RU2600833C1 - Method of treating chronic obstructive pulmonary disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology, and can be used for treating chronic obstructive pulmonary disease. For this purpose, during treatment with glucocorticosteroids and bronchodilators surfactant BL is used, which is administrated by inhalation daily once a day in a dose of 20-25 mg for 10-15 days, then 10 mg every second day for 3-6 weeks, and in case of deterioration, 5-10 25 mg inhalations of surfactant BL daily with continuation of inhalations of glucocorticosteroids and bronchodilators. Inhalations of surfactant BL are performed not earlier than in 30 minutes after receiving glucocorticosteroids and bronchodilators.

EFFECT: method enables to achieve remission, while reducing the number of preparations.

1 cl, 2 ex

Description

The invention relates to medicine, namely to therapeutic methods, and may find application in the treatment of severe diseases of the bronchopulmonary system.

Chronic obstructive pulmonary disease (COPD) is a disease characterized by a persistent violation of the ventilation function of the lungs in an obstructive type, partially reversible, which usually progresses and is associated with an increased chronic inflammatory response of the lungs to the action of pathogenic particles and gases. It is a poorly diagnosed, life-threatening lung disease that interferes with normal breathing and is completely incurable.

Traditionally, COPD combines chronic bronchitis and pulmonary emphysema. Chronic bronchitis is usually defined clinically as having a cough with sputum production for at least 3 months. over the next 2 years. Emphysema is defined morphologically as the presence of a constant expansion of the respiratory tract distal to the terminal bronchioles, associated with destruction of the walls of the alveoli, not associated with fibrosis. In patients with COPD, both conditions are most often present and it is rather difficult to distinguish between them clinically. The concept of COPD does not include bronchial asthma (BA) and other diseases associated with poorly reversible bronchial obstruction (cystic fibrosis, bronchiectatic disease, bronchiolitis obliterans).

One of the global studies (the BOLD project) provided a unique opportunity to estimate the prevalence of COPD using standardized questionnaires and pulmonary function tests in adult populations over 40 in both developed and developing countries. The prevalence of COPD stage II and above (GOLD 2008), according to the BOLD study, among people over 40 was 10.1 ± 4.8%, including for men - 11.8 ± 7.9% and for women - 8.5 ± 5.8%. According to an epidemiological study in Russia, in particular, the Samara region, the prevalence of COPD in the total sample was 14.5% (among men - 18.7%, among women - 11.2%). According to the results of another Russian study conducted in the Irkutsk region, the prevalence of COPD among people over 18 years of age among the urban population was 3.1%, among the rural population - 6.6%. The prevalence of COPD increased with age: in the age group of 50 to 69 years, 10.1% of men in the city suffered from the disease and 22.6% in the countryside. Almost every second man over the age of 70 living in rural areas was diagnosed with COPD.

According to the WHO, COPD is currently the 4th leading cause of death in the world. About 2.75 million people die from COPD each year, which makes up 4.8% of all causes of death. In Europe, mortality from COPD varies significantly: from 0.2 per 100 thousand people in Greece, Sweden, Iceland and Norway to 80 per 100 thousand in Ukraine and Romania. Between 1990 and 2000, mortality from cardiovascular diseases in general and stroke decreased by 19.9 and 6.9%, respectively, while mortality from COPD increased by 25.5%. A particularly pronounced increase in mortality from COPD is observed among women. Predictors of mortality in patients with COPD are such factors as the severity of bronchial obstruction, nutritional status (body mass index), physical endurance according to the test with 6 minutes of walking, and the severity of shortness of breath, the frequency and severity of exacerbations, pulmonary hypertension. The main causes of death of COPD patients are respiratory failure, cardiovascular diseases, lung cancer and tumors of a different location.

