RU2348431C1 - Method of treatment of steroid-dependent bronchial asthma - Google Patents

Abstract

FIELD: medicine; pulmonology.

SUBSTANCE: baseline therapy is combined with introduction of Ronkoleukine inhaled in dosage 250 thousand ME with using nebuliser, and injected simultaneously. Introduction takes two stages, herewith at the first stage Ronkoleukine is injected intravenously drop-by-drop in dosage 250 thousand ME within course 3 procedures every 72 hours, while at the second stage Ronkoleukine is injected every 2 weeks hypodermically in external surface of a shoulder in dosage 250 thousand ME within course 4-6 procedures.

EFFECT: normalised immune disorders and relieved endobronchial inflammations.

2 tbl, 3 ex

Description

The invention relates to medicine, namely to pulmonology, and is intended for the treatment of steroid-dependent bronchial asthma.

Bronchial asthma is one of the most important medical and social problems. Of particular relevance in the practice of Russian doctors are severe forms of bronchial asthma, which account for more than 20% of all cases of the disease in Russia. The treatment of such patients is the most difficult in connection with the occurrence of a large number of side effects from the use of systemic glucocorticosteroids (Artemyev O.V., Kognovitskaya A.I., Yurina T.M. et al. State of the immune and interferon systems in patients with bronchial asthma // Clin. Honey. - 2001. - No. 10. - S.21-23). One of the side effects of glucocorticosteroids in the treatment of severe bronchial asthma is the development of secondary immune deficiency, manifested by depression of the T-cell and phagocytic parts of the immune system against the background of hyperactivity of humoral immunity. Along with an imbalance in systemic immunity in bronchial asthma, dysfunction develops in the local respiratory immune defense system. This contributes to the persistence of pathogenic microorganisms and the increase in exacerbations of the disease. Currently, treatment of patients with severe bronchial asthma is carried out using a large number of drugs that control the course of the disease: inhaled glucocorticosteroids in high doses (800-2000 μg / day beclomethasone dipropionate or equivalent doses of other inhaled glucocorticosteroids), prolonged bronchodilators or anticholinergic drug bromopratate ), inhaled short-acting β ₂ -agonists to relieve symptoms. A more severe exacerbation may require a course of oral glucocorticosteroids. However, despite the ongoing therapy, it is not always possible to completely control the course of bronchial asthma in patients with a severe course of the disease. The low effectiveness of traditional therapy in such patients necessitates the use of new approaches to the treatment of severe asthma, taking into account its immunopathogenesis, including the inclusion of drugs with an immunomodulating effect in the complex therapy regimen (Artemyev O.V., Kognovitskaya A.I., Yurina T. M. et al. The state of the immune and interferon systems in patients with bronchial asthma // Clin. Honey. - 2001. - No. 10. - P.21-23 .; Global strategy for the treatment and prevention of bronchial asthma / Ed. Chuchalina. - M.: “Atmosphere”, 2002. - 160 p.).

A known method of treating bronchial asthma by traditional therapy, including the introduction of thymogen (RU No. 2005103083, IPC A61K 35/26, A61K 39/085, A61P 11/06). A known method of treating bronchial asthma by traditional therapy, with the additional purpose of levamisole and ruzam (RU No. 2005100170, IPC A61K 31/425, A61K 35/74, A61P 11/06). There is a method of treating bronchial asthma in children who often and / or have long-term acute respiratory viral infections, including basic therapy and additionally during the remission period rectally Viferon (RU No. 2001101610, IPC A61K 38/21). There is a method of treating patients with acute and chronic lung diseases, including basic therapy differentially depending on lung disease and the introduction of recombinant interleukin-2 (roncoleukin) intravenously from one to five administrations of 250-500 thousand ME with intervals of 48-72 hours ( Clinical recommendations: Bronchial asthma in adults, Atopic dermatitis / Ed. By academician of RAMP A.G. Chuchalin. - M .: "Atmosphere", 2002. - 272 p .; Kurmanova G.M., Ramazanova Sh.H. Mazhitova ZH; Experience with the use of roncoleukin in children with bronchial th asthma in pristupnaya period // Medical Immunology, 2003 - T.5, №3-4 -. 233). However, these methods of treating bronchial asthma are not effective enough, since the drug does not immediately affect the immunocompetent cells of the main target organ in bronchopulmonary pathology, mainly having a systemic effect on other organs and tissues. A known method of treatment of steroid-dependent bronchial asthma, including inhalation of human leukocyte interferon P for injection daily for 6-8 days at a dose of 10,000 units of the drug, dissolved in 2 ml of distilled water (patent RU 2028083, IPC АВВ 10/00). There is a method of immunocorrection in pneumonia, when 5 inhalations of roncoleukin are prescribed for etiotropic therapy every other day at a dose of 250 thousand ME, through a compression nebulizer (patent RU No. 2305555, IPC A61K 38/20, A61P 11/20, A61N 2/04). The disadvantage of these methods is the predominant focus on the target organ and the lack of correction of systemic immunodeficiency, developing with severe bronchopulmonary pathology. There is also a method of treating patients with bronchopulmonary pathology, where roncoleukin is included in the complex therapy, which was administered subcutaneously at a dose of 250 thousand ME and 250 thousand ME by inhalation through a nebulizer, for a course of 3 injections and 3 inhalations with an interval of 48-72 hours (patent RU No. 2205659, IPC A61K 38/21, A61P 11/00). However, with steroid-dependent bronchial asthma, especially in the acute period of the disease, firstly, the appointment of high concentrations of aerosols causes a high risk of developing bronchospasm due to irritation of the bronchial mucosa, and secondly, a short course of treatment, as a rule, is insufficient to reduce the severity of endobronchial inflammation .

