BRPI0900639A2 - pharmaceutical composition and use thereof for treatment and / or prevention of respiratory tract diseases - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION AND USE OF THIS FOR TREATMENT AND / OR PREVENTION OF RESPIRATORY TRACT DISEASES. The present invention relates to a pharmaceutical composition comprising as active substance a polyglycosis provided with broad immunological activity. A second object of the present embodiment comprises the use of said pharmaceutical composition for the preparation of a medicament effective in the treatment and / or prevention of respiratory tract diseases, in particular asthma, by administering said medicament parenterally. In addition, a third embodiment of the invention involves the use of the composition of the invention as an adjunctive treatment to the therapeutic action of specific allergen immunotherapy.

Description

PHARMACEUTICAL COMPOSITION AND USE OF THIS TREATMENT AND / OR SUPERVISION OF RESPIRATORY DISEASE DISEASES

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition comprising as active substance a polysaccharide of broad immunological activity derived from a structural cell wall component of a microorganism. Another object of the present invention comprises the use of said pharmaceutical composition as a medicament effective in the treatment and / or prevention of respiratory tract diseases, in particular asthma.

BACKGROUND OF THE INVENTION

Currently, chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases and diabetes, cause 60% of all deaths worldwide.

Respiratory diseases, particularly asthma, are endemic in developed countries and have become epidemic in developing countries.

Asthma is an airway reaction to a lesion caused by different agents, that is, it is a chronic inflammatory disorder of the air ducts in the lungs.

The bronchial inflammation may be associated with an individual's genetic disposition, but its overactivation is caused when there is an airway hyperactivity as a response to a causative agent, which causes the disease, such as viral infections, physical exercise and exposure to different allergens.

The respiratory mucosa, once attacked by agentecausai, sends a signal to the bone marrow to produce special defense cells. The medulla interpreted a signal as if the respiratory tract was being invaded by parasites and sends special cells, which will cause an inflammatory process in the airways (bronchi).

The inflammatory process is responsible for the symptoms that characterize asthma, namely: gasping episodes, wheezing, shortness of breath, feeling of chest tightness and cough.

This inflammatory process may also cause bronchial inner wall edema and light decrease, hindering air passage and, therefore, the muscles surrounding the bronchi become hypersensitive, contracting any stimuli.

Although the incidence of asthma is more frequent in children, asthma is a disease that can affect people of all ages, cultures and geographical locations.

Initial knowledge about the disease was restricted, but with advances in research in the medical field, specifically in recent decades, it has become better known its causes and the mechanisms involved. Thus, it was possible to provide the application of new therapeutic techniques, as well as the development of new drugs. However, despite all the advances in technology, asthma is still sometimes a serious and potentially fatal disease.

Although there is no cure for asthma, it is a disease that can be controlled, allowing most individuals with asthma to lead a productive and productive life.

The current treatment of asthma has as its main target the relief of symptoms and reduction of bronchial inflammation.

Although in some cases, epithelial damage secondary to eosinophil persistence maintains the inflammatory process, reducing the response to corticosteroid therapy. In this regard, there is a growing interest in research for the development of new treatments directed to inflammation, especially to immunomodulatory property treatments.

Treatments with immunomodulatory properties comprise a therapeutic strategy that can alter the natural history and progression of asthma, a fact that can be achieved through the use of immune system modulating drugs. In the early stages of immune deviation, the decytocin profile can be redirected, suppressing answerTh2, for increasing the response Thl. Therefore, it is believed that the use of immune-modulating drugs would be more indicated in the early stage of asthma, before any structural or functional pulmonary changes occurred.

An alternative treatment for asthma control in affected individuals, and preserving immunomodulatory properties, is the use of sugar molecules (polysaccharides), found in certain plants or even microorganisms.

Particularly, the polysaccharide that can be used with good potential in the treatment of asthma is a D-glucose biopolymer, specifically beta-glucan (β-glucan), which is one of the major bioactive compounds present in fungi and yeast. Such compound is able to stimulate the immune system and increase, in a short space of time, the natural defenses, in order to favor the resistance of the individual to some diseases.

The structure of beta-glucan comprises branched or unbranched strands, provided with glucose molecule deletions, and helical form.

