following examples.

Example 1. The method of obtaining the active substance of the drug

142 g of 6-methyluracil-5-sulfochloride, 72 g of isoniazid and 1.5 l of dry acetonitrile are boiled with stirring for 10 hours. Filter, dry in air. 205 g of dirty substance are obtained. Next, purification is carried out by recrystallization. Take 100 g of the product, pour 800 ml of hot water, bring to a boil, filter. In this case, it is only necessary to bring to a boil, it is impossible to boil, since the hydrochloride is destroyed and begins to precipitate. Next, ammonia is added to the filtrate to pH = 7, and a precipitate immediately begins to precipitate. It is cooled, washed on the filter with hot water and a small amount of alcohol (not more than 50 cm ³ ). Dried in the air. Get "70 g of the substance.

To 70 g of the substance, add “600 ml of dimethylformamide (until dissolved), heat” to 100 ° C (not higher) and carefully add “400 ml of water until an imperceptible turbidity appears. After that, it is heated to a boil, filtered and the filtrate is allowed to cool. The precipitated precipitate of (2,4-dihydroxy-6-methyl5-pyrimidyl) - (4-pyridinecarbonylhydrazinyl) sulfone is filtered off and washed with water and alcohol. _Mp »253-256 ° C, is not soluble in water, slightly soluble in alcohol, is a white crystalline powder without smell.

Example 2. Obtaining a dosage form in the form of tablets

The main and auxiliary substances are mixed in the ratios indicated in the table. 22 (calculation for tablet weight):

Table 22

Tablet weight (Mt), g Mass composition,% 0.250 0,500 substance according to the invention - 0.1 substance according to the invention - 0.2 40 Lactose - 0.144 Lactose - 0.288 57.6 Aerosil - 0.004 Aerosil - 0.008 1,6 Stearate Sa - 0.002 Stearate Sa - 0.004 0.8

The diameter of the balls is 5mm.

The mass of balls per 100 g of the finished form is 500 g.

The pressing of the tablets is carried out on an RTM-12 press. The tablets are coated on the basis of acetylphthalyl cellulose (AFC) on an 81gea-1 apparatus. Coating composition (mass parts): acetone - 56.4; ethyl alcohol 96% - 37.6; castor oil - 1.0; AFC - 5.0; tropeolin - add to the light brown color of the solution. Coating consumption: amount of coating (ml) = 50% by weight of tablets (g).

Example 3. Obtaining a dosage form in the form of a combination tablet. Tablets are prepared according to known technology. The composition is given in table. 23.

Table 23

Components Weight mg ' one 2 3 4 5 6 substance according to the invention up to 400 up to 400 up to 400 up to 400 up to 400 up to 400 Isoniazid up to 100 - Up to 75 - - Refampicin - up to 150 up to 150 up to 150 up to 150 up to 150 pyrazinamide - up to 300 - - - up to 300 ethambutol -  - - - up to 150 up to 250

Use standard targeted additives and excipients to formulate the dosage form.

Example 4. Obtaining a dosage form in the form of gelatin capsules

The drug in gelatin capsules of 0.1 g and 0.2 g each is obtained by packing the substance of the invention manually in capsules No. 1 and No. 0 using capsules with a locking device

- 14 013052 PTO. Composition: the substance according to the invention is 0.1 g and 0.2 g without fillers and preservatives.

A sample of the substance according to the invention 10.0 g is placed on the capsule plate, distributed on the surface of the plate and then in accordance with the description of the capsule process.

Gelatin capsules consist of quinoline epu - 0.05%, titanium dioxide - 1.0%, gelatin - up to 100%. The substances included in the capsule are approved for medical use in Russia.

Example 5. Obtaining a dosage form in the form of a suspension (syrup).

For 100 ml of the final dosage form, take the substance according to the invention - up to 4 g, fructose - up to 20 g, flavorings, as well as target additives until freshly prepared suspension is preserved (by bringing it to 100 ml with boiled water) for up to 10 days in a cool dark place location.

Targeted additives and auxiliary substances - propylene glycol, sodium cyclamate, xanthan gum, fructose syrup, sodium benzoate, sodium saccharinate monohydrate, ethanol 95%, orange flavor 51.941 / A, sodium citrate dihydrate, maltodextrin KM8 X-50, distilled water - are introduced into conventional amounts used for the preparation of suspensions (syrups), according to known technology.

Shake the prepared suspension before each use.

Example 6. Obtaining a dosage form in the form of injections.

A drug for injection is a powder of a medicinal product comprising the active substance and its pharmaceutically acceptable salts in a dosage of 0.1-0.5 g.

Obtaining a medicinal product in the form of injections is carried out by a known method in accordance with the following scheme.

Ampoules Solvents (Vials)

Preparation of ampoules (vials) for filling ▼

Solution preparation

Ampulation (filling). Bottle corking.

Quality control

Sterilization

The therapeutic effect of the above forms of the claimed drug is similar.

The advantages of the claimed drug are as follows.

The toxicity of the claimed drug is 7000 mg / kg, and the toxicity of Phenazide 2000 mg / kg. Since the toxicity of Phenazide is 3.5 times higher, the claimed drug can be used for resistant forms of diseases, as well as in large doses and for a longer time.

In a preclinical study on cultures of mycobacteria, it was found that the claimed drug at a concentration of 20 μg / ml has a bactericidal and, at concentrations of 8-10 μg / ml, bacteriostatic effect against isoniazid-sensitive laboratory strains of mycobacterium tuberculosis, while in Phenazide these indicators are almost 2 times overstated, which indicates a higher antibacterial activity.

In addition, the claimed drug is devoid of side effects that are inherent in Phenazide: cannot be used for cardiopulmonary failure, severe forms of coronary heart disease.

The modern treatment concept for tuberculosis patients provides, along with basic chemotherapy, the appointment of various immunomodulatory agents, which increases the risk of adverse reactions and increases the cost of treatment.

Great prospects in increasing the effectiveness of chemotherapy for tuberculosis patients are opened by the use of drugs that possess, along with antimycobacterial immunocorrective action. Such is the claimed drug.

The claimed drug is stable during storage. Does not change the appearance, phys

- 15 013052 biological characteristics and biological properties for several years, for example 3 years or more.

Claims (4)

CLAIM 1. Drug containing the active substance and target additives, characterized in that it contains as an active substance (2,4-dihydroxy-6-methyl-5-pyrimidyl) - (4-pyridinecarbonylhydrazinyl) sulfone of formula (III) O or isomers in an effective amount. 2. The drug according to claim 1, characterized in that it further comprises at least one anti-tuberculosis agent. 3. The drug according to claim 2, characterized in that it contains isoniazid, refampicin, pyrazinamide as anti-tuberculosis drugs. 4. Drug in one of the paragraphs.1-3, characterized in that it is made in the form of tablets, combined tablets, capsules, syrup and injections.