RU2600822C1 - Method of treating chronic obstructive bronchitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology, and can be used for treating chronic obstructive bronchitis. For this purpose, receiving inhaled bronchodilators, not earlier than 30 minutes after their administration, surfactant BL is also used, administrated by inhalation daily once a day in an amount of 20-25 mg for 10-12 days, wherein dose of inhaled bronchodilators is reduced up to their cancellation and inhalation of surfactant BL is continued every second day in a dose of 10 mg per inhalation up to relief of symptoms; in case of disease exacerbation additional daily 5-6 inhalations of 25 mg of surfactant BL are made, if necessary, with use of inhaled bronchodilators.

EFFECT: method enables prolonging remission up to 2 years and more at decreased frequency of exacerbations and reduction of receiving bronchodilators.

1 cl, 2 ex

Description

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

Obstructive bronchitis is an inflammatory disease of the bronchi in which the airway is impaired.

Chronic bronchitis is usually defined clinically as having a cough with sputum production for at least 3 months over the next 2 years.

The chronic form of obstructive bronchitis, as a rule, develops in adults. Risk factors for its development include smoking, hereditary genetic pathology, in which patients have a deficiency of α ₁ -antitrypsin, adverse environmental conditions (air pollution, high humidity), occupational hazards (working with silicon, cadmium, cement, in coal mines, metallurgy, etc.).

The chronic form of the disease is characterized by a prolonged absence of symptoms of obstructive bronchitis. The disease proceeds with periods of remission and exacerbations, most often caused by hypothermia and acute respiratory infections. Clinical symptoms occur during periods of exacerbation of the disease and depend on its stage and level of damage to the bronchial tree. The first visit to a doctor is usually associated with the appearance of shortness of breath and cough, which is usually accompanied by sputum production. These symptoms are most pronounced in the morning. Since the disease progresses slowly, in most cases shortness of breath, which initially occurs only during physical exertion, appears on average 7-10 years later than a cough.

Exacerbations of chronic obstructive bronchitis are usually associated with acute respiratory infections, so cough with purulent sputum and increased shortness of breath are often not regarded as signs of this particular disease. Over time, exacerbations of the disease begin to occur more often, and periods of remission are significantly reduced. As bronchitis progresses, "wheezing" breathing joins the cough, and shortness of breath can vary from a feeling of lack of air during usual physical exertion to severe respiratory failure.

The most common symptoms of chronic bronchitis include a fairly moderate cough, mainly in the morning, after waking up. During the period of exacerbation of the disease, cough is greatly enhanced - it annoys the patient throughout the day. In all cases, the cough is wet, sputum is separated without much effort. Fatigue and weakness join. If a person - especially a smoker - may not pay much attention to a light cough, then weakness and fatigue are unlikely to go unnoticed. Later appear: shortness of breath, sweating and fever up to 38-39 ° C.

Treatment of chronic obstructive bronchitis in most cases is an extremely difficult task. First of all, this is explained by the main regularity of the development of the disease by the steady progression of bronchial obstruction and respiratory failure due to the inflammatory process and bronchial hyperreactivity and the development of persistent irreversible disturbances in bronchial obstruction due to the formation of obstructive emphysema. 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. The low effectiveness of the treatment of chronic obstructive bronchitis is due to the late visit of the patient to the doctor, when there are already signs of respiratory failure and irreversible changes in the lungs.

Drug treatment of chronic obstructive bronchitis involves the use of bronchodilators, the appointment of mucoregulatory therapy, correction of respiratory failure, anti-infection and anti-inflammatory therapy (for exacerbations of the disease).

Timely adequate comprehensive treatment of chronic obstructive bronchitis in many cases can reduce the rate of disease progression, leading to an increase in bronchial obstruction and respiratory failure. The main objectives of the treatment are to reduce the frequency and duration of exacerbations, increase working capacity and exercise tolerance.