Generically, the mechanism of dabeta-glucan immunological action is directly related to the activation of delucocytes, stimulation of phagocytic, cytotoxic and antimicrobial activity, including the production of reactive oxygen and nitrogen intermediates, thus promoting the creation of a defense system against viruses, bacteria, fungi. eparasites (anti-insect). Beta-glucan can also stimulate the production of pro-inflammatory ecytocin mediators such as interleukins IL-8, IL-Iβ, IL-6 einterferon, TNF-α, and induce a number of non-specific immune responses.

The use of glucan for the treatment of asthma control, as well as for the treatment of allergic diseases in general, is discussed in the literature due to its immunomodulatory feature.

WO 2008102151 relates to a method of treating asthma and diseases related to abnormal pulmonary function in animals, comprising the use of a beta- (1,3) -D-glucan with one or more beta- (1,3) side chains. ) bound thereto by soluble oral administration of a high amount of a beta- (1,3) -glucan. Although this document refers to a method of treating asthma and diseases related to pulmonary function through the use of a beta-glucan, this document does not refer to the application of the method to humans, nor does it mention an effective evaluation of the domedication action in immunomodulation. allergic status, as well as its possible adverse events. In addition, those skilled in the art can prove the risks related to the human administration of a high dose single dose of an immunomodulator, which would lead an a priori subject not to use the disclosed technique for the treatment of asthma and function-related diseases. lung human.

EP 0759089 relates to a process for obtaining beta (1-6) glucanase as well as the use of the product obtained in the treatment of yeast glucan, especially from Saccharomycescerevisiae yeast. Additionally, the product obtained is suitable for use in enhancing stimulation of the animal immune system. However, the use of beta- (1-6) -glucanase in the treatment of asthma and allergic diseases is not anticipated or suggested.

DE10109798 discloses a composition comprising a mixture of beta-glucans, selected vitamins and metals, as well as their use as a food additive or as a medicine for the treatment, prevention of asthma and other diseases. It is noted that the disclosed composition is an association of complex substances which, although used for household purposes in the treatment and prevention of asthma, is administered as a food additive, departing from the subject matter of the present patent application.

US2007066563 describes a method of preparing an insoluble glucan hydrogel from fungi and by alkaline deprotection and subsequent disposal of water-soluble components. Said hydrogel has antibacterial activity and immunostimulant and can be used for preparation of cosmetic products, pharmaceuticals and food.Particularly, the microorganism used in this document was the mushroom Pleurotus ostreatus. Although glucan used is an insoluble glucan, its use as a pharmaceutical product for the treatment, prevention or cure of asthma is not foreseen throughout this document.

Regarding the scientific literature related to the subject, the discussion is based on the use of soluble glucans administered orally and / or by air, for relief of allergic symptoms, induction of immune response related respiratory diseases, among other purposes. There is also a research line directed to the use of soluble daglucana, which is administered by intratracheal injection. However, such research is still at a preliminary stage, with tests being performed on animal test subjects, and there are no results to prove the efficacy of soluble glucan through intratracheal administration in humans, as this type of administration would be an inappropriate method for clinical practice.

Although the state of the art discusses the subject, those skilled in the art still point to aspects lacking effective solutions, such as lack of effective drugs for the treatment of asthma, little potent effect of oral glucan administration, side effects associated with dose administration. single high daglucana, lack of maintenance of the effect of the drug used after its suspension, difficulties in complying with the prescriptions of drugs for chronic diseases and daily use, among others.

Additionally, there is also a technical lack related to the use of glucan in its insoluble form, for the treatment and / or prevention of diseases related to the respiratory tract, more specifically, asthma.

Accordingly, the present invention has been developed to provide the art for the use of glucan as an effective and long-acting drug for the treatment and / or prevention of respiratory tract-related diseases, particularly asthma.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising as active substance a polysaccharide from a structural component of the yeast cell wall. More specifically, said active substance is a polyglycosis with broad immunological activity.

A second object of the present embodiment comprises the use of said pharmaceutical composition for the preparation of a potentially effective drug for treatment and / or prevention of respiratory tract diseases, in particular asthma, by administering said drug parenterally. It may preserve the drug-acting composition for a prolonged period, even after suspension of drug use, in addition to allowing the prescribed use period to be optimized due to the intrinsic properties of the drug.

