The tool that has anti-allergic effect

 

(57) Abstract:

The invention relates to medicine, specifically to pharmacology. A new tool, with anti-allergic action. The tool is a glucuronic acid and was previously known as a stimulator of granulomatosa. The invention expands the Arsenal of tools stated purpose and effect at the earliest stages of the formation of allergic reactions associated with the production of immunoglobulins. 4 table.

The invention relates to medicine, specifically to clinical immunology, and can be used for pharmacological correction of abnormalities in the immune system observed in allergic diseases.

Currently, for the treatment of allergic diseases, widely used drugs with antihistamine action, which either block the H1receptors (diphenhydramine, fenkarol, pipolphen and so on), or inhibit the release and activity of histamine and other mediators of Allergy (kromolin-sodium, nedocromil-sodium, ketotifen, oxatomide) [1].

Most of these drugs has expressed to varying degrees sedative effect that ogranicavanje [1]. Moreover, these medicines are mainly used to relieve acute symptoms of Allergy. The closest comparator drug (prototype) can be considered tavegil - an antihistamine with all the characteristic of this group of drugs side effects.

It should be emphasized that the effect of antihistamines is at the stage pathogenicity changes, when it was accompanied by the formation of complexes of antigen-antibody and developed an allergic reaction caused by the action of biologically active substances (including histamine). In this regard, the study of means, which could arrest the development of allergic reactions to earlier stages (before the formation of the complex antigen-antibody), is of interest and is relevant.

The problem solved by this invention is the expansion of the means of having antiallergic activity and acting on the earliest stages of the formation of allergic reactions associated with the production of immunoglobulin E.

The problem is solved by identifying new, has not been studied so far, the properties of glucuronic acid, its anti-allergic Housego granulomatous [3] and the functional activity of polymorphonuclear leukocytes [4].

The use of glucuronic acid on a new appointment was made possible thanks to the identified new properties. First it is shown that the glucuronic acid suppresses the development of anaphylactic shock, reduces the amount of immunoglobulin E and G1 (IgE and IgGl), suppresses a local reaction to an allergen.

Glucuronic acid is one of the main components of glycosaminoglycans of the extracellular matrix [4]. These structures with a high content of glucuronic acid are involved in the regulation of several processes: cell adhesion [5], the production of various cytokines, chemokines and expresii their receptors [6], the functions of dendritic cells [7], T - and b-lymphocytes [8; 9; 10], which determines the quality and intensity of the immune response (IR).

What's new is that glucuronic acid is used as a means of having antiallergic activity. Thus, the proposed solution meets the criteria of the invention, namely, a “novelty”, “inventive step” and “capable of industrial application”.

New properties proved experimentally. Experiments conducted on mice and rats. Glucuronic acid (ha) was administered to mice at a dose of 50 mg/kg of body weight undupe entered the same number FR/br. Animals two or three times received sensitizing injections of ovalbumin (OVA) with aluminum hydroxide (A1) (both Sigma) under the skin of the thigh: ovalbumin, 100 μg/mouse, aluminium hydroxide 5 mg/mouse in FR in a volume of 0.1 ml with an interval of 2 weeks between immunizations. Animals of the control group were injected 0.1 ml of FR at the same time also subcutaneously.

The influence of ha on the occurrence of anaphylactic reactions was investigated using 58 male mice of BALB/c. Response to sensitizing the introduction of OVA (see above) was assessed by the severity of anaphylactic reactions developing after injection of the resolving dose of ovalbumin. The resolving dose was administered intravenously (10 µg in 0.1 ml FR in retroorbital sinus) on the 7th day after the last immunization. Glucuronic acid was injected through two schemes: 1 - for 21 days at 2-fold immunization), starting simultaneously with the first sensitizing injection of OVA; 2 - within 10 days (3x immunization), starting 10 days before the introduction of the resolving dose of OVA. The results of anaphylactic reactions were taken into account according to the following criteria:

- - no reaction;

+ - cyanosis, slight cramps, depression;

++ - cyanosis, clonic seizures the ptx2">The influence of glucuronic acid on a local reaction to an allergen (ovalbumin) was estimated using the delayed-type hypersensitivity using 30 male mice of BALB/c as follows. Animals were senzibilizirani double injection of OVA, as described above. On the 7th day after the last injection in the small of the back legs was administered 20 μg OVA in 0.05 ml FR (the“power paw”), in the contralateral paw were administered 0.05 ml FR (“control arm”). Local inflammatory response was assessed after 4 hours on the difference in mass experienced (Mo) and control (MC) feet. Both legs cut off immediately after slaughter of the animals on the ledge in the bone below the joint a little and tibial bones and above the heel joint. Method and dose of injection glucuronic acid described above, the duration 10 days 10 days prior to the induction of local reactions. Index response (IR) for each mouse was calculated by the formula:

