RU2625744C1 - Method for prevention of exacerbation of bronchial asthma and chronic obstructive pulmonary disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is intended for prevention of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) exacerbations. Against the background of basic therapy, interferon inducer Tiloron is prescribed according to the following scheme: 1st year - 1st day - 250 mg once, 2nd day - 125 mg once and then 2 days later 125 mg once, 1.25 per course; for the 2nd year the course is repeated in the preseason ARVI period: 1st day - 250 mg, 2nd - 125 mg and then 2 days later 125 mg once, 750 mg per course.

EFFECT: decreased severity and frequency of infectious exacerbations of bronchial asthma and chronic obstructive pulmonary disease and prolongation of remission time.

2 cl, 6 tbl, 1 ex

Description

Technical field

The invention relates to medicine, namely to pulmonology and immunology-allergology, and can be used for the prevention of exacerbations of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD).

State of the art

In the structure of obstructive airways diseases, the prevalence of AD and COPD ranges from 15 to 25% (Postma DS, Reddel HK, ten Hacken NH, van den Berge M. Asthma and chronic obstractive pulmonary disease: similarities and differences. Clin. Chest Med. 2014; 35 (1): 143-156 .; Louis S., Zeki AA, Schivo M. et al. The asthma-chronic obstructive pulmonary disease overlap syndrome pharmaceutical-therapeutic considerations. Expert. Rev. Clin. Pharmacol. 2013; 6 (2 ): 197-219).

The course of AD and COPD can be mild, moderate, severe, and is compared only according to approved criteria.

At present, the BA + COPD phenotype has been isolated, which is characterized by a more severe course of the disease with a high degree of frequent exacerbations, causing inflammation and an imbalance of cytokines, which can lead to allergization of the body and subsequent development of AD. [Miravitlles M, Soler-Cataluna J.J., Calle M. et al. Spanish COPD Guidelines (GesEPOC) pharmacological treatment of stable COPD. Aten. Primaria. 2012; 44: 425-437). Respiratory viral and bacterial infections (Mycoplasma pneumoniae and Chlamydia pneumoniae], causing inflammation and an imbalance of cytokines, can lead to allergization of the body and the subsequent development of AD.

A team of experts from GINA and GOLD-2014 prepared and published the document “Diagnosis of diseases of chronic airflow limitation: asthma, COPD and asthma - COPD overlap syndrome”, which highlights the problem of the cross BA / COPD syndrome (BA / COPD) - overlap syndrome [ Belevsky A.S. Cross syndrome of bronchial asthma and chronic obstructive pulmonary disease. // Practical pulmonology. 2014; 2: 12-19]. Patients with this phenotype of the disease often give more severe exacerbations and are more difficult to respond to standard methods of treatment.

The presence of “overlap syndrome” (overlap syndrome) in clinical practice causes difficulties in both diagnostic and therapeutic aspects. Often, in the presence of AD + COPD in patients receiving inhaled glucocorticosteroids (ICS) according to AD treatment protocols, it is not possible to achieve control over AD symptoms. In the presence of neutrophilic inflammation in the bronchi, the effectiveness of the action of inhaled corticosteroids decreases, which, in turn, increase the concentration of neutrophils in the respiratory tract [Qiu Y., Zxo J., Bandi V. Et all. Dronchial mucosal inflammation and upregulation of CXC chemoattractants and receptors i9n severe exacerbations of asthma. Thorax. 2007; 62: 475-482].

The presence of neutrophilic inflammation is characteristic of a group of patients with frequent exacerbations of AD + COPD.