In developed countries, the total economic costs associated with COPD in the structure of pulmonary diseases occupy 2nd place after lung cancer and 1st place in direct costs, 1.9 times higher than direct costs for bronchial asthma (BA). Economic costs for 1 patient associated with COPD are 3 times higher than for a patient with AD. A few reports of direct medical expenses for COPD indicate that more than 80% of the material resources are allocated to inpatient care for patients and less than 20% to outpatient care. It was found that 73% of expenses fall on 10% of patients with severe course of the disease. The greatest economic damage is caused by treatment of exacerbations of COPD. In Russia, the economic burden of COPD, taking into account indirect costs, including absenteeism (absenteeism) and presentism (less effective work due to poor health) is 24.1 billion rubles. The most common symptoms of COPD are shortness of breath (or a feeling of lack of air), pathological sputum (a mixture of saliva and mucus in the airways) and chronic cough. As the disease gradually develops, daily physical activity, such as climbing stairs several steps or carrying a suitcase, can be significantly more difficult.

Under conditions of exposure to risk factors (both active and passive smoking, exogenous pollutants, bioorganic fuel, etc.), COPD usually develops slowly and progresses gradually. The peculiarity of the clinical picture is that for a long time the disease proceeds without pronounced clinical manifestations. The first signs that patients see a doctor are a cough, often with sputum production, and / or shortness of breath. These symptoms are most pronounced in the morning. In cold seasons, “frequent colds” occur. This is the clinical picture of the debut of the disease.

Although COPD is completely incurable, its treatment can still slow down the development of the disease and improve the quality of life of patients.

Due to the fact that COPD does not have specific manifestations and the criterion for diagnosis is a spirometric indicator, the disease may remain undetected for a long time. The problem of hypodiagnosis is also associated with the fact that many people suffering from COPD do not feel sick due to lack of shortness of breath at a certain stage of the disease and do not fall into the doctor's field of vision. It follows that in the vast majority of cases, the diagnosis of COPD is carried out at the disabling stages of the disease.

To prevent the development of the disease, it is very important to stop smoking. Various forms of treatment can help alleviate symptoms and improve the quality of life for people with the disease.

Diagnosis of COPD should include the following areas: identification of risk factors, objectification of symptoms of obstruction, and monitoring of respiratory function of the lungs.

A diagnosis of COPD should always be confirmed by spirometry. The post-bronchodilation value of the ratio of forced expiratory volume in one second (FEV1) to the volume of forced vital capacity of the lungs (FVC) of less than 70% is an obligatory sign of COPD that exists at all stages of the disease.

The generally accepted standard for the treatment of COPD, depending on the severity and stage of the disease, is the regular use of bronchodilators, and subsequently combinations of inhaled glucocorticosteroids (IHS) and bronchodilators (short-acting β ₂ agonists, for example, salbutamol), and then long-acting β ₂ agonists ( tiotropium bromide).

Continuous use of IHS and β ₂ long-acting agonists (tiotropium bromide) reduces the frequency of exacerbations and improves the quality of life of patients. However, prolonged use of such a combination of drugs is associated with an increased incidence of pneumonia. In the advanced stages of COPD of 4th severity with a ratio of the duration of forced expiration in one second to the forced vital capacity of the lungs (FEV ₁ / FVC) less than 0.4, patients are forced to receive additional oxygen insufflation using special equipment (oxygenators). Often they lose sensitivity to the standard treatment of exacerbations (a combination of injectable glucocorticosteroids (IHS) and long-acting β ₂ -agonists, as well as systemic glucocorticosteroids, prednisone or diprospam) and are in a serious condition when they are forced to transfer to non-invasive mechanical ventilation (NIVL) .

The most common drug for treating COPD is the β ₂ -alagonist salbutamol (ventolin), which is considered one of the safest beta-adrenergic agonists. Drugs are more often used by inhalation, for example, using a spinhaler, at a dose of 200 mg no more than 4 times a day. Despite its selectivity, even with the inhaled use of salbutamol, some patients (about 30%) have undesirable systemic reactions in the form of tremors, palpitations, headaches, etc. This is because most of the drug settles in the upper respiratory tract, is swallowed by the patient and absorbed into the bloodstream in the gastrointestinal tract, causing the described systemic reactions. The latter, in turn, are associated with the presence of minimal reactivity in the drug.