The influence of glucuronic acid on the production of IgE and IgGl-specific antibodies in serum was determined by the method of passive cutaneous anaphylaxis (PKA). Serum was obtained from 18 mice of BALB/c mice immunized with OVA as described above, on the 7th day after the second immunization. Method and dose of injection GC described above, the duration widenening mice-males. The serum of immunized mice at various dilutions were injected in a volume of 30 μl intradermally in the back area. The resolving dose of OVA (0.5 mg in 0.2 ml of 0.5% solution of Evans blue in FR) was administered to mice in retroorbital sinus 2 hours after intradermal injection of serum. The intensity of PKA was assessed after 30 min colouring of the skin, which animals were scored, the skin useprofile, the severity of the reaction was determined by the square of dyed ridge, measured on the inner surface of the skin.

Titers of IgE antibodies specific for OVA, was identified in 12 mongrel rats-males. Animals intradermally into the abdomen injected the serum of immunized mice at various dilutions in the volume of 30 µl. Allowing the injection of OVA did the rat tail vein 24 hours after passive immunization (100 μg OVA per 100 g of body weight in 1 ml of 0.5% solution of Evans blue in FR). The intensity of PKA was assessed after 30 min colouring of the skin, similar to the above PKA in mice.

Statistical processing of data was performed using t-student criterion. Differences in performance were considered significant at p<0,05.

It was established experimentally that the introduction of GC reduces realizatsii mortality has decreased in 2 times: from 9 mice of the control group died 8, in the experimental group of 9 animals were killed 4. The duration of the course introduction of the Ledger in 10 days with three times of immunization in the control group of 10 animals died 9, and experienced from 10 killed 5. Thus, regardless of the severity of anaphylactic shock glucuronic acid reduces mortality.

When local response to OVA in pre-immunized with the same substance of the animals also received a reduction in its intensity under the influence of the introduction of the Ledger (PL. 2). When double immunization and course Ledger duration 10 days (the beginning of the course 10 days prior to local injection of antigen) the severity of the reaction was reduced to 1/4 as compared with the control group not treated with GC.

Glucuronic acid, as shown by the experiments, leading to a reduced level IgGl antibodies specific for OVA, serum double-OVA immunized mice (table.3). In exchange introduction Ledger duration 10 days (the beginning of the course 10 days prior to taking whey) allergen-specific IgGl antibodies in PKA was detected in only 1 animal in the credits, 1/4 and 1/8. Two other mouse gave no reaction in any of the titles of the investigated sera.

Introduction glucuronic acid also causes a decrease in the level of IgE antibodies, specificaly (the beginning of the course 10 days prior to taking whey) allergen-specific IgE antibodies in PKA was detected only in 2 animals in the titre of 1/4, other breeding sera did not cause any reaction.

Thus, the obtained experimental data show that the glucuronic acid has anti-allergic effect. In comparison with the existing antihistamines, antiallergic means the Ledger has the advantage of being able to inhibit the development of allergies in the first - immunological stage, by reducing the formation of immunoglobulin classes E and Gl, and therefore, accordingly, release and subsequent production of biologically active substances that have a damaging effect on cells and tissues.

Literature.

1. Mashkovsky M. D. Medicines. Manual for doctors, fourteenth edition, revised, corrected and augmented. M: the New wave. - 2002. - Volume 1.

2. Patent No. 2020936.

3. Patent No. 2058137.

4. Laurent T. C., Fraser, J. R. E. Hyaluronan. FASEB J, 1992, V. 6, 2397-2404

5. Knudson, S. C., Knudson W. Hyaluronan-binding proteins in development, tissue homeostasis, and disease. // FASEB J. - 1993. - V. 7. - P. 1233-1241.

6. Camenisch, T. D., McDonald J. A. Hyaluronan is bigger better? / 7 Am. J. Respir. Cell Mol. Biol. - 2000. - V. 23. No. 4. - R. 431-433.

7. Termeer, C. C., Hennies J., Voith U, Ahrens T., Weiss J. M, Prehm P., Simon J. C. Oligosaccharides of hyaluronan are potent activators of dendritic cells. // J. - .89. No. 8. - R. 2901-2908.

9. Seth A., Gote L., Nagarkatti m, Nagarkatti P. T-cell-receptor independent activation of cytolytic activity of cytotoxic T lymphocytes mediated through CD44 and gp90MEL-14. // Proc. Natl. Acad. Sci. USA. - 1991. - V. 88. - P. 7877-7881.

10. Hammond D. M., Nagarkatti, P. S., Gote L., Seth, A., Hassuneh, M. R., M. Nagarkatti Double-negative T cells from MRL-lpr/lpr mice mediate cytolytic activity when triggered through adhesion molecules and constitutively express perform gene. // J. Exp. Med. - 1993. No. 178. - P. 2225-2230.

The use of glucuronic acid as a means of providing anti-allergic effect.



 

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