Among the main mediators of chronic systemic inflammation, there are:

- pro-inflammatory interleukins (IL-1, 2, 6, 8, 9, 12, 18) [Not J.Q., Foreman MG, Shumansky K. Associations of IL-6 polymorphisms with lung function decline and COPD // Thorax. 2009; 64: 698-704],

- tumor necrosis factor (TNF-α) [Franciosi L.G., Page C.P., Celli B.R. Markers of disease severity in chronic obstructive pulmonary disease // Pulm Pharmacol Ther. 2006; 19: 189-199],

- C-reactive protein (C-RB) [Pinto-Plata V.M., Mullerova H., Toso J.F. C-reactive protein in patients with COPD, control smokers and non-smokers // Thorax. 2006; 61: 23-28].

The relationship between the humoral and cellular parts of the immune system reflects the leukocyte index (LI), [Kobets TV, Nekrasov VN, Motrich AK The role of leukocyte indices in assessing the adaptive-compensatory capabilities of Chukchi children with recurrent bronchitis at the stage of spa treatment // Bulletin of physiotherapy and balneology. 2003, pp. 47-48; Ostrovsky V.K., Mashchenko A.V., Yangolenko D.V., Makarov S.V. Blood counts and leukocyte intoxication index in assessing severity and determining prognosis for inflammatory, purulent and purulent-destructive diseases // Klin. lab. Diagnostics. - 2006. - No. 6. - S. 50-53], characterizes the ratio of lymphocytes to neutrophils (myelocytes, metamyelocytes - young, stab, segmented), reflects the relationship of the humoral and cellular parts of the immune system. Norm = 0.41 ± 0.03.

The patent literature describes a method of treating atopic bronchial asthma in which vilosen was used (patent SU 1776414, A61K 35/26, 11.23.1992). In this method, the treatment of COPD is not described. But vilosen is currently not used in the Russian Federation as an immunomodulator, in addition, it does not apply to interferon inducers.

A known method of treating COPD (patent RU 2323728, A61K 31/4412, 05/10/2008). This material discusses the use of Mexidol only in patients with COPD. In addition, according to the pharmacological properties, Mexidol is declared as an antioxidant and is only of indirect importance for restoring the functions of non-specific immune defense, it is not an inducer of interferon. Monitoring the condition of patients was carried out in a short time period - up to 30 days, which does not give reason to draw a conclusion about its effect on the immune system.

It is known that the most common cause of exacerbation of AD and COPD are viral infections and a virus-induced decrease in interferon status.

In the available literature there are no analogues of the use of interferon inducers for the prevention of the severity and frequency of infectious exacerbations of AD and COPD.

The objective of the invention is to propose a method for the prevention of exacerbation of bronchial asthma and chronic obstructive pulmonary disease, which reduces the severity and frequency of infectious exacerbations of bronchial asthma and chronic obstructive pulmonary disease and prolongs the time of remission.

The essence of the proposed method lies in the fact that against the background of basic therapy, an interferon inducer is prescribed, and Tiloron is used in its quality.

Tiloron is prescribed according to the following scheme:

1st year - 1 day - 250 mg once, 2nd day - 125 mg once, and then after 2 days for the third 125 mg once, per course - 1.25 g,

for the 2nd year, the course is repeated in the pre-season ARVI period:

1st day - 250 mg, 2nd day - 125 mg and then after 2 days - 125 mg once, per course - 750 mg.

Tiloron is prescribed from the first days of exacerbation in the first year of treatment and in the second year of treatment with a preventive goal 2-3 weeks before the seasonal rise in the incidence of SARS and influenza.

Tiloron is a synthetic low molecular weight compound with antiviral properties and the ability to induce interferon when administered orally; there are reports of its antitumor and anti-inflammatory properties. In dosage forms (tablets, capsules), it is used in the form of dihydrochloride.

Tiloron is the first of the described oral effective low molecular weight interferon inducers. It induces the production of interferons of 3 main classes - α (alpha), β (beta) and γ (gamma). The main producers of interferons in the human body are intestinal epithelial cells, liver cells - hepatocytes, T-lymphocytes and granulocytes. In addition, it crosses the blood-brain barrier and induces the formation of interferons in neuroglia cells and brain neurons.

