Complex preparation based on allergens of birch pollen and muramylpeptides

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to complex injection preparation for treating polynoses by ASIT method. Said preparation is obtained by simple mixing birch pollen allergoid and muramylpeptide without carrying out chemical conjugation of components, with 2 mg of muramylpeptide being added per 1000 PNU dose.

EFFECT: invention provides considerable enhancement of immune response and stimulates high level of production of specific IgG-antibodies, as well as makes it possible to reduce course of treatment of polynoses, which reduces possibility of complications.

1 dwg, 2 tbl

 

The invention relates to the field of medicine.

Today allergic diseases in varying degrees, affects up to 20% of the population of the planet. The overall incidence of allergic diseases in the Russian Federation is approximately 20 million people, including pollen allergies 8 million people. The problem of adequate therapy for allergies is as high as ever.

Antihistamines, so widely advertised in the media, kopurua clinical manifestations in a given time, do not eliminate the cause of the disease. Allergenspecific immunotherapy (ASIT) allows to eliminate the cause of the disorder. Introduction according to a certain scheme of increasing doses of allergen leads to the development against him significant amounts of antibodies of IgG class, which bind enter the body the allergen, avoiding, thus associating it with IgE and start the cascade alligatoroidea reactions. Is the so-called "switching" of the immune system with IgE response to IgG response. Now for ASIT used mainly allergens obtained water-salt extraction.

Allergic is a chemically modified allergen and has advantages over the latter, since the chemical modification of a decrease allergenicity and risk guidance Anafi is aktionscode shock. The transformation of the allergen in allergic by chemical modification in the presence of formaldehyde, resulting in the interaction of high - and low-molecular components, contributes to the preservation of the properties of allergoids to induce the synthesis of antibodies. This action is reinforced by a rigid, stable structure of the molecule allergoids, resistant to the effects of denaturing agents, in contrast to the source of the allergen, and also contributes to the prolongation of action allergoids as destruction in the body of the patient will be slower.

Reduced allergenicity polymerized allergen is connected, on the one hand, by reducing the number of antigenic determinants as a result of their reaction with aldehyde groups, and on the other hand, the unavailability of reagents other determinants, hidden inside a high-molecular polymer. Positive impact on immunogenicity has an increased molecular weight and create a more rigid intramolecular bonds.

In this regard, prospective can be combined, modified allergen with muramylpeptide. Combining allergoids with muramylpeptide gives an opportunity to significantly enhance the immune response, to encourage a high level of production of specific IgG-antibodies that provide protection of the patient after contact with the allergen is his body.

Drugs muramylpeptides some exist only since 1974, and permission for medical use have only 2 drugs: reported in Japan and Likopid in Russia. The latter is currently undergoing clinical trials in the United States, England, Australia and Denmark. There is no data about the use of muramylpeptides when allergic. Produced a comprehensive drug-based allergens of birch pollen and muramylpeptides has no analogues in Russia and abroad.

The main target in the body for immunomodulators of microbial origin, including muramylpeptides series, are phagocytic cells. Under the influence of these immunomodulators amplification of the functional properties of phagocytes: the intensity of phagocytosis and intracellular killing absorbed bacteria and the production of cytokines necessary for the initiation of humoral and cellular immunity.

Using a combination of allergoids and immunomodulator can reduce the course of treatment (45 injections to 15), which reduces the possibility of complications (anaphylactic reactions) during the course of treatment.

Thus, high efficiency, safety and low cost integrated product based on allergens of birch pollen and muramylpeptides makes it very promising and con aristosporum on the market antiallergic drugs.

Analogues of the present invention is not revealed.

The objective of the invention is to create a comprehensive drug-based allergens of birch pollen and muramylpeptides for the treatment of allergic rhinitis.

The technical result of the claimed invention is the significant strengthening of the immune response and stimulation of high-level production of specific IgG-antibodies that provide protection of the patient after contact with the allergen into his body.