Treatment of COPD begins with bronchial blockers (β ₂ agonists) of short, and then long-term action, but then, as the disease progresses, the doctor prescribes a combination of IHC and β ₂ agonists (most often this is a combined drug Symbicort).

Closest to the proposed one is the method recommended by the Federal Clinical Recommendations for the diagnosis and treatment of COPD (2013). The method is that a patient with COPD is prescribed an IHC twice a day, for example beclamethasone 200-600 mg; or budesonide 400-800 mg or more, 1500 mg for nebulizer inhalation, or fluticasone 500 mg. In addition to GCI, selective β ₂ -adrenoreceptor agonists (β ₂ -denomimetics) are prescribed, for example, salbutamol in an inhaler with a dispenser - 0.1 mg (single dose) - no more than 2 doses when stopping bronchospasm. In the absence of effect, inhalation can be repeated after 5-15 minutes. The next inhalation can be carried out after 4-6 hours, in total no more than 6 times a day. Then you can use the combined drug Symbicort (160 / 4.5 μg), 1 breath 2 times a day. Symbicort is a mixture of budesonide - IHC and formoterol, a selective β ₂ -adrenoreceptor agonist.

However, this method, like others currently used, has a number of significant drawbacks.

So, untimely and inadequate steroid therapy can lead not only to an uncontrolled course of exacerbations of COPD, but also to the development of life-threatening conditions that require the appointment of a much more serious systemic steroid therapy. In turn, prolonged systemic steroid therapy, even in small doses, can form iatrogenic diseases and syndromes (vasculitis, osteoporosis, Itsenko-Cushing's syndrome, obesity, hypertension, diabetes mellitus, myodystrophy, etc.). All currently existing IHCs are absorbed in the lungs, and thus, inevitably, some of them enter the systemic circulation. The risk of systemic adverse effects of IHC depends on the dose and activity of IHC, as well as bioavailability, absorption in the intestine, metabolism during the first passage through the liver and half-life of the part that was absorbed in the lungs and, probably, in the intestine. Therefore, systemic effects may be different in different IHSs. It should be noted that prolonged use of IHC is often accompanied by osteoporosis (risk of fracture of the bones, including the femoral neck) and oral candidiasis - painful for the patient.

A serious disadvantage of the prototype is the constant presence of the inhaler in the patient’s hands and the ease of its use, often leading to the reception of unacceptably high doses of IHS and β ₂ -adrenomimetics, which can lead to very serious complications both from the bronchopulmonary apparatus and from the cardiovascular system (tachycardia , heart rhythm disturbances, etc.). These complications are directly related to an overdose of the main drug.

Complications arising from an overdose of β-adrenergic agonists are due to:

1) the deterioration of bronchial obstruction due to the expansion of the bronchial vessels with prolonged stimulation of β2 receptors and an increase in edema of the bronchial mucosa (especially of small caliber);

2) a long stimulating effect of β-adrenostimulants on the heart, as a result of which the heart constantly works in extreme mode under conditions of prolonged hypoxia, which leads to serious metabolic disorders in the heart muscle. As a result, the development of heart rhythm disturbances is possible. In this case, palpitations, tremors, headaches, tachyarrhythmias, and increased irritability may develop.

It should be noted that the main disadvantage of the prototype method in the treatment of COPD is not the achievement of remission, but only relief of symptoms and an improvement in the quality of life of people suffering from this disease. In addition, patients have to take a large number of the above, not indifferent, and sometimes dangerous for the body preparations.

The technical result of the present invention is to achieve remission in this severe and completely incurable disease, as well as reducing the number of drugs taken.