The claimed invention solves the problem of increasing the effectiveness of the treatment of steroid-dependent bronchial asthma.

The technical result is the normalization of immune disorders, a decrease in the severity of endobronchial inflammation.

This is achieved by the fact that in the known method for the treatment of steroid-dependent bronchial asthma, including basic therapy using roncoleukin as an immunomodulator, administered in the form of injections and inhalations at a dose of 250 thousand ME, carried out using a nebulizer, the introduction of roncoleukin is carried out in two stages, while at the first stage, roncoleukin injections are performed at an interval of 72 hours intravenously in a dose of 250 thousand ME with a course of 3 procedures, and at the second stage, roncoleukin injections are performed subcutaneously at an interval of 2 weeks into the external shoulder surface in a dose of 250 thousand ME in a course of 4-6 procedures. In the proposed method of treatment, a combination of local effects of roncoleukin on immunocompetent cells of the tracheobronchial tree and systemic effects of the drug normalizes the immune disorders that occur with steroid-dependent bronchial asthma.

Roncoleukin is a dosage form of recombinant human interleukin-2. It is a complete structural and functional analogue of endogenous human IL-2, which has an immunocorrective effect aimed at enhancing antibacterial, antiviral, antifungal and antitumor immunity. Recombinant human interleukin-2 restores the functions of the T-cell component of the immune system, eliminates the subpopulation imbalance of Th1 and Th2 lymphocytes and is able to increase the number of glucocorticosteroid receptors on human peripheral blood mononuclear cells. In the proposed method used roncoleukin for injection (Roncoleukin, ampoules 250 thousand ME), manufactured by LLC Biotech, St. Petersburg, Russia; registration certificate No. 000122/012000, issued by the Ministry of Health of the Russian Federation of 08.31.95