A third embodiment of the invention involves the use of the composition of the invention as an adjunctive treatment of the therapeutic action of specific allergen immunotherapy. More specifically, the composition may be used for the prevention of respiratory tract-related diseases, especially asthma.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the flowchart of patients submitted to the use of the pharmaceutical composition comprising glucan.

Figure 2 shows the percentual graphical representation of patients free of local pain complaint during the 8 weeks in which the pharmaceutical composition comprising glucan was applied.

Figure 3 shows the percentual graphical representation of patients in whom palpation of the injection site was free of any nodulation in the 8 weeks of the study in which the pharmaceutical composition comprising glucan was applied. Figure 4 shows the percentual graphical representation of patients free of the complaint. body pain during the eight weeks of pharmaceutical composition comprising glucan.

Figure 5 shows the percentual graphical representation of fever-free patients during the eight weeks in which the pharmaceutical composition comprising glucan was applied.

Figure 6 shows the percentual graphical representation of patients without complaints of headache during the eight weeks in which a pharmaceutical composition comprising glucan was administered.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising as active substance a polysaccharide derived from a structural component of the cell wall of a microorganism having effective pharmacological activity for the treatment and / or prevention of respiratory tract disorders such as influenza, rhinitis allergic, sinusitis. , nosebleeds, bronchitis, and especially asthma.

Proper control of these diseases, specifically arinitis and asthma, prevents the patient from developing a quadroclinic of atopic dermatitis, an episode common to patients with respiratory tract infections. More specifically, said active substance consists of a polyglucose, such as a D-glucose. more specifically insoluble beta-glucan, and even more specifically, beta- (1,3) -D-glucan, which is a broad immune activity because they are not present in animal cells.

Said glucan is extracted from microorganisms such as yeast of the species Agaricus brasiliensis, Lentinula edodes, Paracoccidioides brasiliensis,

Saceharomyces eerevisiae, among others. However, for present embodiment, the glucan selected for use was preferentially isolated from the yeast of the Saccharomyees eerevisiae species, and has as its main characteristic an immunomodulatory activity, when related to respiratory tract diseases, specifically asthma.

The preparation of glucan for use in the pharmaceutical composition now developed followed the steps established by usual methods used by those skilled in the art. For the present embodiment, the method used for daglucan preparation was the method described by Northcote, DH and Horne, RW - The chemical composition and structure of the yeastcell wall. Bioehem J. 1952 May; 51 (2): 232-6. In order to better support the detailed description of the present invention, the steps of the daglucan preparation process will be described herein:

Stage 1 - Weigh Yeast. Cerevisiae by placing in a suitable container such as a beaker;

Step 2 - Add an alkaline solution, such as a 3% solution of sodium hydroxide (NaOH), under stirring, until a homogeneous suspension is obtained;

Step 3 - Heat the above suspension for a period of about 6 hours to approximately 100 ° C;

Step 4 - Centrifuge the suspension preferably at 4000 rpm for about 30 minutes;

Step 5 - Decant the supernatant;

Step 6 - Add to the precipitate 3% NaOH solution and warm in a 100 ° C water bath for a further 3 hours;

Step 7 - Centrifuge wash the above suspension with distilled water until the supernatant is light in color;

Step 8 - Wash the precipitate with 70% ethanol for at least twice, Step 9 - React with acetic acid at approximately 0.5N for about 6 hours in an oven at approximately 70 ° C;

Step 10 - Wash at least three times with distilled water in centrifuge at 4000 rpm until the supernatant becomes light discoloration and pH 7 for acid removal;

Phase 11 - Dilute the suspension in saline (used in injectables), whose concentration will be 2.0 mg / mL;

Step 12 - The above solution will be immediately packaged in a suitable container such as in a 20 liter carboy with rubber cap, sterilized by tindalization at about 80 ° C for one hour for three consecutive days;

Phase 13 - Perform sterilization tests on standardized culture media;

Stage 14 - Material ready to be filled into sterile room;

The pharmaceutical composition of the present embodiment comprises an effectively effective amount of debeta (1,3) -D-glucan associated with a pharmaceutically acceptable carrier. This vehicle is selected from substances that do not have secondary effect when associated with glucan. However, for a preferred embodiment of the present invention, pharmaceutically acceptable carriers for association with glucan are preferably intralipid, desodium chloride, phenol and sterile water.