Closest to the proposed is a method for the treatment of chronic obstructive bronchitis, recommended by the Federal Clinical Recommendations (2013). The method is based on the use of bronchial blockers, agents that improve mucociliary clearance, and agents that dilute phlegm - mucolytics. In chronic bronchitis, treatment begins with m-anticholinergics (atrovent, spiriva), in case of insufficient effect, β ₂ long-acting agonists are added (tiotropium bromide) or a combined bronchodilator Berodual is used, which contains two components with bronchodilator activity: ipratropium bromide (m- anticholinergic blocker) and phenoterol hydrobromide (β ₂ -adrenomimetic). This method is taken by us as a prototype.

However, the prototype, as well as other currently used methods of treating chronic obstructive bronchitis, has a number of significant disadvantages: for example, m-anticholinergic drugs in case of an overdose cause numerous side effects, such as dry mouth, decreased visual acuity, increased intraocular pressure, tachycardia, urinary retention, atonic constipation, often stagnation of bile, sometimes there is mental excitement, hallucinations, euphoria, dizziness. In case of an overdose of drugs of this group, the administration of m-cholinomimetics is ineffective, since m-anticholinergics reliably bind the receptor and shield it from interaction with acetylcholine or its imitators (unilateral antagonism).

With respect to β ₂ -adrenergic agonists, as well as combination preparations, for example, berodual, it should be noted that a serious disadvantage is the constant presence of the inhaler in the patient’s hands and the ease of its use, which often leads to unacceptably high doses of both m-anticholinergic and β ₂ -adrenomimetics, which is fraught with very serious complications both from the bronchopulmonary apparatus and from the cardiovascular system (tachycardia, cardiac arrhythmias, etc.).

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 β ₂ receptors and an increase in edema of the bronchial mucosa (especially 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 when using combined bronchodilators. for example, a berodual, which contains two components with bronchodilator activity: ipratropium bromide (m-anticholinergic blocker) and phenoterol hydrobromide (beta ₂ -adrenomimetic), the risk of side effects increases, since this inhaled drug can give a total side effect of two active principles : and m-anticholinergic, and β-adrenergic agonist.

As our observations of patients with chronic obstructive bronchitis showed, the currently recommended treatment causes only a slight decrease in the frequency of exacerbations of the disease and an improvement in the quality of life of such patients, without affecting the mechanisms of protection of the bronchi and pulmonary parenchyma, which could lead to a long-term remission of the disease .

Thus, the main disadvantage of the prototype in the treatment of chronic obstructive bronchitis is the fact that it does not provide long-term remission in the condition of patients. In addition, patients have to take a large number (up to 5 or more) of the above, not indifferent, and sometimes dangerous for the body drugs.

The technical result of the present invention is to achieve long-term remission in the treatment of chronic obstructive bronchitis and reduce the number of drugs taken by introducing surfactant into the course of treatment.

This result is achieved by the fact that in the known method for the treatment of chronic obstructive bronchitis by inhalation dilators, according to the invention, against the background of the action of these drugs, surfactant-BL is additionally used not earlier than 30 minutes after their administration, which is administered inhalation daily once a day in an amount of 20-25 mg for administration within 10-12 days, then inhalation of surfactant-BL is continued every other day at a dose of 10 mg for inhalation until the symptoms of the disease are relieved, and in case of exacerbation of the disease, odyat 5-6 inhalations of surfactant-BL 25 mg daily, continued use of bronchodilators as needed.

It is advisable to achieve a positive therapeutic effect even during inhalation of surfactant-BL gradually reduce the dose of inhaled bronchodilators, until they are completely canceled.

It should be noted that in chronic obstructive bronchitis, 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), which saved the lives of several thousand 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 (IVL), or by administering the drug endobronchially using rigid and flexible fibrobronchoscopes under intensive care conditions, which was caused by severe the condition of such patients in critical condition on mechanical ventilation. These methods are not suitable for outpatient treatment.

