RU2635968C1 - Method for treatment and prevention of allergic spectrum states - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: use of a peptide, which is sodium gamma-D-glutamyl-D-tryptophan as an antiallergic drug for treatment or prevention of pathological conditions with allergic syndrome, selected from at least one: allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma, is proposed.

EFFECT: relief of residual manifestations in the disease remission.

3 cl, 1 tbl, 6 ex

Description

The invention relates to medicine and relates to antiallergic drugs.

Allergy is one of the most common diseases caused by an increased sensitivity of the body to exogenous allergens, which significantly reduces the quality of life of patients. In most patients, allergic manifestations are associated with IgE-class antibodies, and therefore they are classified as IgE-mediated allergies. This group includes diseases involving atopic mechanisms. Atopy is understood as an individual or family ability, usually in childhood or adolescence, to sensitize and produce IgE antibodies in the usual contact with allergens, usually of a protein nature, with the development of typical symptoms such as asthma, rhinoconjunctivitis, eczema or allergic rhinitis.

According to the latest data, up to 15-20% of the general population of the population suffers from allergic rhinitis in developed countries, bronchial asthma - from 4 to 11%, among which from 50 to 80% are patients with allergic (atopic) bronchial asthma, various manifestations “Drug allergy” is noted by more than 25% of inpatients.

In the light of modern scientific ideas, allergy is considered as a form of immunopathology, which is manifested by an immunodeficiency state and an imbalance in the quantitative ratios and functional activity of subpopulations of T- and B-lymphocytes.

Given the nature of allergic reactions, a search is under way for eliminating such an organism's sensitivity to allergens. Various methods of influencing the immune system for this purpose are known.

In particular, specific immunotherapy is referred to such methods as a treatment method consisting in repeated repeated administration of small and gradually increasing doses of a certain allergen into the body. It has been proven that such tactics lead to a gradual loss of sensitivity of the immune system to this substance. Specific immunotherapy is prescribed in cases where an allergen is precisely identified. The main limitations of this method are the high risk of developing adverse reactions (primarily allergic) and the inability to apply to several allergens simultaneously.

The basis of the treatment of allergies is drug therapy, which includes drugs, and if indicated, immune preparations, such as allergy vaccines or autohemotherapy.

For example, patent 2395305, publ. 07/27/2010, which discloses a method for the treatment of allergic diseases by means of autolymphocytotherapy, including the preliminary preparation of autologous lymphocytes from the patient’s venous blood and their subsequent subcutaneous administration, characterized in that the suspension of autologous lymphocytes in physiological saline is administered in doses from 0.1 to 1, 0 ml of suspension at a concentration of autologous lymphocytes of 105-107 cells / ml, the introduction is carried out from 4 to 10 times with an interval between them from 2 to 6 days.

A known method of treating neurodermatitis, belonging to the group of allergic dermatoses using autohemotherapy (application RU 94026137 A1, publ. 08.27.1996).

In patent RU 2396090 C2, publ. 08/10/2010, a method is described for preventing or treating allergies with a mucosal vaccine containing an antigen drug carrier, which is a complex containing pulmonary surfactant protein B or at least one fragment thereof, pulmonary surfactant protein C or at least one fragment thereof, and at least one lipid and antigen, wherein said mucosal vaccine induces a therapeutically significant mucosal immunity.

A known method of treating allergic diseases using a vaccine based on a protein with an IgE epitope in combination with immunomodulating agents (US 20060052592 A, published. March 9, 2006).

On the pharmaceutical market in the Russian Federation there are a number of drugs that act on the immune system and are widely used in various diseases associated with its disorders. Immunomodulators of the first generation, obtained on the basis of extracts of the thymus tissue, include tactivin and thymalin. A complex immunoglobulin preparation, which contains human immunoglobulins of three classes: Ig A (15-25%), Ig M (15-25%) and Ig G (50-70), is used for allergic dermatoses, combined with intestinal dysfunction. Representative of a new generation of synthetic immunomodulators - polyoxidonium is one of the few immunomodulators recommended for use in acute infectious and allergic processes.