The pharmaceutical composition now obtained is subjected to microbiological tests for its characterization. The following tests were performed: sterility test, glucan concentration concentration analysis and glucan biological activity analysis, which was determined by its ability to increase the phagocytic action of macrophages in presence of sensitized red blood cells.

The results obtained for the tests showed that the pharmaceutical composition, which is the object of the present embodiment, is preferably in the form of a sterile, slightly milky suspension, with a pH between 6.0 and 7.0 and a concentration of glucan content of approximately 9 mg to 11 mg per 5ml. Preferably, the glucan ether is 10mg / 5mL.

For the present embodiment, the dose of glucan, preferably beta- (1,3) -D-glucan, administered in the pharmaceutical composition is in the range of about 0.5 to 2mg. Preferably, the concentration of glucan used in said composition was about 2mg.

The effect of the active substance of the pharmaceutical composition, which is the object of the present embodiment, is potentiated when the composition is administered by parenteral means, either by injection or infusion. Parenteral avia could be selected from the group consisting of intravenous, intraarterial, intramuscular, subcutaneous, intradermal, intraosseous, and intratumoral application.

Due to the presence of glucan, the action of the drug containing such active substance may be preserved for a prolonged period, even after discontinuation of drug use, in addition to the fact that the prescribed period of use may be optimized due to the properties of the drug.

The potent effect of the insoluble glucan-containing pharmaceutical composition, which is the object of the present invention, is used as a medicament for the treatment and / or prevention of respiratory tract diseases, especially asthma, by injectable administration, preferably by intramuscular or subcutaneous administration of the pharmaceutical composition, is superior to the effect. when given orally.

This effect is due to the fact that insoluble injectable glucan has a broad immunomodulatory effect due to the presence of long chains.

The long-acting characteristic may promote fundamental changes in the way the body reacts to the allergens. These alterations constitute a different aspect of the related technique, since currently the various drugs available lack any maintenance after their suspension. These alterations include the promotion of macrophage and dendritic cell activation, resulting in a higher production of regulatory cytokines and typeThl, acting on allergic diseases such as interleukin IL-IO.

The increase in IL-IO interleukin in the serum of patients who used the medication, comprising glucan as a substance, allows us to infer the possibility of using medication to act in the treatment of other allergic diseases, such as allergic rhinitis and atopic dermatitis, besides, of course, use for treating asthma specifically.

In addition to increasing IL-IO interleukin production, specifically, when assessing the potential for the use of pharmaceutical composition as an effective asthma treatment drug, the result is a statistically significant reduction in wheezing episodes, and daytime and nighttime shedding of patients, which are quite significant symptoms in asthma.

Given that about 60% of the patients who used the pharmaceutical composition now developed had increased interleukin IL-10 production in serum after an 8-week period, it can be seen that this composition can also act as a potent drug against allergic rhinitis and atopic dermatitis. The drug, which is the object of the present invention, also has, as a technological differential, characteristics related to its prescription.

Adolescents and pre-adolescent schoolchildren are known to have difficulties in complying with prescription drugs for chronic daily use. Thus, the use of the medicament of the present invention may be prescribed for administration in reduced doses and once weekly or even biweekly.

Additional characteristics regarding the use of pharmaceutical composition involve prior agitation before application, so that there is adequate homogenization. In addition, it is important that the exchange of needles occurs between the act of aspirating the contents of the ampoule and the application of the medication to the patient. Preferably, the application should be done by deep intramuscular route, in addition to observing the application site rotation.

Finally, it is an object of the present invention to use a pharmaceutical composition containing glucan as a substance as the sole medicament for treating and / or preventing allergic diseases, in particular asthma. Said drug acts effectively on the patient's immune response to allergic diseases, especially asthma, by increasing the production of IL-10 interleukin. In order that the invention may be better understood, the following will be detailed in the form of examples. However, the examples described herein are purely illustrative and not limiting forms of the invention.