Example 1

Patient I., 54 years old, medical history No. 406, from 02.21.05 to 03.03.05 was hospitalized in the pulmonology department of GB No. 4 due to exacerbation of the mixed form of steroid-dependent bronchial asthma. Dry cough in the morning notes since childhood. Since 1996, attacks of difficulty breathing have been disturbing, in 1999 the diagnosis of bronchial asthma was verified, treatment with inhaled glucocorticosteroids was prescribed. In connection with the persistence of asthma symptoms with the constant intake of 1800 mcg per day of becloson, 15 mg of prednisolone orally has been connected to treatment since 2001. At the time of admission, he complained of an increase in asthma attacks up to 5-6 times a day, of which 1-2 times at night, poorly stopping with bronchodilators, paroxysmal cough with viscous mucopurulent sputum and shortness of breath during physical exertion. During auscultation in the lungs, scattered dry wheezing was heard against the background of hard breathing. In the hemogram: 5,600 leukocytes per μl, ESR 18 mm / h, eosinophils 4%. Endoscopically revealed bilateral diffuse purulent endobronchitis, the sediment bronchoalveolar washout almost completely consisted of neutrophils. A sharp decrease in PSV was noted, the spread reached 50%. Among the indicators of the immunogram, attention was drawn to a decrease in the number of T-lymphocytes to 45%, T-helpers to 21%, an increase in B-lymphocytes to 26%, reduced phagocytic activity of neutrophils (PI-19%, PS-1.5 c.u.). The treatment with the additional appointment of roncoleukin. Roncoleukin was administered by inhalation using a compression nebulizer at a dose of 250 thousand ME at the same time as an intravenous drip of the drug at a dose of 250 thousand ME three times with an interval of 72 hours. In the process of treatment, sputum acquired a mucous character, cough decreased. At discharge, breathing in the lungs remained stiff, no wheezing was heard. The degree of obstructive disorders decreased: FEV ₁ increased by 42%, POS by 48.2%, MOS _25-75 by 15%, however, there was a large spread of diurnal fluctuations in PSV (41%). In a general blood test, a decrease in ESR to 5 mm / h was observed. In the endocytogram of bronchial washes, the number of neutrophils remained elevated (before treatment - 92%, by day 15 of therapy - 88%). The number of T-lymphocytes increased to 62%, T-helpers - up to 34% against the background of a decrease in the content of B-lymphocytes to 7%. The phagocytic activity of neutrophils has grown (FI-29%, PS-2.5). Hospitalization 13 days. Two weeks after discharge from the hospital, I received an additional 4 times inhalation treatment with roncoleukin through a nebulizer at a dose of 250 thousand ME and simultaneously with subcutaneous administration at a dose of 250 thousand ME with an interval of 2 weeks. By the end of treatment, nighttime asthma symptoms stopped, daytime suffocation attacks only occurred with significant physical exertion, the need for bronchodilators decreased to 0-2 times a day. PSV increased to 82% of due; FEV ₁ reached 93.4%, PIC - 96.3%, MOS _25-75 - 67%. With fibrobronchoscopy, a picture of catarrhal endobronchitis, the degree of inflammation I, the neutrophil content in the lavage fluid decreased almost 2 times compared with the indicator before treatment (45.1%). Positive clinical and functional dynamics occurred against the background of a decrease in the dose of systemic glucocorticosteroids, and by the 4th month of observation, prednisone was canceled.

Example 2

Patient P, 48 years old, medical history No. 2694, was admitted on 11/23/06 to the pulmonology department complaining of daily day and night symptoms of asthma, the need for bronchodilators up to 10-15 times a day, paroxysmal dry cough and sneezing when inhaling pungent odors and cold air, in the morning cough with the separation of scanty mucopurulent sputum, labored nose breathing, weakness, sweating. Since 1990, he suffers from allergic rhinitis (sensitization to pollen allergens), since 1999 there are attacks of suffocation in the summer, inhaled glucocorticosteroids (aldecine 800 mcg / day), bronchodilators as needed. After 2-3 years, she began to notice an increase in asthma attacks and the appearance of a cough with yellow-green sputum on the background of acute respiratory viral infections. Since 2000, continuously taking becloson at a dose of 1600 mcg per day. In connection with the persistence of frequent asthma symptoms during therapy since 2002, systemic glucocorticosteroids (prednisone in a maintenance dose of 30 mg per day) have been connected to treatment. According to the anamnesis, despite the basic therapy received, the patient has high bronchial hyperreactivity, which was confirmed by a 43% scatter in PSV and a high demand for bronchodilators. Deterioration of health about 3-4 days after hypothermia. An objective examination revealed hard breathing with scattered wheezing, intensifying on forced expiration. In the general analysis of blood at admission - leukocytes of 18.2 thousand per μl, ESR 12 mm / h, eosinophils 14%, stab neutrophils 4%. In the general analysis of sputum - leukocytes are completely, in the cytogram - the predominance of neutrophils. An endoscopic examination was diagnosed with bilateral diffuse purulent endobronchitis, the degree of inflammation II, the content of neutrophils in the lavage fluid - 32.4 × 10 ⁴ / L. With spirography, a significant violation of the function of external respiration by a mixed type was found. According to immunological blood tests, a depression of the T-cell immune response and a decrease in the phagocytic activity of neutrophils were detected. Standard therapy with roncoleukin was performed. The drug was administered by inhalation using a compression nebulizer at a dose of 250 thousand ME simultaneously with intravenous drip of the drug at a dose of 250 thousand ME three times with an interval of 72 hours. After the first procedure, an increase in temperature to 37.2 ° C was noted, on other days the temperature was within normal limits. The treatment was well tolerated. In the dynamics after 14 days, the daily symptoms of asthma were completely absent; decreased the number of night attacks of suffocation, the need for bronchodilators, the number of wheezing in the lungs. PSV reached 63% of what was expected, but PSV scatter during the day remained significant - 46%. Spirogram indicators are an increase in FEV ₁ from 51.4% to 68.9%, PIC from 39.4% to 60% and MOC _25-75 from 27.2% to 48.5%. In a general blood test, normalization of the content of leukocytes and eosinophils was noted. There was a positive dynamics of the endoscopic picture in the form of transition of purulent bronchitis into catarrhal, but the content of neutrophils in the lavage fluid remained at the same level. By the same time, the immunogram indicators improved: the number of T-lymphocytes increased from 25% to 48%, the phagocytic index increased from 18 to 44% (norm 52-69%). The duration of inpatient treatment was 16 days. Two weeks later, on an outpatient basis, the patient continued treatment with Roncoleukin inhaled through a nebulizer at a dose of 250 thousand ME with a subcutaneous injection of 250 thousand ME into the outer surface of the shoulder with a course of 6 procedures with an interval of 2 weeks. By the end of treatment, nighttime asthma symptoms stopped, nasal breathing improved, the need for bronchodilators decreased to 0-3 times a day. Along with positive clinical dynamics, there was a positive dynamics in indicators of the function of external respiration: PSV reached 84% of the due, PSV spread - 14%, FEV ₁ - 88.1%, POS up to 82.7% and MOS _25-75 to 63.8% . With fibrobronchoscopy, catarrhal endobronchitis, the degree of inflammation 0-1, neutrophils in the lavage decreased to 14.6 × 10 ⁴ / L. According to the immunological examination revealed normalization of phagocytic activity of neutrophils and T-cell immunity, a decrease in the CEC from 148 cu to 15 cu, a decrease in the content of CD95 ⁺ cells from 0.12 × 10 ⁹ / L to 0.06 × 10 ⁹ / L. Persistent clinical and functional dynamics allowed to reduce the maintenance dose of prednisolone to 10 mg per day.