Nevertheless, having extensive experience with surfactant preparations, we made an attempt for the first time to use it for the treatment of chronic obstructive bronchitis. And in cases where patients did not have positive dynamics from standard therapy - the use of bronchodilators, mucolytics and agents that enhance mucociliary clearance - and in the case of a bacterial infection - and broad-spectrum antibiotics, we tried to add surfactant to the treatment 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 the development of chronic obstructive bronchitis. As a surfactant preparation, we used surfactant-BL developed by us, while discontinuing the use of antibiotics in the treatment regimen. Against the background of inhaled bronchodilators, small doses of surfactant-BL were inhaled in patients, starting from 20-25 mg per administration. In most patients with chronic obstructive bronchitis, the amount of sputum did not increase, but patients noted a sharp relief of inspiration. Within 5-7 days of inhalation, the amount of sputum decreased, the cough stopped completely. If during the study of the function of external respiration there was a significant increase in forced expiratory volume in one second and forced vital capacity of the lungs, this allowed continued inhalation of surfactant-BL with the possibility of gradual withdrawal of bronchodilators already during the first 10-12 or subsequent days of inhalation of the drug. If the symptoms of the disease did not completely stop, inhalation of the surfactant was carried out against the background of bronchodilators, but with a decrease in the number of inhalations, depending on the condition of the patient, up to their complete cancellation. To completely stop the symptoms of bronchitis, inhalation of surfactant-BL was continued every other day at a dose of 10 mg per administration, which, as our observations showed, required no more than 3-6 weeks, even in severe forms of bronchitis. And in the case of an exacerbation of the disease on the background of acute respiratory viral infections or influenza, an additional course of inhalation of surfactant-BL was carried out, including, as a rule, no more than 5-6 daily inhalations of 25 mg per administration. At the same time, a number of patients in such cases required additional administration of bronchodilators, as a rule, no more than 1-2 times a day.

Doses and modes of administration of surfactant-BL were determined by us empirically as a result of long-term observation of patients.

The essence of the method is as follows.

A patient suffering from chronic obstructive bronchitis, while taking bronchodilators, not earlier than 30 minutes after their administration, is additionally prescribed surfactant-BL, which is administered by inhalation daily once a day in an amount of 20-25 mg per administration for 10-12 days. Depending on the patient’s condition, it is already possible to reduce the dose of bronchodilators these days, until they are canceled, then the administration of surfactant-BL is continued every other day at a dose of 10 mg for inhalation until the symptoms of the disease are relieved, and in case of exacerbation of the disease, another 5-6 inhalations of surfactant are carried out -BL 25 mg daily, if necessary, using inhaled bronchodilators.

The essence of the method is illustrated by examples.

Example 1

Patient K., 53 years old, suffers from chronic obstructive bronchitis for 8 years. He complains of coughing, especially in the morning, and shortness of breath, even with little physical activity, smokes for more than 20 years, 20-25 cigarettes a day.

From the anamnesis: Exacerbations of the disease are, as a rule, 2-3 times a year and last up to 3 months. This exacerbation arose in early February 2013 against the background of a flu disease (a seasonal epidemic was associated with H3N2 flu). Complaints of fever (above 38.5 ° C), severe wet cough, headache, muscle pain and severe weakness. Starting from the second day of the disease, I took the antiviral drug Tamiflu, Aspirin, Vitamin C, 1 g for 5 days, a heavy drink. The main symptoms of the disease disappeared: the temperature returned to normal, the headache disappeared, the weakness decreased, but the cough and shortness of breath persisted. A clinical blood test revealed lymphopenia and eosinophilia. Mustard plasters, hot foot baths and expectorants (ACC, tincture of marshmallow root) within 4 weeks did not eliminate the cough. The outpatient doctor prescribed salbutomol in the morning and evening, but even during the week he did not have a positive effect. A spirometric examination performed during the period without exacerbation in March 2013 showed that the volume of forced expiration in one second (FEV ₁ ) is 56% of the norm in accordance with the patient’s age, gender and height, which indicated the obstructive nature of the pathological process and moderate severity of bronchitis. The increase in the volume of FEV ₁ in response to inhalation of salbutomol (standard test) was 10%, indicating irreversible obstruction.

