RU2297846C2 - Method for treatment of focal and infiltrative pulmonary tuberculosis - Google Patents

Abstract

FIELD: medicine, phthisiology.

SUBSTANCE: method involves administration of anti-tuberculosis preparations simultaneously with cycloferon as inductor of gamma-interferon by the following schedule: 0.3-0.6 g orally on 1, 2, 4, 6, 8, 11, 14, 17, 20 and 23 days and then 3 times per a week for 2 months. Invention promotes to normalization of cytokine status based on enhancing response of T-helpers of 1-st type (Th1-response) and reducing response of T-helpers of 2-d type (Th2-response), decreasing the immunoglobulin E level that, in turn, promotes reducing infiltrative foci in pulmonary tissue accompanying with resorption of exudates and pleural layers being among them in patients with multiple drug resistance and ceasing secretion of microorganisms. Invention can be used in treatment of focal and infiltrative pulmonary tuberculosis.

EFFECT: improved method of treatment.

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Description

The invention relates to medicine, namely to phthisiology, and can be used in the complex treatment of focal and infiltrative pulmonary tuberculosis.

In the last decade, there has been a significant increase in the incidence of tuberculosis. This indicator in 2001 increased compared to 1991 by 2.7 times (87.3 per 100 thousand of the population) and is at the level of 1967 - 86.0 per 100 thousand of the population.

In the structure of the clinical forms of pulmonary tuberculosis, focal and infiltrative tuberculosis is 60.3-78.2%. The leading treatment for patients with pulmonary tuberculosis is chemotherapy - one of the main factors that determine the prospects for the fight against tuberculosis [1].

Many years of experience in the use of etiotropic drugs in tuberculosis allowed domestic and foreign researchers to note certain limits of chemotherapy in achieving a clinical effect. Modern tuberculosis chemotherapy has expanded and approved the pathogenetic direction in the treatment of patients, since an increase in the body's defenses creates favorable conditions for acting directly on the pathogen [2, 3]. According to some authors [4], immunological imbalance is detected in 98% of patients with pulmonary tuberculosis. It would not even be an exaggeration to say that it is the immune status as such that forms one or another clinical and morphological feature of tuberculosis.

Modern knowledge about the "capabilities" of the immune system of a patient with pulmonary tuberculosis and anti-TB drugs to suppress tuberculosis infection, about the "capabilities" of Mycobacterium tuberculosis to avoid the immune response and resist the effects of chemotherapy justify the use of immunotropic drugs. Their main effect should be focused on enhancing the bactericidal activity of macrophages [5, 6] by Thi T-helper producing gamma-interferon and interleukin 2 (IL2).

The possibilities of immunotropic drugs should be used primarily in case of focal and infiltrative pulmonary tuberculosis. This is due to the fact that under the constantly changing properties of Mycobacterium tuberculosis (genotype, virulence, resistance to anti-TB drugs), an ever longer, prone to complications and relapses, course of these forms of tuberculosis is observed. In addition, the likelihood of the risk of not getting an effect from them or getting negative consequences increases precisely in severe tuberculosis (caseous pneumonia, disseminated, cavernous pulmonary tuberculosis).

It should be especially noted that the available data on the effectiveness in the case of tuberculosis of certain immunotropic drugs have a clearly insufficient level of evidence [7, 8, 9].

The system of interferons (IF) has a significant place in the development of the protective mechanisms of the body. The tuberculosis process is accompanied by severe violations in the IF system [10]. Patients with active tuberculosis are characterized by an increase in the level of IF in serum with a simultaneous decrease in the IF-producing ability of cellular elements [11, 12]. In this regard, the researchers' desire to use gamma-interferon preparations, the key cytokine responsible for the Thi response in tuberculosis, is quite justified in phthisiology. However, the use of recombinant gamma-interferon preparations as immunocorrective replacement agents in the complex treatment of pulmonary tuberculosis did not always give positive results; moreover, inhibition of the production of endogenous gamma-interferon was noted [12].

The closest technical solution (prototype) is a method for the treatment of focal and infiltrative pulmonary tuberculosis (RF Patent No. 2242222, IPC A61K 31/136, publ. 12/20/2004) [13], including the simultaneous administration of anti-TB drugs, the additional introduction of an inductor gamma interferon amixin in a dose of 0.125 g for 36 days. The first two days, 2 tablets, and then 1 tablet after 48 hours.