After oral administration of the drug, interferon production is distributed according to the scheme: intestine → liver (after 4-6 hours) → blood (after 20-24 hours) → lungs, spleen, brain and other tissues (after 48 hours).

It has been shown that Tiloron leads to a noticeable and significant increase in interferon titers. It activates bone marrow stem cells, stimulates humoral immunity, increases the production of immunoglobulins IgM, IgA, IgG, affects antibody formation, reduces the degree of immunosuppression, and restores the ratio of T-helper cells / T-suppressors.

In addition, the mechanism of its antiviral action is associated with inhibition of the translation of virus-specific proteins in infected cells, as a result of which replication of the virus is suppressed.

Tiloron is effective against influenza viruses and causing SARS viruses, ghetto and herpes viruses, including cytomegaloviruses and others.

After oral administration, it is rapidly absorbed from the digestive tract. Bioavailability is 60%, binding to plasma proteins is about 80%. Not subject to biotransformation. T _1/2 - 48 hours. It is excreted unchanged with feces (70%) and urine (9%). Does not cumulate. [MoH instruction on the use of tilorone; Tilorone. Medical Subject Headings (MeSH database). US National Library of Medicine (10/14/2009)].

The choice of Tiloron was due to its main pharmacological effects: induction of interferon, anti-inflammatory, antimicrobial and antiviral activity, immunomodulating properties.

We have shown that Tiloron is well combined with basic therapy for bronchial asthma and COPD, plays the role of an inducer of immune responses in response to the activation of infectious agents.

Basic therapy means the use of combination therapy, including the administration of glucocorticoids (GCS) and long-acting beta-blockers (DDBB), for example, multidisk preparations (active substances - fluticasone propionate and salmeterol) or turbuhaler (active substances - budesonide and formoterol).

In addition, an m-anticholinergic drug is prescribed, in particular the drug Spiriva Respimat (5 mcg per day with a single dose).

During the exacerbation period, all patients receive antibacterial therapy (most often prescribed amoxicillin and clavulanic acid) and antiviral therapy (ingavirin or tamiflu) according to GOLD recommendations.

Drugs are recommended depending on the severity of the exacerbation and taking into account the presence of the most common pathogens - pneumococcus, staphylococcus, hemophilic bacillus, etc.

The microorganisms most often causing exacerbation of AD and COPD inhibit the production of interferons and thereby contribute to the development of inflammation.

The effect of the immunomodulator Tiloron on the content of respiratory viruses, as well as bacteria Streptococcus pneumonia, Mycoplasma pneumonia, Chlamidiae pneumoniae and cytokines in the sputum of patients with the BA + COPD phenotype, antigens and antibodies to mycoplasmas and chlamydia in blood serum was studied, and its effectiveness in prevention is shown BA + COPD,

The possibility of implementing the proposed method is confirmed by the following data, but is not limited to them.

Example.

A group of 28 patients with a verified diagnosis of AD and COPD according to GINA-14 and GOLD-14 criteria was under dynamic observation for 3 years.

The average age was 61.23 ± 11.3 years. Duration of the disease> 14.8 ± 3.2 years.

FVD indicators, the volume of therapy was determined according to the GINA and GOLD criteria.

All patients received multidisk preparations (50/250 × 2 r / d or 50/500 × 2 r / d,) or turbuhaler (4.5 / 160, 2 breaths × 2 times a day), as well as Spiriva as basic therapy Respimat (5 mcg per day with a single dose).

During the exacerbation period, all patients received amoxiclav 875/125 mg 2 times a day or augmentin containing amoxicillin and clavulanic acid, 875/125 mg 2 times a day, Ingavirin 90 mg × 1 r / d for 5 days, or Tamiflu 75 mg × 2 r / d for 5 days.

Immunomodulating therapy was not prescribed to them.

The FVD study was carried out on a spiroanalyzer with a computer assessment of Valenta, Russia (flow-volume curve analysis) before and after inhalation of a bronchodilator - salbutamol (400 mcg).