March 25, 2013 the patient, having learned from a friend about the effectiveness of surfactant-BL, which he took in the form of inhalation for severe bronchitis, sought advice from the Russian Science and Technology Center about the acquisition and possibility of using this drug.

According to the results of X-ray (signs of emphysema), as well as research data on impaired external respiration, reported by the patient, she was prescribed inhalations of surfactant-BL 20 mg daily 1 time per day, which she took against the background of inhalation of berodual (a mixture of m-anticholinergic and prolonged β ₂ -agonist tiotropium bromide). After the first two inhalations of surfactant-BL, her sputum increased, after 5 days the amount of sputum decreased, the cough became painless and stopped on the 6th day, shortness of breath with a little physical exertion decreased. The measurement of FEV ₁ gave a value of 67%, significantly higher in comparison with the previously indicated patient (56%). This allowed to cancel the patient inhalation of berodual and continue inhalation of surfactant-BL. After four inhalations of surfactant-BL at a dose of 25 mg for the introduction of cough and shortness of breath with moderate physical activity stopped. To consolidate the achieved positive effect, inhalations of surfactant-BL were continued at a dose of 10 mg every other day for 3 weeks, still without inhalation of berodual. The study of the function of external respiration showed that OFE ₁ is 74%, which indicated a significant improvement in the patient's condition and its transition to a mild severity group. The patient received only 320 mg per course of surfactant therapy.

To date (August 2015), exacerbations of chronic bronchitis in the patient have not been. Remission to date is more than 2 years without taking bronchodilators. The patient also notes that in the time elapsed since the end of treatment with surfactant-BL, she did not suffer from colds and ARVI.

Example 2

Patient M., born in 1944 in July 2011, was hospitalized in the therapeutic department S.-Pb. State Medical University named after Acad. I.P. Pavlova with a diagnosis of interstitial pneumonia.

From the anamnesis. During the treatment of pneumonia, the main emphasis was on antibiotics in large doses. With this diagnosis and improved epicrisis, he was discharged at the end of July. However, in early December 2011, the patient suffered from acute respiratory viral infections and soon felt obvious signs of exacerbation of obstructive chronic bronchitis, which he suffers for more than 15 years with periodic exacerbations, usually 2-3 times a year for at least 3 months (he smokes for more than 40 years more than 25 cigarettes in a day). During exacerbations, as a rule, he received bronchodilators (m-anticholinergics) or a combination of bronchodilators berotek, which usually temporarily gave a positive effect. With the appearance of purulent sputum, he was periodically prescribed antibiotics. During this exacerbation (early December 2011), according to the results of the examination, a pulmonologist confirmed an exacerbation of chronic bronchitis, and an assessment of the function of external respiration revealed that FEV _{1 was} 52%, which confirmed the obstructive nature of the process. The study of the effect of the introduction of bronchodilator (salbutomol) showed that the increase in the FEV value of ₁ was only 8%, which indicated the irreversibility of bronchial obstruction. Radiologically determined increased airiness of the pulmonary fields (emphysema). The patient was recommended to quit smoking and was prescribed inhalations of a long-acting bronchodilator - Spiriva (tiotropium bromide, a specific anticholinergic drug with a long-lasting effect that has an affinity for all subtypes of muscarinic receptors (M1-M5). The drug did not give an effect for 3 weeks, relief was extremely moderate and unstable. The cough with profuse sputum continued.