Amixin is a derivative of fluorenes - 2,7-bis- [2 (diethylamino) ethoxy] fluorene-9-OH-dehydrochloride hydrochloride. The immunomodulatory effect of amixin is realized by stimulating the synthesis of alpha, beta and gamma interferons in certain populations of cells (T cells, NK cells, macrophages) and organs (mainly the intestines, liver, brain). The ability of amixin to remodel protective reactions in case of tuberculosis infection has been proven in an animal experiment [14].

However, the use of amixin alone (when other gamma-interferon inducers are known, such as cycloferon, curantyl, ridostin, neovir, half-dan, larifan, kagocel, etc.) as a component of complex means for treating tuberculosis is not enough to effectively treat this disease. In addition, it should be noted that the effect of amixin on the condition of the liver affected by the intoxication load on the body is not well understood. As clinical experience shows, massive antibacterial, detoxification and symptomatic drug therapy for tuberculosis leads to an increase in intoxication load, disrupting normal hepatic metabolism and causing the appearance of clinically significant liver diseases.

The technical result of the invention is to expand the range of application of gamma-interferon inducers in the composition of the means for the treatment of pulmonary tuberculosis due to the use of cycloferon, which is interferonogenic (in particular, promotes the induction of endogenous gamma-interferon), antiviral, including anti-HIV, anti-inflammatory, antiparasitic, antipromotor, hepatoprotective and radioprotective activity.

The specified technical result is achieved by the fact that in the method of treating focal and infiltrative pulmonary tuberculosis, including the conduct of etiopathogenetic therapy by the use of anti-TB drugs and the simultaneous administration of the gamma-interferon inducer for a time sufficient to obtain a stable therapeutic effect, according to the invention as an inducer of gamma-interferon use cycloferon according to the following scheme: (0.3-0.6) g reg os in 1, 2, 4, 6, 8, 11, 14, 17, 20, 23 days and then 3 times a week for 2 months.

In patients with pulmonary tuberculosis, cycloferon has not previously been used. The authors of this proposal for the first time have shown and justified that the use of cycloferon in the complex treatment of pulmonary tuberculosis allows for a fundamentally new level to correct violations of immune homeostasis and restore liver function.

Cycloferon - N- (1-deoxy-d-glucitol-1-yl) -N-methylammonium-10-methylcarboxylate of acridanone (RF patent No. 2036198, IPC С07Н 5/06, publ. 27.0595). Cycloferon is one of the highly effective low molecular weight inducers of endogenous interferon. This drug, manufactured by the Polisan company (St. Petersburg), is the best studied and the safest. Cycloferon can be used for active tuberculosis and with prophylactic purposes to prevent relapse. Cycloferon is able to overcome the blood-brain barrier, therefore it is active in tuberculosis of the nervous system.

The drug induces high titers of alpha and gamma interferon in organs and tissues containing lymphoid elements (mucosa of the small intestine, spleen, liver, lungs), overcomes the blood-brain barrier. Cycloferon is effective against influenza viruses, herpes, hepatitis, AIDS, tick-borne encephalitis, cytomegalovirus, various enteroviruses. Enhances the effect of antibiotic therapy for intestinal infections. The drug has anticarcinogenic and antimetastatic effects, preventing the formation of tumors through activation of the body's immune defense.

The immunomodulating effect of Cycloferon is expressed in the activation of phagocytosis, natural killer cells, cytotoxic T-lymphocytes under the action of interferon, and correction of the body's immune status in immunodeficiency states of various origins.

Drugs that are used to treat tuberculosis (isonicotinic acid hydrazide and its derivatives) have hepatotoxicity through their toxic metabolites, causing necrosis of the liver cells, their cytolysis and liver steatosis. Markers of toxic liver damage include transaminase enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltranspeptidase (GGT), and some others. In the clinic, the most commonly used for the diagnosis of toxic load on the liver is the measurement of ALT and ACT activity, with an increase in the activity of these enzymes by a factor of two or more compared to the norm, one can think of a cytolytic syndrome and toxic liver damage of various degrees. On the contrary, with a decrease in ALT and ACT activity to normal, it can be considered that toxic liver damage is reduced. It is possible that one of the effects of cycloferon is its ability to strengthen the hepatic membrane, since its chemical structure is membranotropic. The positive effect of cycloferon on Kupffer cells is proved, the main function of which is the absorption of exo- and endogenous substances, their metabolism and the isolation of metabolic products, as well as the secretion of monokines. It is likely that cycloferon, which is close in its chemical structure to cellular components, changes the metabolism of hepatocytes and Kupffer cells, making them less susceptible to the damaging effects of anti-TB drugs.