This result is achieved by the fact that in the known method of treating COPD with a combination of IHC and bronchodilators according to the invention, against the background of the action of these drugs, not earlier than 30 minutes after their administration, surfactant BL is additionally used, which is administered inhalation daily once a day in an amount of 20- 25 mg per administration for 10-15 days, then inhalation is continued every other day at a dose of 10 mg for inhalation until the cough and dyspnea cease with moderate exercise, and in case of exacerbation of the disease, an additional 5-10 and 25 mg of surfactant-BL ngalium daily, continuing the use of IHS and bronchodilators.

It should be noted that with COPD, many physiological and molecular mechanisms for the protection of the bronchi and pulmonary parenchyma, developed by the nature and evolution of mammals, suffer. This concerns the mechanisms of cleaning the tracheobronchial tree from pathogenic flora by intensifying mucociliary clearance, activating macrophages, suppressing the molecular components of the systemic inflammatory response, etc.

One of such powerful natural complexes of physiological and molecular mechanisms for protecting the bronchi and pulmonary parenchyma, in our opinion, is pulmonary surfactant.

Known data on it and our long-term studies have shown that one of the mechanisms of action of pulmonary surfactant is its ability to absorb some bacteria and viruses on its surface, to aggregate the lipopolysaccharide of gram-negative bacteria. Surfactant promotes the capture of bacteria by alveolar macrophages (AM), activates mucociliary clearance, stimulates AM activity, inhibits the synthesis of aggressive cytokines produced by leukocytes and eosinophils entering the alveolar space due to an increase in the permeability of the alveolocapillary membrane.

Based on these studies, we previously developed and introduced into medical practice methods of treating critical conditions accompanied by severe respiratory failure, in the complex treatment of which we use the pulmonary surfactant preparation we received - surfactant-BL. These are methods of treating acute bronchopneumonia complicated by atelectasis (Patent No. 2149014), postnatal pneumonia in newborns (Patent No. 2149015), adult respiratory distress syndrome (Patent No. 2149016), respiratory failure in critical conditions in children (Patent No. 2149017), prevention pneumonia and respiratory distress syndrome of adults with aspiration of gastric contents (Patent No. 2149018), a method for the treatment of acute lung injury syndrome after extended surgery (Patent No. 2195958) and a method for the treatment of inhalation lesions (Patent No. 2238757), the use of which helped save thousands of patients, both newborns and adults.

Each of these methods is a justifiably invasive invasive method of administering large doses of surfactant-BL either by emulsion into the endotracheal tube for patients undergoing mechanical ventilation (ALV), or by administering the drug endobronchially using rigid fibrobronchoscopes under intensive care conditions, due to the severe condition of the patients, in critical condition on mechanical ventilation. Such methods are justified for the treatment of patients on mechanical ventilation in the conditions of resuscitation, and are not suitable for outpatient treatment.

Nevertheless, having extensive experience with surfactant preparations, we attempted to use it for the treatment of COPD.

In cases where patients did not have positive dynamics from standard therapy and it was impossible to achieve remission, we tried to add surfactant to the inhalation regimen. First of all, we explained to patients that it is necessary to quit smoking or, in extreme cases, significantly reduce tobacco consumption, since smoking is the most important risk factor for developing COPD. As a surfactant preparation, we used surfactant-BL developed by us. Against the background of IHC and bronchodilators, not earlier than 30 minutes after their administration, small doses of surfactant-BL were inhaled in patients, namely 20-25 mg per administration, such inhalations were required from 10 to 15. In most patients with COPD in the case of dry (unproductive ) cough after two or three daily inhalations, the amount of sputum excreted increased, the cough became less painful or the pain disappeared, patients noted a sharp relief of inspiration. Within 5-7 days, the amount of sputum decreased and the cough stopped completely. When studying the function of external respiration, a significant increase in the forced expiratory volume in one second and the forced vital capacity of the lungs were noted. This made it possible to continue inhalation of surfactant-BL with the possibility of reducing the number of taken, primarily IHC, already during the first 10-15 days of inhalation of surfactant-BL. If the severity of the disease (cough and shortness of breath) did not decrease, inhalation of surfactant-BL was carried out against the background of IHC and bronchodilators, but with a decrease in the number of inhalations up to complete cancellation, depending on the patient's condition. To significantly improve the condition of a patient with COPD, inhalation of surfactant-BL was continued every other day at a dose of 10 mg per administration, as our observations showed, for 3-6 weeks. And in the case of a worsening of the patient's condition (the appearance of shortness of breath with little physical exertion), an additional course of inhalation of surfactant-BL was carried out, including, as a rule, no more than 5-10 daily inhalations of 25 mg per administration. In this case, patients in such cases required an additional intake of IHC and bronchodilators, as a rule, no more than 1-2 times a day.