Example 3 (without inhalation administration of roncoleukin).

Patient Z., 42 years old, medical history 3459/290. I was hospitalized in the pulmonology department of the MUZ GB No. 4 from 03.21.05 to 04.04.05. Suffers from bronchial asthma for 20 years, since 1993, a constant intake of 15 mg of prednisone per day. Upon admission, she complained of constant attacks of suffocation, the need for bronchodilators up to 10 times a day, of which 3-4 times at night, cough with hard-to-remove yellow sputum, fever up to 37.4 ° C, weakness, sweating. Auscultation in the lungs was heard hard breathing with a large number of buzzing and wheezing. In the general blood test, an increase in leukocytes to 15.1 thousand in μl with a stab shift in the leukoformula up to 9% was noted. When bronchial fibrobronchoscopy was determined bilateral diffuse purulent endobronchitis, degree of inflammation II, with a high content of bronchial epithelium and neutrophils in the washout from the bronchi (24.5 × 10 ⁴ / l). When spirography recorded a sharp decrease in all indicators. The study of the immune status revealed depression of the T-cell link in the form of a decrease in the number of T-helpers (8.5%), an increase in the number of CD95 ⁺ cells (0.2.1 × 10 ⁹ / L) amid an increase in the content of B-lymphocytes (21 %) and the level of the CEC (201 units). Roncoleukin was intravenously dripped at a dose of 500 thousand ME three times with standard therapy with an interval of 72 hours. Against the background of the therapy, there was a decrease in the severity of coughing, a decrease in daytime asthma symptoms with the preservation of nightly attacks of suffocation, normalization of body temperature, and exacerbation stopped by day 18. Auscultation listened to hard breathing with occasional wheezing. PSV increased from 47% to 64% of the due, however, a large daily spread remained (49%). The hemogram showed a decrease in leukocytes to 9.8 thousand per μl, the number of stab neutrophils decreased slightly - 8%. The immunogram showed an increase in T-helpers (up to 18.4%), a decrease in B-lymphocytes to 16%, the level of CEC and the content of CD95 ⁺ cells remained elevated. The bronchoscopic picture did not change significantly, lavage fluid was characterized by an increased content of neutrophils (21.5 × 10 ⁹ / l). After two weeks, the patient underwent 5-fold subcutaneous administration of roncoleukin at a dose of 500 thousand ME with an interval of 2 weeks. Despite immunocorrection, night-time suffocation symptoms persisted (up to 3-4 times a week), wheezing on forced expiration, and high variability of PSV (32%). No endoscopically significant dynamics were detected. The patient continued to take prednisolone in a maintenance dose of 15 mg per day.