The detection of RNA and DNA of viruses and bacteria Mycoplasma pneumonia, Chlamidiae pneumonia was carried out by PCR method of RNA viruses - rhinoviruses, respiratory syncytial viruses; parainfluenza viruses of types 1-4; DNA viruses - adenoviruses of groups B, C, E and DNA of pathogens of mycoplasmas and pneumonia chlamydia - using the method of gene probes.

The detection of antibodies to Chlamydia pneumoniae — antibodies of the IgA, IgM, IgG class — in blood serum was performed using the indirect microimmunofluorescence reaction.

The titers of specific antibodies to C. pneumoniae of classes IgG≥1: 64 and IgA≥1: 8 or IgM≥1: 8 were diagnostically significant; IgG titers≥1: 128 in the absence of IgA and IgM.

To eliminate cross-reactions between chlamydia species, antibodies to C. trachomatis were simultaneously determined.

The analysis of antigens and specific antibodies to Mycoplasma pneumoniae was carried out by aggregate hemagglutination with human erythrocytes (blood type 0, rhesus negative) after treatment with glutaraldehyde with sensitized rabbit anti-mycoplasma antibodies.

A titer of antigens of ≥1: 8 was considered to be diagnostically significant. RPGA - antibody titer ≥1: 32

To study interferon status, the following characteristics were determined:

- the level of production of IFN-α by leukocytes upon induction by Newcastle virus (Kansas strain) IFN-β (in the CITY-lab laboratory, Moscow);

- the level of production of IFN-Y by leukocytes upon inducing their PHA at a dose of 10 μg / ml;

- the content of type 1 interferons (IFN-α / β) and type 3 IFN-Y in sputum by PCR-RNA;

- the content of cytokines - IL-1β IL-4 IL-6 IL-8 IFN-α IFN-Y TNF-α in induced sputum by ELISA + TGF-β1.

Clinical characteristic:

The severity of the disease - cf. severe - 12 men and 13 women, heavy - 1 man and 2 women.

The age of patients - with moderate severity - 66.22 ± 10.32, with severe - 56.12 ± 3.92.

The frequency of acute respiratory viral infections and infectious exacerbations of BA + COPD, requiring the use of antibiotic therapy, was 2.44 ± 0.92 times a year. In moderate course - 1.8 ± 0.22; in severe course - 2.9 ± 0.99.

From the materials of table 1 it follows that with a more severe exacerbation, the parameters of the HPF and saturation of the peripheral blood with oxygen were significantly lower.

From the data of table 2 it follows that during the period of exacerbation of the disease, the main indicators of quality of life and indicators characterizing chronic systemic inflammation had lower values and did not return to reference values.

From table 3 it is seen that the viral-bacterial flora has a significant negative effect on the microbiocenosis of the mucous membranes of the upper and lower respiratory tract.

It should be noted a pronounced functional insufficiency of the IFN system, which is manifested by a deficiency in the production of IFN-α and IFN-Y by blood leukocytes for the corresponding stimuli, which contributes to the chronicity of intracellular infections and allergization of the body, as well as an imbalance of cytokines in sputum (see table 4).

The pro-inflammatory cytokines IL-8, TNF-α, and IL-1β are involved in the pathogenesis of both AD and COPD.

Increased production of IL-6, IL-4 and TGF-β1 contributes to fibrotic processes.

Taking into account the pathogenesis of systemic inflammation in AD + COPD and frequent exacerbations of AD + COPD, Tiloron therapy was performed according to the following scheme:

1st year: 1 day - 250 mg once, 2nd day - 125 mg once, and then after 2 days for the third 125 mg once, per course - 1.25 g.

In the 2nd year, the course was repeated in the pre-season ARVI period:

1st day - 250 mg, 2nd day - 125 mg and then after 2 days - 125 mg once, per course - 750 mg.