The essence of the method is illustrated by examples.

Example 1

Patient K., 64 years old, suffers from COPD for more than 20 years, smokes for more than 40 years at 20-25 cigarettes per day.

From the anamnesis. A sharp exacerbation began in April 2011. The cough intensified with excessive secretion of sputum mixed with saliva. Over the past 14 years, the patient has been on combination therapy with symbicort (160 / 4,5) and tiotropium bromide. Complaints of shortness of breath while walking, a feeling of tightness in the chest, the patient tried to move less. With exacerbations, he repeatedly received antibiotic courses. Periodically received systemic glucocorticosteroids (prednisone 10 mg per day). Shortness of breath at rest. Spirometry showed that FEV ₁ is 40% of the norm, and the FEV ₁ / FVC ratio is less than 60%. X-ray - increased airiness of the pulmonary fields (emphysema). Over the past two weeks, the patient was treated at the BMedA therapy clinic (St. Petersburg) for all the indicated therapy and oxygen support (mask) for 5-6 hours a day, he also received prednisone 10 mg per day, but no improvement from the therapy was observed , the patient practically lost sensitivity to IHC and bronchodilators. Against the background of this therapy, inhalations of surfactant-BL 25 mg daily are prescribed. After the third inhalation, some relief was noted. The time spent on oxygen support was reduced to two hours a day. After 6 inhalations, there was a feeling of the possibility of a deep breath. The amount of sputum decreased. After the 10th inhalation, the patient ceased to need oxygen support, stopped receiving prednisone and he continued inhalation of surfactant-BL 20 mg daily. A total of 15 inhalations of surfactant-BL were performed, after which the drug was inhaled (10 mg each) every other day for 6 weeks (20 inhalations). After completing the course of surfactant therapy, the patient continued to receive symbicort, but at a lower dose - 80 / 4.5 and without tiotropium bromide. Before discharge, spirometry showed that FEV _{1 was} 50% (a significant improvement), and the postbronchodilator test with a short-acting bronchodilator (salbutomol) increased FEV _{1 by} 10% (which confirms the irreversibility of bronchial obstruction). From 2011 to the present, twice (in May 2012 and April 2013) there was a deterioration in condition, shortness of breath and cough with sputum intensified. Both times, against the background of an increased dose of symbicort (160 / 4,5), 6 inhalations of surfactant-BL were performed daily. Both exacerbations quickly stopped and the patient returned to the regimen at a lower dose of symbicort. From May 2013 to the present (more than 2 years), there has been no deterioration. In total, the patient received 550 mg of surfactant-BL during the first course of treatment.

Conclusion: For the first time in the entire treatment period, the patient has a remission, which to date is 2 years. The patient continues to take IHS and bronchodilators, but no more than 2 times a day.