The invention is illustrated by graphs in figures 1-4, clearly demonstrating the effectiveness of the treatment of patients with focal and infiltrative pulmonary tuberculosis according to the main criteria for the variability of tuberculosis. Figure 1 shows a diagram of the reduction of symptoms of intoxication. Figure 2 shows the dynamics of reducing bacterial excretion during therapy with cycloferon. Figure 3 shows the dynamics of the closure of the decay cavities. Figure 4 shows the dynamics of the activity of the enzymes ACT and ALT during treatment.

Description of the method of treatment with cycloferon

At the end of the introductory period, cycloferon is prescribed to patients who meet the requirements for inclusion in the treatment process, simultaneously with four drugs of specific therapy. The following regimen of administration of the drug is provided: (0.3-06) g reg os in 1, 2, 4, 6, 8, 11, 14, 17, 20, 23 days and then 3 times a week for 2 months.

Data on the practical use of the drug Cycloferon

The proposed method of treatment with cycloferon was used in a prison for the complex treatment of pulmonary tuberculosis. 75 people were taken into the study, 31 of them received standard chemotherapy, and 44 patients were additionally prescribed the cycloferon immunocorrector according to the following scheme: 0.6 g reg os in 1, 2,4, 6, 8, 11, 14, 17, 20, 23 days and then 3 times a week for 0.3 g reg os for 2 months.

The study group consisted of males, mostly young people under 20 years old - 9 people, 21-30 years old - 46 people, 31-40 years old - 11 people, more than 40 years old - 9. Patients were distributed according to the forms of tuberculosis as follows: the group of patients receiving standard chemotherapy, patients with infiltrative tuberculosis amounted to 24 people, disseminated - 8 people, without decay - 19, with decay - 13, seeding - 9, VK + - 13, VK- - 19. In the experimental group receiving Cycloferon, patients with an infiltrative form made 36 people, disseminated - 8 trap, without decay - 27, with decay - 17, seeding - 10, VK (+) - 22, VK (-) - 23.

In addition to routine examination methods (clinical examination, clinical and biochemical analyzes, microbiological examination of sputum, X-ray examination of the lungs), a cytokine profile was studied (IL-β, TNF, IL-4, IL-6, IFN-γ, GCS-F). Prior to treatment, in all patients with tuberculosis, a pronounced imbalance of cytokines was determined, which characterized the defectiveness of the anti-inflammatory defense system in tuberculosis.

As a result of the treatment (see Figs. 1–4), a pronounced positive symptomatology was observed in the group of patients receiving cycloferon (earlier elimination of intoxication, abacillation and closure of decay cavities. Radiologically in patients who did not receive treatment with cycloferon, positive dynamics occurred due to compaction of foci (i.e., the formation of tuberculoma), when taking cycloferon, the formation of residual changes occurred in the form of fibrosis. In patients who did not take cycloferon, hepatitis developed in 2-3 months of treatment otoxic syndrome accompanied by an increase in thymol test and transaminases. In the group of patients treated with cycloferon, hepatotoxic effect was not observed. This circumstance can probably be explained by the activation of Kupffer liver cells, given the phagocyte-stimulating effect of cycloferon. However, in the group of patients with disseminated tuberculosis treated with cycloferon , persistent ESR and leukocytosis were noted, which can be explained by the activation of pro-inflammatory cytokines. The improvement in the clinical picture correlated with the normalization of the cytokine status (an increase in the Th1 response and a decrease in the Th2 response), which provides protective immunity in tuberculosis.

- The heterogeneity of the distribution of serum cytokines in patients with pulmonary tuberculosis was revealed.

- Initially low values of pro-inflammatory cytokines (IL1-beta, TNF), growth factors (G-CSF) in patients with pulmonary tuberculosis are noted. With respect to the pleiotropic cytokine (IL6), no significant changes were obtained compared to the normative ones; the proinflammatory cytokine (IL4) ranges from low to normal in different groups.

- During treatment, there are dynamic changes in the level of serum cytokines, most pronounced in the group of patients taking cycloferon.

Thus, with the use of cycloferon, the levels of cytokines repertoire for the Th1 response increase and decrease for the Th2 response, which correlates with clinical signs: improvement of liver function, minimization of radiological manifestations. After 6 months of treatment, bacterial excretion is reduced by 30% compared to standard chemotherapy. The rates of closure of decay cavities increase by the 6th month of treatment by 110% compared to standard chemotherapy. Damage to the liver during treatment is reduced by 30-40% compared with standard polychemotherapy.