Example 1: Patient Selection:

For a preferred embodiment of the present embodiment, a group of about 18 patients, aged from 6 to 12 years old, with mild or moderate asthma-resistant, have been selected for use of the pharmaceutical composition for the treatment of asthma. inadequate disease control despite regular use of the correct treatment (inhaled corticosteroid) for a period of 30 days. Inadequate control of the disease is characterized by the evaluation of exacerbations of the clinical picture of asthma and the need for rescue medication.

After the selection of the patients, who could be submitted to the use of the pharmaceutical composition containing glucagon, used as a drug, they underwent adequate and regular treatment with the use of about 400 mcg / day of corticosteroids over a period of 30 days, and were followed by observation. (run in period).

At the end of this period, the patients were reassessed and those who had no control of asthma symptoms, after appropriate and regular use of the usual medication, remained under observation to be directed to the rest of the pharmaceutical composition comprising glucan.

The patients who remained under observation were submitted to complementary exams, such as complete blood count, transaminases, urea, creatinine, expiratory flow doping and others, in order to severify if there was any abnormality that would prevent them from using the pharmaceutical composition of the invention.

Following the step of ascertaining clinical impediments, the treatment period was initiated for the group of patients able to use the pharmaceutical composition herein.

Example 2: Administration of the Comglucan pharmaceutical composition.

During this stage, patients selected according to Example 1 continued to receive usual asthma medication (corticosteroid) in order not to interrupt the treatment already started for ethical reasons, plus a dose of the pharmaceutical composition of the invention containing glucan for a 60 day period. It should be clarified that only the patients mentioned in example 1, who did not have control of asthma symptoms, after the proper and regular use of corticosteroids underwent agglucan treatment. Therefore, it is clear that a control of asthma symptoms will be due solely and exclusively to the use of the inventive composition containing glucan. In the first 30 days of treatment, patients received about 0.25 ml (0.5 mg) of the pharmaceutical composition comprising glucan by of the subcutaneous route once a week.

Each weekly application of glucan was performed in a different member, so that the occurrence of local side effects was also evaluated, with greater vigilance for the occurrence of an abscess, a complication that may arise when using the parenteral route.

In the final 30 days of use of the pharmaceutical composition, in the group of selected patients, there was an increase in the interval between glucan applications. Therefore, each patient received about 0.25mL (0.5mg) deglucan subcutaneously every 15 days.

Prior to each application of the pharmaceutical composition of the invention, the patient underwent a clinical-visual examination to verify the presence of hyperemia, pain, nodulation, or abscess at the site of application.

The literature reports that continuous application of beta- (1,3) -D-glucan may cause fever, headache, asthenia, myalgia and hyperemia, pain, nodulation or abscess at the application site. Thus, the investigation of possible adverse effects related to the use of glucan with medicine were constantly evaluated, as well as any other possible symptoms. In addition, to rule out the occurrence of drug-induced spasm and monitor asthma control, peak measures were performed. of expiratory flow daily.

For this group of patients, glucan was administered for a current 60-day period, followed by an additional 30 days after the end of medication use, in order to assess the adverse events that the drug could cause in patients.

In general, the pharmaceutical composition of the invention was applied to patients via the subcutaneous route, comprising about 6 (six) applications in each patient. In all there were about 108 (one hundred and eight) applications.

Illustratively, the flow of patients during the study followed the scheme shown in the flowchart, shown by Figure 1.

At the end of 60 days, the use of the pharmaceutical composition comprising glucan was discontinued and the patients evaluated.

Example 3: Clinical evaluation of patients after the use of the pharmaceutical composition containing glucan. The evaluation of the use of the pharmaceutical composition for the treatment of asthma was focused on the search for adverse events, specifically the active search for symptoms such as pain at the site of asthma. application of medication, nodulation, abscess, body pain, fever and headache.

Regarding pain at the application site, the evaluation result is shown in Figure 2. There is a seasonality in the graph curve. Always on the first day of the week, when the injection is given, the percentage of patients free of local pain is lower than the other days of the week.

Figure 3 shows the graphical result for the evaluation for the presence of nodulations at the injection site. The presence of nodulations was verified by half palpations at the application site, after about 8 (eight) weeks of treatment. The graphic result shows that the continuous use of the pharmaceutical composition comprising glucan as an injectable drug did not provide patients with a significant degree of nodular development.