Example 2

Patient S., 53 years old. I turned for consultation at the Russian Science and Technology Center on April 12, 2012. Suffers from COPD for the past 10 years. Smokes for more than 30 years on a pack of cigarettes (20 cigarettes) per day. Complaints of coughing in the morning with scanty phlegm for over 20 years. Three years ago, shortness of breath appeared when walking. Spirometry indices FEV1 / FVC = 55% and FEV1 53% of the due. According to spirometry indicators, the patient has a second degree of disease severity. When x-ray elevated airiness of the pulmonary fields (signs of emphysema). Over the past 5 years, the patient receives symbicort 80 / 4.5 and tiotropium bromide. In March 2012, a severe exacerbation of the disease developed after the flu. The cough intensified, he tormented the patient all day and night with a large amount of mucopurulent sputum, an increase in temperature to 38 ° C. A course of amoxicillin and ciprofloxacin for 7 days and antipyretics were added to the main treatment. On the third day, the temperature returned to normal, but cough with sputum continued throughout the day and night, and an increase in the dose of symbicort to 160 / 4.5 did not give a result. Friends advised to turn to the Russian Center for Science and Technology for the purpose of conducting a course of surfactant therapy. The patient was prescribed a course of surfactant-BL at 20 mg for 10 days. After 6 inhalations, the cough decreased significantly, the patient began to sleep at night and felt significant relief. After 10 inhalations, the patient switched to a lower dose of Symbicort 80 / 4.5 and he continued the course of surfactant-BL 10 mg every other day for 3 weeks. The cough remained only in the mornings with a small amount of sputum. Spirometry after completing the course of surfactant therapy showed that FEV1 / FVC = 65% and FEV1 60% of the due, which indicated a significant improvement in the patient's condition. The patient drew attention to a significant increase in exercise tolerance, shortness of breath decreased when walking. After undergoing treatment, the patient for these three years did not have exacerbations and worsening conditions. The patient received 10 inhalations of 25 mg of surfactant-BL and 10 inhalations of 10 mg each. Only 350 mg of the drug.

Conclusion: the patient first achieved remission - the absence of exacerbations and worsening of the condition for 3 years.

To date, the proposed method has been treated 8 patients with COPD. Two patients (severe disease) received 10 inhalations of 25 mg of surfactant-BL and 5 inhalations of 20 mg against the background of IHC and bronchodilators, and then 10 mg from 15 to 20 inhalations every other day. In five patients, ARVI or influenza caused a deterioration in condition, which required additional courses of surfactant-BL 25 mg daily (10-15 inhalations). The consumption of surfactant-BL for the first course of therapy in these patients ranged from 450 mg to 550 mg. Remissions - from 1 year to two years after the first course of surfactant therapy, and more than 1-3 years to date, after additional short courses of surfactant therapy. In all patients, it was possible to reduce the number of accepted IHS and bronchodilators. At the same time, in two severe patients undergoing oxygen therapy and having lost sensitivity to standard therapy with IHD and bronchodilators, it was for the first time possible to restore sensitivity to standard therapy and to remove patients from a critical state, i.e. remove from oxygen therapy.

The proposed method for the treatment of COPD can significantly increase remissions between exacerbations of the disease, allows for COPD of 4th severity to quickly remove them from chronic respiratory failure, stop oxygen support and restore sensitivity at this stage of the disease to the treatment of IHS and bronchodilators. In addition, after a course of surfactant therapy, patients with COPD are in a stable condition to date for up to 3 years with a significant reduction in the doses of the combined combination of IHS and bronchodilators.

The method was developed at the Russian Science and Technology Center of the Ministry of Health of the Russian Federation together with Biosurf LLC and has been tested to date in 8 patients with a positive result.

Claims (1)

A method of treating chronic obstructive pulmonary disease by inhalation of glucocorticosteroids and bronchodilators, characterized in that not earlier than 30 minutes after taking glucocorticosteroids and bronchodilators, surfactant-BL is additionally administered, which is administered inhalation once a day at a dose of 20-25 mg for administration for 10 -15 days, then 10 mg every other day for 3-6 weeks, and if the condition worsens, 5-10 inhalations of surfactant-BL 25 mg daily with continued inhalation of glucocorticosteroids and bronchodi yatatorov.