Among synthetic domestic immunopreparations, the bestim-gamma D-glutamyl-L-tryptophan sodium salt may be indicated. The drug was developed at the SSC GosNII OCHB, St. Petersburg and is authorized by the Ministry of Health of the Russian Federation for clinical use in the treatment of patients with secondary immunodeficiency states (http://www.rlsnet.ru/tn_index_id_28773.htm). Although some studies have been presented showing its effect in allergic bronchial asthma, the drug is an immunostimulant, which is dangerous in many allergic, especially acute, conditions.

Also, another stereoisomer-thymodepressin (gamma-D-glutamyl-D-tryptophan sodium) has been registered in the Russian Federation as an immunosuppressant for the treatment and prevention of autoimmune diseases: (http://www.rlsnet.ru/tn_index_id_15947.htm).

Thymodepressin has no indications and references to rhinoconjunctivitis and polynosis, no indications of allergic asthma. To date, it has not been recommended in clinical practice as an antiallergic drug.

The objective of the present invention is to expand the range of antiallergic agents.

The problem is solved by the use of a regulatory peptide (PI) - an analogue of one of the regulatory peptides of Timus, which we named Danaxen and which is a synthetic peptide, in the treatment and prevention of pathological conditions with allergic syndrome. The object of the invention is the use of a peptide, which is gamma-D-glutamyl-D-tryptophan sodium, as an anti-allergic agent for the treatment or prevention of pathological conditions with allergic syndrome, selected from at least one: allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma.

We have established and demonstrated the significant impact of this PI on various forms of the systemic allergic process in the acute stage and at the stage of remission as a prophylactic.

The technical result is the effectiveness of prevention and relief of residual manifestations in remission, as well as in the treatment of acute pathological conditions with an allergic syndrome, selected from at least one: allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma.

At the stage of treatment with the acute phase of the disease, the patient begins treatment at a random choice of the investigational drug (PI) or placebo (P) in a 3: 1 ratio, in addition, the patient receives symptomatic therapy according to the clinical judgment of the attending physician for 14 days + 10 days, if necessary + 10 days.

After the formation of remission, the patient receives maintenance therapy according to randomization during the acute phase of PI or P regimen for 16 weeks.

With the next exacerbation on any day up to 52 weeks from the start of treatment under this protocol, the patient changes the “Sleeve” of the study to the opposite, so if the patient received P at the stage of entering treatment, then he is transferred to PI and vice versa.

The remission stage repeats the algorithm - maintenance therapy continues on the same agent that was used in the acute period.

A simple, blind, randomized, cross-sectional study (patient, caregiver).

Placebo control (as a placebo - nasal spray containing saline).

The effectiveness of treatment is determined by the following indicators:

1. The number of exacerbations in the groups of PI vs P.

2. The duration of remission in the groups of PIs against P.

3. The difference between the study (IG) and the control group (CG) in terms of the scales of the overall clinical impression, according to the criteria of FitzGerald M. et al., 2012, SCORAD scale.

4. Levels of eosinophils in the clinical analysis of blood and Ig E.

5. The difference in the drug load of concomitant and symptomatic therapy.

6. The difference in the index of adverse events associated with the complex treatment of AS.

The study involved 300 patients with clinically validated atopic syndrome, regardless of hospital status.

Randomization 3 (study drug): 1 (control - placebo). The treatment regimen as part of the study protocol. One of the forms for research can be selected nasal spray dosed.

γ-D-glutamyl-D-tryptophan sodium 1 dose of 500 mcg.

Bottle of 10 ml (80 doses).

The dosage regimen of the claimed drug:

The period of acute clinical manifestations of bronchial asthma:

- The first course. 14 days, 2 doses, 2 times a day (a total of 4 doses per day).

- Two days off.

- Second course. 10 days, 2 doses, 2 times a day (4 doses in total).

- While maintaining clinical relevance. Third course. 10 days, 2 doses, 2 times a day (4 doses in total).

The period of acute clinical manifestations of allergic rhinitis, allergic conjunctivitis:

- The first course. 14 days, 2 doses, 1 time per day.

- Two days off.

- Second course. 10 days, 2 doses, 1 time per day.

- While maintaining clinical relevance. Third course. 10 days, 2 doses, 1 time per day.

Clinically significant remission period:

- For 16 weeks, twice a week, 1 dose per day.

- Stop treatment until 52 weeks of observation or until the disease worsens.

- In the case of an exacerbation of the disease, the second stage begins - the extension of the study with a second course - “Acute stage” - “16 weeks of maintenance therapy”.