Cycloferon increases the formation of reactive oxygen species by phagocytes, contributing to complete phagocytosis with elimination of captured pathogens, and increases the level of NK of peripheral blood cells.

The main effect of cycloferon that distinguishes it from analogues is its ability to cause the formation of pro-inflammatory and anti-inflammatory cytokines. It is known that a decrease in cytokine production is associated with tuberculosis. Cycloferon is a bioregulator of the cytokine network. This is a very important circumstance that allows considering cycloferon as the drug of choice in the treatment of tuberculosis.

Another difference between cycloferon and analogues: cycloferon is an inducer of the synthesis of endogenous interferon, which undergoes control and regulatory mechanisms (repressor translation), which provide protection against interferon oversaturation.

Benefits of using cycloferon;

- production of endogenous interferon that does not have antigenicity;

- long circulation of endogenous interferon;

- It goes well with various medications used in the clinic for the fight against tuberculosis, providing a synergistic effect with combined use;

- rapid penetration into the blood, low level of binding to serum proteins, high bioavailability in organs, tissues, biological fluids;

- activation of the immune system, anti-inflammatory and antiproliferative effect;

- the prevailing method of elimination from the body - through the kidneys (93% of the drug administered);

- hepatoprotective effect: reduction of liver damage during treatment with cycloferon as part of complex therapy by 30-40% compared with standard polychemotherapy (Figs. 1-4);

- the speed and reliability of the subjective effect, relative cheapness.

Sources of patent and scientific and technical information

1. Khomenko A.G. Tuberculosis Yesterday, Today, and Tomorrow // Probl. tube - 1997. - No. 3. - S.9-11.

2. Vasiliev A.V. Correction of the immune status of patients with tuberculosis with modern methods of pathogenetic therapy // Treatment of patients with pulmonary tuberculosis. - L., 1983. - S.7-11.

3. Selitskaya R.P. Immunopathogenetic mechanisms in the respiratory system with tuberculosis and ways of possible correction: Author. dis ... Dr. med. - St. Petersburg, 1993.

4. Khonina N.A., Nikonov S.D., Shpilevsky S.V. and others. Features of immunity in patients with various forms of pulmonary tuberculosis // Probl. tube - 2000. - No. 4. - S.21-23.

5. Hergert V.Ya. Immunology of tuberculosis // Tuberculosis today: problems and prospects: Scientific. tr and mat. Conf. in memory of M.M.Averbakh. - M., 2000. - P.18-20.

6. Chackerian A.A., Perera T.V., Behar S.M. Gamma interferon-producing CD + 4 T lymphocytes in the lung corre late with resistance to infection with Mycobakterium tuberculosis // Infect. immun. - 2001 .-- Vol.69. - P.2666-2674.

7. Litvinov V.I., Gergert V.Ya., Moroz A.M. et al. Immunology of tuberculosis (current state of research) // Vesti. RAMS. - 1999. - No. 7. - S.8-11.

8. Evidence based medicine working group. Evidence based medicine: a new approach to teaching the practice of medicine // JAMA. - 1992 .-- Vol.268. - P.2420-2425.

9. Fridman L.N. Tuberkulosis (Current Concept and Treatment) - 2000 - 518 p.

10. Ershov F.I. The interferon system is normal and with pathology. - M., 1996 .-- 240 p.

11. Khokholov Yu.A. The clinical significance of the indicators of the interferon system in patients with pulmonary tuberculosis: Author. Candidate of Medical Sciences - 1985. - 17 p.

12. Parfenov VV, Selitskaya RP, Sokolova GB and others. The first experience of using gammaferon in the treatment of patients with tuberculosis // Molecular basis of the pathogenesis and diagnosis of tuberculosis and other pulmonary pathology. - M., 1995. - P.40-41.

13. RF patent No. 2242222, IPC A61K 31/136, publ. December 20, 2004 (prototype).

14. Sokolova G.B., Kunichan A.D., Mozhokina G.N. and other Amiksin in the treatment of experimental tuberculosis // Large target journal on tuberculosis. - 2000. - No. 11-12. - S. 19-23.

Claims (1)

A method of treating focal and infiltrative pulmonary tuberculosis, including conducting etiopathogenetic therapy by using anti-TB drugs and simultaneously administering an gamma interferon inducer for a time sufficient to obtain a stable therapeutic effect, characterized in that cycloferon is used as an inducer of gamma interferon according to the following scheme: 0 , 3-0.6 g orally in 1, 2, 4, 6, 8, 11, 14, 17, 20, 23 days and then 3 times a week for 2 months.

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