To solve this problem was developed complex injectable drug based on allergens of birch pollen and muramylpeptides for the treatment of allergic rhinitis method ASIT, while the integrated product was obtained by simple mixing of allergoids and received muramylpeptide without chemical conjugation components. At the dose of 1000 PNU of allergoids was added 2 mg of muramylpeptide.

The drug is intended for treatment of allergic rhinitis method ASIT. Introduction according to a certain scheme of increasing doses of the drug produce against him significant amounts of antibodies of IgG class, which bind enter the body the allergen, avoiding, thus associating it with IgE and start the cascade alligatoroidea reactions. Is the so-called "switching" of the immune system with IgE response to IgG response.

The proposed image is the buy is illustrated in the following graphics.

Table 1 presents the results of determining the immunogenicity of the integrated product based on allergens of birch pollen and muramylpeptides.

Table 2 presents the results of the evaluation hypoinsulinaemia activity allergoids pollen of birch and integrated product based on allergens of birch pollen and muramylpeptides during the experiment.

Figure 1 shows the OD values in the ELISA when neutralization of IgE antibodies to the allergen, allergoids and integrated product based on allergens of birch pollen and muramylpeptides.

The composition of the complex injectable-based allergens of birch pollen and muramylpeptides obtained by simple mixing of allergoids and muramylpeptide without chemical conjugation of the components, where the dose of 1000 PNU of allergoids add 2 mg of muramylpeptide, was chosen empirically by studies in laboratory animals. At the first stage were used 5 doses of muramylpeptide 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg Doses were recalculated for mice (hybrids (CBA×S B1/6) F1weighing 19-21 g) calculated that the planned single therapeutic dose is intended for a human weighing 70 kg together with immunomodulating activity was assessed by the effect of the drug received muramylpeptide on the ability to develop ant is celebritysee cells (AFC) in response to the introduction of thymusdependent antigen sheep red blood cells (EB). The results were evaluated by the sum of the two series of experiments, each of which was performed on the 5 experimental groups of mice and the control group (10 mice per group).

It is established that the course introduction to mice drug muramylpeptide at doses of 1, 2 and 5 mg leads to a 2-fold increase in the number of KLA in the spleens of immunized mice. For doses of 0.5 mg and 10 mg marked increase in the number of KLA 1.5 times. The effect is not due to an increase in the number of nucleated cells (ASC) in the spleens, and by increasing the number of active antitelomerase. For the second phase of the study were prepared 3 variants of the comprehensive drug where to 1000 PNU of allergoids added to the selected dose of muramylpeptide (1 mg, 2 mg, 5 mg).

The second phase was to assess the effect of drugs on the basis of the allergens of birch pollen and muramylpeptides on cytokineproducing of human lymphocytes, using commercial test kits Bender Medsystems. Investigated the content of IL-4 in supernatants lymphocytes, stimulated by the allergen, allergoids or complex drug-based allergens of birch pollen and muramylpeptides (after pre-incubation for 18 hours). Drugs, containing 1 and 2 mg muramylpeptide, had no effect on the production of IL-4 in healthy donors and in patients with allergic rhinitis. For preparation containing 5 the g muramylpeptide, a slight increase in the content of IL-4 in supernatants. Was optimal doses of 1 mg and 2 mg muramylpeptide 1000 PNU of allergoids.

According to research results, preference was given to a preparation containing more immunomodulator - 2 mg muramylpeptide 1000 PNU of allergoids.

Since developing the drug is intended for treatment of allergic, then add muramylpeptides should not change the allergenic properties of the drug in comparison with the original allergoids.

Compared the immunogenicity and residual allergenicity. Moreover, the immunogenicity should not be below, and the residual allergenicity is not higher than the corresponding values for the original allergoids.

Determination of immunogenicity and the residual allergenicity of the drugs was performed in enzyme-linked immunosorbent assay. On polystyrene plates were applied, respectively:

- allergic (series SAB-11-1) manufactured from allergen of birch pollen (series SB-11-1) obtained in the fgbi "SSC Institute of immunology" FMBA Russia, as a control, as the original drug;

- complex injectable drug based on allergens of birch pollen and muramylpeptides obtained by simple mixing of allergoids and muramylpeptide, without the need for chemical conjugation of the components, where the dose of 1000 PNU of allergoids was added 2 mg muramyl is eptide.