- A patient who has reached the turn of 52 weeks is considered to have successfully completed the study.

- A group of patients who went into the second extended phase is evaluated at 20 weeks after the start of treatment with PI / P as part of the second exacerbation.

The endpoint of the study is 52 weeks from the start of treatment or 20 weeks after the start of treatment as part of a second exacerbation.

The agent may be in a form suitable for parenteral or oral administration. In particular, it can be a solution for i / m administration, drops or spray for the nose, aerosol, tablets, capsules, etc.

The possibility of carrying out the invention is also represented by the following examples of clinical studies.

Inclusion Criteria:

1. Clinically validated diagnosis of atopic syndrome with the predominance of one of the options for systemic representation:

a. Allergic rhinitis.

b. Allergic conjunctivitis.

c. Allergic bronchial asthma.

2. Age from 6 to 47 years.

3. Provided by the custodian informed consent to participate in the study.

Exclusion Criteria:

1. Clinically significant severe somatic and mental illness.

2. Infectious and fungal infections.

3. The need for systemic glucocorticoids.

Criteria for achieving the objectives of the study:

1. Visual analogue scale "Severity of symptoms" for the patient / caregiver.

2. Recovery or significant positive difference compared with the control group of the level of eosinophils in the clinical analysis of blood.

3. Recovery or significant positive difference compared with the control group of the level of Ig E.

4. Evaluation of respiratory syndrome according to the criteria of FitzGerald M. et al., 2012.

5. Assessment of the dermatological complex: dynamics according to the SCORAD scale (Scoring of Atopic Dermatitis) in comparison with the control group.

Example 1. Allergic rhinitis complicated by conjunctivitis

Patient A., born in 1987.

Anamnesis. The last few years have suffered from seasonal exacerbations of chronic allergic rhinitis. From the beginning of April 2016, it noted the presence of colorless watery discharge from the nasal passages, frequent paroxysmal sneezing; sensations of severe itching and swelling in the nasal passages; difficulty in nasal breathing. The feeling of stuffiness in the nasal passages is greatly enhanced closer to the night. The last week the condition was complicated by joining conjunctivitis: there is redness of the eye sclera, severe lacrimation and constant itching in the eyes. The patient's face acquired pallor and puffiness. In addition, an allergic cough is noteworthy.

Diagnosis: Allergic rhinitis complicated by conjunctivitis.

The patient received 2 doses of gamma-D-glutamyl-D-tryptophan sodium (0.5 mg / dose) nasal spray in each nasal passage daily for 14 days as a component of complex therapy with antihistamines oral for the first three days, then as monotherapy. On the third day of treatment, the symptoms of rhinitis were significantly relieved; on the 5th day of treatment, drug remission occurred both in the manifestations of rhinitis and in the accompanying allergic symptoms.

Example 2. Clinical study. Allergic rhinitis caused by plant pollen. Allergy of NOS caused by plant pollen. Hay fever. Pollinosis. Treatment of the acute phase of gamma-D-glutamyl-D-tryptophan sodium in the form of a nasal spray.

An open, uncontrolled study of the effectiveness of the nasal gamma-D-glutamyl-D-tryptophan sodium spray for the treatment of the acute stage of allergic rhinitis (including conditions complicated by conjunctivitis) as a monotherapy was carried out: 2 doses (0.5 mg / dose) in each nasal passage daily for 14 days.

The study included patients with an outpatient appointment with an allergist at a city hospital in Moscow. Patients suffered from seasonal hay fever for many years and were treated with rhinoconjunctivitis during spring flowering in the spring of 2016.

The study drug was allowed to be taken together with oral antihistamines in the first three days, then, until the 14th day of treatment, patients received 2 doses (0.5 mg / dose) Gamma-D-glutamyl-D-tryptophan sodium nasal spray in each nasal passage daily as monotherapy.

The study involved 40 patients. In 31 patients, clinical remission occurred on the fifth day of treatment; in 9 patients, minimal watery discharge from the nose remained until the 10th day of treatment, which did not affect daily activity. Not one of the treated patients had any adverse events associated with the treatment.

Example 3. Clinical study. Allergic rhinitis caused by plant pollen. Allergy of NOS caused by plant pollen. Hay fever. Pollinosis. Prevention of exacerbation of allergic rhinoconjunctivitis Gamma-D-glutamyl-D-tryptophan sodium in the form of a nasal spray.