In this regard, on December 22, 2011, the patient turned to the Russian Center for Science and Technology, where, according to the results of an X-ray, as well as a study of the function of external respiration, which confirmed a decrease in FEV of ₁ to 52%, a course of surfactant therapy was prescribed by inhalation of the drug surfactant BL 20 mg for inhalation, which he took 30 minutes after inhalation of the spirit. After the third inhalation of surfactant-BL, cough and sputum production significantly decreased, the general condition improved, the patient began to sleep well at night. The measurement of FEV ₁ showed a value of 65% of the norm, which indicated a significant improvement in the state of the function of external respiration. After 9 inhalations of 20 mg of surfactant-BL, a pronounced positive effect was noted, the cough decreased sharply and was only once in the morning, and after taking another 3 inhalations of 25 mg of surfactant-BL, the cough disappeared. The patient felt significant relief when breathing. Shortness of breath while walking disappeared. The study of the function of external respiration showed that FEV ₁ is 69% of the norm, while a test to reduce bronchial obstruction for the introduction of a short-acting bronchodilator (salbutomol), an increase in FEV ₁ gave an increase of 17%. These data made it possible to cancel the inhalation of Spiriv and continue the inhalation of surfactant-BL every other day, 10 mg per administration until the symptoms of the disease were completely stopped, which took 5 weeks (18 inhalations) of surfactant-BL 10 mg without taking Spiriv. The patient required 435 mg of surfactant-BL for the course of surfactant therapy.

Over the next 1 year and 4 months, the patient did not have exacerbations, he stopped suffering from colds. However, in June 2013, the patient again began to exacerbate chronic bronchitis against the background of another ARVI (the patient did not stop smoking). A strong, excruciating cough and shortness of breath began again. The patient again turned to the RSCRHT with a request to conduct another course of surfactant therapy. After 6 inhalations of surfactant-BL 25 mg daily with the use of a bronchodilator - Spirit cough and sputum production stopped, and only in the morning there was a slight painless sputum discharge. The patient stopped taking the spirit. Spirometry showed that FEV ₁ remained at the level of 70%, which was achieved 1.5 years ago after the first course of surfactant therapy. To date (August 2015), the patient has not had exacerbations and shortness of breath with moderate physical activity without taking bronchodilators.

Conclusion The first remission of chronic obstructive bronchitis lasted 1 year 4 months, the second - to date and has been more than 2 years.

To date, the proposed method has been treated 18 patients, many years suffering from chronic obstructive bronchitis. Of these 18 patients, 12 (moderate patients) for relief of exacerbation, one course of surfactant-BL was enough for 10-12 inhalations daily at a dose of 20-25 mg of the drug for administration and subsequent inhalations every other day for 10 mg for administration of surfactant-BL within 2-6 weeks with the complete cancellation of bronchodilators in the course of such treatment. In 6 patients, after 1.5-2 years, exacerbations of bronchitis were noted (as a result of colds or flu), for treatment, an additional 5-6 daily inhalations of 25 mg of surfactant-BL were required, while only two patients took 1- during treatment 2 times a day bronchodilator. Continuation of remission to date in 8 patients - more than 2 years, in 6 patients - more than 1.5 years, in 4 patients - more than 1 year.

The proposed method in comparison with the known has several significant advantages.

1. Lengthening the remission of the disease up to 2 years or more without exacerbations, which distinguishes the claimed method from the prototype.

2. A significant reduction in the frequency of exacerbations of chronic obstructive bronchitis, and in the case of exacerbation - a quick relief of the disease.

3. A relatively small amount (250-450 mg) of an expensive drug - surfactant - BL, necessary for the treatment of chronic bronchitis with the achievement of a sufficiently long remission.

4. A significant reduction in the intake of bronchodilators - not more often 1-2 times a day during treatment or during an exacerbation of the disease and not in all patients.

The method was developed in 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 18 patients with a positive result.

Claims (2)

1. A method of treating chronic obstructive bronchitis with inhaled bronchodilators, characterized in that, 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 by inhalation daily once a day in an amount of 20-25 mg per administration within 10-12 days, after which the inhalation of surfactant-BL is continued every other day at a dose of 10 mg for administration until the symptoms of the disease are relieved, and in case of exacerbation of the disease, 5-6 inhalations of surfactant-BL are additionally administered 25 mg daily, continuing, if necessary, the use of bronchodilators. 2. The method according to p. 1, characterized in that when a positive therapeutic effect is achieved already during inhalation of surfactant-BL, the doses of inhaled bronchodilators are gradually reduced until they are completely canceled.