The immunogenicity of the drug is determined by the ability to interact with specific to it IgG from serum samples of patients. As a positive control was used pulirovaniya serum with a high content of specific IgG-antibodies. Serum for her, containing not less than 10 mgA/l were selected using commercial fluoroimmunometric sets on the instrument ImmunoCAP (Pharmacia biotech). The results determine the immunogenicity of the drug are presented in table 1.

It is seen that the optical density of the obtained product and the controls are very similar, the difference unreliable (p>0,05). Thus, it is shown that the immunogenicity of manufactured drug has not changed compared with the original allergoids from birch pollen.

As the original allergoids made the drug should have a reduced specific activity compared with purified allergen of birch pollen, from which the mixture is allergenic activity of the source of the allergen must exceed the allergenic activity of allergoids or mixture not less than 40%.

The determination was performed inhibition ELISA. As a positive control was used pulirovaniya serum with a high content of specific IgE antibodies. Serum for her, containing not less than 85 kUA/l were selected using the com is ical fluoroimmunometric sets on the instrument ImmunoCAP (Pharmacia biotech).

The results are presented in figure 1. The results of the reaction were evaluated on the chart on the difference OP compared samples at 2 points of the linear section of the calibration curves, and the difference should be not less than 40%. From Fig.1 shows that the binding of allergen-specific IgE reference serum above, since the OD values in the ELISA by neutralizing antibodies significantly lower than for the corresponding concentrations of allergoids and drug that shows better binding with specific IgE reference serum. In two points of the linear section of the calibration curve the difference OP for allergen and allergoids, along with produced on the basis of the drug exceeded 40%. Thus, we obtained the drug, like the original allergie pollen of birch, have lower allergenicity compared with the allergen.

Comparative evaluation of the immunogenic properties of allergoids pollen of birch and complex injectable-based allergens of birch pollen and muramylpeptides the ability to stimulate the synthesis of blocking IgG antibodies in the process of hyposensitization laboratory animals.

Sensitization with allergen birch was performed by intraperitoneal injection of 10 μg/mouse in a volume of 0.2 ml with adjuvant's adjuvant, three times, with an interval of 7 days.

As donors have used mice-hibrido is (females weighing 20 g) from kennel "High" GUNST RAMS. Studies were performed on 30 sensitized mice.

Carried out the course of hyposensitization 20 sensitised animals: the 1st group (10 animals) - allergoids pollen of birch, 2-nd group (10 animals) - complex injectable drug based on allergens of birch pollen and muramylpeptides, 10 sensitised animals constituted the control group.

Course hyposensitization was carried out according to the following scheme:

Injection of 0.01 μg/mouse

Injection of 0.05 μg/mouse

Injection of 0.1 μg/mouse

Injection of 0.1 μg/mouse

Injection of 0.1 μg/mouse

Injection of 0.5 μg/mouse

Injection of 0.5 μg/mouse

Injection of 1.0 μg/mouse

Injection of 1.0 μg/mouse

Injection of 2.0 μg/mouse

Injection of 2.0 μg/mouse

11 injection of the drug was sufficient to produce intense stimulation of IgG response. Through 3 days after hyposensitization animals were decapotable, collected the blood in a test tube, centrifuged, and separated serum, which is then used to determine the ELISA specific IgG antibodies. The results are shown in table 2.

The level of IgG-unit-antibodies in mice after hyposensitization allergoids compared to sensitized the same allergen animals increased by 60%, and after hyposensitization comprehensive drug - 150%.

Shown to increase the immunogenicity of the claimed what about the complex injectable compared with the original allergoids.

Complex injectable drug based on allergens of birch pollen and muramylpeptides for the treatment of allergic rhinitis method ASIT obtained by simple mixing of allergoids and muramylpeptide, without the need for chemical conjugation of the components, whereby the dose of 1000 PNU of allergoids add 2 mg of muramylpeptide.



 

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