A group of patients - 30 people suffering from seasonal hay fever (rhinoconjunctivitis clinic) for at least 3 years, underwent preventive treatment with Gamma-D-glutamyl-D-tryptophan sodium in the form of a nasal spray - 1 dose (0.5 mg / dose) into the nasal passage daily for 7 days 2 weeks before the start of the expected cycle of “color dusting”. 23 patients in the current season did not develop a clinically significant exacerbation of allergic rhinoconjunctivitis. In 7 patients, the clinical exacerbation was insignificant and cost an additional course of treatment with Gamma-D-glutamyl-D-tryptophan sodium in the form of a nasal spray. Adverse events caused by the treatment were not observed.

Example 4

Patient B. born in 1993. Allergic bronchial asthma.

The patient has a history of exudative diathesis, atopic dermatitis, various allergic reactions. For the first time, an asthma attack developed at the peak of a respiratory infection. Then, over the past 4 years, conditions of bronchial asthma of various clinical intensities lasting from 2 to 5 weeks develop every spring and autumn. Pollen asthma occurs during the flowering season of plants. In the onset of exacerbation, allergic rhinitis and conjunctivitis develop, and asthma attacks occur already against the background of these diseases.

Treatment. The patient received 2 doses of gamma-D-glutamyl-D-tryptophan sodium (0.5 mg / dose) nasal spray in each nasal passage twice a day - morning and evening, daily for 14 days as a component of complex therapy with oral antihistamines drugs for the first three days, then as monotherapy. After a 2-week course, the patient did not take treatment for 2 days, then repeated a 14-day course.

On the third day of treatment, the symptoms of bronchial asthma were significantly relieved; on the 5th day of treatment, drug remission occurred.

Example 5

Patient S. born in 1985. Allergic (household, dust) asthma.

The patient has a history of exudative diathesis, atopic dermatitis, various allergic reactions. For the first time, an attack of atopic asthma developed at the peak of a respiratory infection. The disease runs year-round. Manifestations of the disease are facilitated when leaving home. Heavier condition in the winter. Exacerbations develop with the formation of a paroxysmal prolonged cough. The patient describes such exacerbations that can be limited only to a cough clinic without conditions with difficulty breathing.

Treatment. The patient received 2 doses of gamma-D-glutamyl-D-tryptophan sodium (0.5 mg / dose) nasal spray in each nasal passage twice a day - morning and evening, daily for 14 days as a component of complex therapy with oral antihistamines drugs for the first three days, then as monotherapy. After a 2-week course, the patient did not take treatment for 2 days, then repeated a 14-day course.

By the end of 10 days of treatment, the symptoms of bronchial asthma were significantly relieved; at the beginning of the second cycle of treatment, drug remission began.

Adverse events associated with the treatment were not observed.

Example 6. Relief of residual manifestations in remission

Patient M., born in 1993. Allergic (household, dust) asthma.

The patient has a history of exudative diathesis, atopic dermatitis, various allergic reactions. For the first time, an attack of atopic asthma developed at the peak of a respiratory infection. The disease runs year-round. Manifestations of the disease are facilitated when leaving home. Heavier condition in the winter. Exacerbations develop with the formation of a paroxysmal prolonged cough. The patient describes such exacerbations that can be limited only to a cough clinic without conditions with difficulty breathing.

During periods of remission, the patient, despite significant relief in the manifestation of the disease, continues to occasionally note dry unproductive cough, hypersensitivity to various allergens (pet hair), which manifests itself in the form of rhinoconjunctivitis.

Treatment. The patient received Gamma-D-glutamyl-D-tryptophan sodium at 1 dose (0.5 mg / dose) of nasal spray in each nasal passage twice a day - morning and evening, daily for 7 days as monotrepia every two months.

During the year of observation, the patient noted a significant increase in the quality of remission and a decrease in the severity of residual allergic conditions.

Adverse events associated with the treatment were not observed.

Claims (3)

1. The use of a peptide, which is gamma-D-glutamyl-D-tryptophan sodium, as an anti-allergic agent for the treatment or prevention of pathological conditions with allergic syndrome selected from at least one: allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma. 2. The use of the peptide according to claim 1, where these pathological conditions are acute conditions. 3. The use according to claim 1 or 2, where the antiallergic agent is used in the form of a drug, which is a spray for nasal use.