Under observation there were 60 patients with steroid-dependent bronchial asthma in the acute stage who were admitted for inpatient treatment to the pulmonary department of the multidisciplinary City Hospital No. 4 of Cheboksary. The study included patients aged 38-80 years with steroid-dependent bronchial asthma with their informed consent when identifying violations in the immune status. In our method, in 30 patients with steroid-dependent bronchial asthma, in addition to standard conventional therapy, Roncoleukin was administered by inhalation using a compression nebulizer at a dose of 250 thousand ME with intravenous drip of the drug at a dose of 250 thousand ME three times with an interval of 72 hours, and then after 2 weeks inhaled through a nebulizer at a dose of 250 thousand ME in with subcutaneous injection into the outer surface of the shoulder at a dose of 250 thousand ME in a course of 4-6 procedures with an interval of 2 weeks. The control group consisted of 30 patients with steroid-dependent bronchial asthma who received inhalation therapy with a 0.9% sodium chloride solution simultaneously with intravenous drip administration of roncoleukin at a dose of 500 thousand ME three times with 72 hours, and then after 2 weeks 5 ml of a 0.9% sodium chloride solution is inhaled through a nebulizer in combination with subcutaneous administration of roncoleukin at a dose of 500 thousand ME, in a course of 4-6 procedures with an interval of 2 weeks. Both groups were homogeneous in gender, age composition, and concomitant pathology. For the period of treatment with roncoleukin, the use of other drugs or any procedures with an immunotropic effect was not allowed. All patients underwent dynamic observation of the main clinical, laboratory, and functional parameters. Indicators of immune status, endobronchial inflammation were evaluated before the administration of roncoleukin, 2 weeks and 4 months after the start of therapy. The selected dates allowed us to evaluate the initial state of immunoreactivity of patients and to monitor changes in the immune status and local inflammation during treatment.

Based on the data obtained (table 1), it was found that both methods of administering roncoleukin against the background of basic therapy provide positive dynamics of indicators of general immunity (CD3 ⁺ , CD4 ⁺ , CD16 ⁺ , CD95 ⁺ , CD20 ⁺ - peripheral blood lymphocytes, circulating immune complexes, serum immunoglobulins) after 14 days from the start of therapy. There were no significant differences in the dynamics of immunological parameters of the compared groups. At the same time, a significantly more pronounced decrease in the activity of endobronchial inflammation (table 2) is observed with the combined administration of the drug only at the end of 4 months. Statistical processing of the results was carried out using statistical software packages "STATISTICA 6.0 FOR". The methods of variation statistics and nonparametric analysis were applied.

Thus, the proposed method significantly increases the effectiveness of the treatment of steroid-dependent bronchial asthma: it allows to achieve a significant improvement in the bronchoscopic picture in the form of a decrease in the severity of endobronchitis and a decrease in the content of neutrophils to lavage fluid, is accompanied by normalization of the HPF indices, accelerates the achievement of remission and reduces the maintenance dose of systemic glucocorticosteroids.

table 2
The dynamics of endobronchial inflammation in patients with steroid-dependent AD under the influence of various treatment methods Indicators The main group M ± SD (n = 30) Control group M ± SD (n = 30) Significance of differences, p < initially after treatment initially after treatment one 2 3 four 2-4 lavage cellularity, × 10 ⁶ / ml 0.85 ± 0.3 0.35 ± 0.2 * 0.75 ± 0.21 0.46 ± 0.2 * 0.05 neutrophils in flush, × 10 ⁴ / ml 32.1 ± 9.7 15.5 ± 4.8 * 29.6 ± 9.4 18.1 ± 4.4 * 0.05 eosinophils in flush, × 10 ⁴ / ml 11.3 ± 3.5 10.4 ± 2.8 10.2 ± 2.4 9.6 ± 1.9 - severity of endobronchitis, I / II 5/25 28/2 ^# 7/23 22/8 ^# 0.05 Note: * - p <0.001 - significant differences compared with the original data, # - <0.001 - significant differences with the original data by the xi-square method

Claims (1)

A method for the treatment of steroid-dependent bronchial asthma, including basic therapy using, as an immunomodulator, roncoleukin administered simultaneously in the form of inhalations in a dose of 250 thousand ME, carried out using a nebulizer, and injection, characterized in that the introduction of roncoleukin in the form of injections and inhalations is carried out in two stage, while in the first stage, roncoleukin injections are administered intravenously in a dose of 250 thousand ME with a course of 3 procedures with an interval of 72 hours, and in the second stage, roncoleukin injections are performed with an interval of 2 weeks subcutaneously into the outer surface of the shoulder in a dose of 250 thousand ME in a course of 4-6 procedures.