The results regarding the evaluations for body pain and asthenia complaints are shown in Figure 4. It is observed that this type of complaint was more frequently reported only in the first week of application of the pharmaceutical composition. On the other hand, fever is more common in the second week of application, as shown in Figure 5.

Additionally, a small percentage of patients complained of headache, as shown in Figure 6.

To detect any adverse event in asthmatic patients, the Daily Expiratory Flow Peak (PEF) was analyzed, which was obtained in the morning during the 8 (eight) weeks of application. Results are shown in Table 1.

Table 1: Result of the comparison of the variable PEFobtained in the morning between IFl and week 8

<table> table see original document page 24 </column> </row> <table>

p-value = 0.051 (Friedman test) It can be observed that there was a tendency (p = 0.051 Friedman test) for an improvement of the parameter (PEF) after the use of glucan-containing medication.

The occurrence of adverse events was low, especially considering that it was events that occurred in some patients only at the beginning of local treatment, and the most common event was local pain. No serious adverse event requiring treatment to be discontinued was detected in any patient.

During the research period it was also observed that patients had improvement of asthma symptoms such as wheezing, cough and nocturnal asthma symptoms.

The invention described herein is not limited to this embodiment and those skilled in the art will realize that any particular feature introduced therein should be understood solely as something that has been described for ease of understanding and has been realized to depart from the inventive concept described. Limiting features of the object of the present invention are related to the claims which are part of this report.

Claims (24)

1. Pharmaceutical composition for the treatment and / or prevention of respiratory tract diseases characterized in that it comprises as active substance an insoluble glucan and a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 1, characterized in that the glucan is in a concentration ranging from about 9 to 11mg / 5ml. Pharmaceutical composition according to claim 1, characterized in that the glucan is a beta-glucan. Pharmaceutical composition according to claim 3, characterized in that beta-glucanaser is beta- (1,3) -D-glucan. Pharmaceutical composition according to claim 2 and 4, characterized in that glucan is in a concentration of about 10mg / 5ml. Pharmaceutical composition according to claim 1, characterized in that it is effective for respiratory tract diseases selected from influenza, allergic rhinitis, sinusitis, nosebleeds, bronchitis and asthma. Pharmaceutical composition according to Claim 6, characterized in that it is specifically effective against asthma. Pharmaceutical composition according to claim 1, characterized in that it is additionally effective against atopic dermatitis. Pharmaceutical composition according to Claim 1, characterized in that the glucan used is extracted from yeasts of the species Agaricus brasiliensis, Lentinula edodes, Paracoccidioides brasiliensis, Saccharomyees eerevisiae. Pharmaceutical composition according to claim 9, characterized in that it is preferably isolated from S. eerevisiae. Pharmaceutical composition according to claim 1, characterized in that the carrier is any substance which has no side effect with glucan. Pharmaceutical composition according to claim 11, characterized in that the pharmaceutically acceptable carrier is selected from intralipid, sodium chloride, phenol and sterile water. Pharmaceutical composition according to Claim 1, characterized in that it is preferably in the form of a suspension. Pharmaceutical composition according to claim 1, characterized in that the daglucan effect is enhanced when the composition is applied via the parenteral route. Pharmaceutical composition according to Claim 14, characterized in that the effect of glucan is potentiated when the composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intradermal, intraosseous, and intratumoral application. 16. Use of an insoluble glucan characterized by being for the preparation of a medicament for treating and / or preventing respiratory tract diseases. Use according to claim 16, characterized in that it is for the treatment of asthma. Use according to claim 16, characterized in that the glucan is a beta-glucan. Use according to claim 18, characterized in that the beta-glucan is beta- (1,3) -D-glucan. Use according to claim 19, characterized in that the beta- (1,3) -D-glucan is from 5mg to 2mg. Use according to claim 16, characterized in that the medicament is prescribed at reduced doses and once weekly. Use according to claim 16, characterized in that the medicinal product is prescribed in reduced doses and at once every 15 days. 23. Use of an insoluble glucan characterized by being for the preparation of an adjuvant drug therapeutic action of allergen-specific immunotherapy. Use according to claim 23, characterized in that it is an adjunct to the therapeutic action of asthma immunotherapy.