Research results

The frequency of acute respiratory viral infections and infectious exacerbations of BA + COPD, requiring the use of antibiotic therapy, decreased a year later and amounted to 0.97 ± 0.12 times a year. The same trend continued in the second year of observation. However, in the third year of observation, the frequency of acute respiratory viral infections and exacerbations increased slightly to 1.22 ± 0.32, but was significantly lower than before the start of therapy.

FVD indicators have changed little, but quality of life indicators have improved significantly. Thus, the ACQ score decreased to 2.31 ± 0.98 after a year and remained at the same level in the third year of observation. Assessment of dyspnea on the mMRC scale in points was 1.44 ± 0.91 after a year, 1.46 ± 0.76 after 2 years, and 1.51 ± 0.88 after 3 years, although it increased slightly, but remained lower than before starting Tilorone therapy.

Molecular biological and immunoserological examination, especially when studying biomarkers of systemic inflammation and cytokine balance, showed a positive dynamics of the indicators.

As can be seen from the data presented in Table 5, the level of biomarkers of systemic inflammation decreased one year after the course of Tiloron and remained at low numbers and 3 years after treatment.

From the data in table 6, one can see a positive dynamics in restoring the functions of the IFN system, which is manifested by an increase in the production of IFN-α and IFN-Y by white blood cells by appropriate stimuli, which helps to reduce the inflammatory process. The pro-inflammatory cytokines IL-8, TNF-α, and IL-1β, are involved in the pathogenesis of both AD and COPD and tend to normalize.

The production of IL-6, IL-4 and TGF-β1 decreased, which may favorably affect the reduction of fibrosis processes during inflammation.

The choice of an interferon inducer - Tiloron was due to its main pharmacological effects and the positive effect we established on the interferon status of patients with AD and COPD during follow-up for 3 years. It is important to note that the cells of the respiratory tract producing interferons retained their ability to actively respond to repeated exposure to pathogens for 3 years.

In the available literature there are no analogues of the use of interferon inducers for the prevention of the severity and frequency of infectious exacerbations of BA + COPD with long-term follow-ups (72 months) of the positive effect of the Tiloron therapy used against the background of basic therapy.

Thus, it has been shown that with timely diagnosis of causative viral and bacterial pathogens, restoration of innate immunity indicators against the background of basic therapy for exacerbation of bronchial asthma and chronic obstructive pulmonary disease due to the use of an interferon inducer, Tiloron, the proposed method helps to prevent the disease and prolongs the remission time , expands the arsenal of treatments for the disease.

Abbreviations used in the text

BA - bronchial asthma,

DDBB - long-acting beta-blockers,

IL-1, 2, 6, 8, 9, 12, 18 - pro-inflammatory interleukins,

LI - leukocyte index,

IHC - inhaled glucocorticosteroids,

PS BA / COPD - cross syndrome of BA / COPD,

C-RB - C-reactive protein,

FVD - function of external respiration,

TNF - tumor necrosis factor,

COPD - chronic obstructive pulmonary disease,

IFN-α - interferon alpha,

IFN-Y - interferon gamma,

IL-4 - interleukin-4,

IL-6 - interleukin-6,

IL-1β - interleukin-1-betta,

IL-8 - interleukin-8,

mMRC (Modified Medical Research Council) - dyspnea scale,

TNF-α - tumor necrosis factor,

TGF-β1 is a transforming growth factor - beta-1.

Claims (4)

1. A method for the prevention of exacerbations of bronchial asthma and chronic obstructive pulmonary disease, including basic therapy, characterized in that it is additionally prescribed an interferon inducer - tilorone. 2. The method according to p. 1, characterized in that appoint tilorone according to the following scheme: 1st year - 1 day - 250 mg once, 2nd day - 125 mg once, and then after 2 days for the third 125 mg once, per course - 1.25 g, for the 2nd year, the course is repeated in the pre-season ARVI period: 1st day - 250 mg, 2nd day - 125 mg and then after 2 days - 125 mg once, per course - 750 mg.