KR20170071996A - Pharmaceutical composition of the prevention or treatment of allergic diseases comprising pdks inhibitor as an effective component - Google Patents

Abstract

The present invention relates to a medicament for the treatment or prophylaxis of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies containing an PDKs inhibitor as an active ingredient A cosmetic composition and a health functional food for preventing or treating an allergic disease. The PDKs inhibitor as an active ingredient of the present invention exhibits an antiallergic effect similar to that of cromolyn, a commercially available mast cell stabilizer. Therefore, it can be used as a drug, a cosmetic, and a health functional food for the prevention or treatment of allergic diseases High value.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for preventing or treating an allergic disease containing an inhibitor of PDKs as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating allergic diseases,

The present invention relates to a medicament for the treatment or prophylaxis of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies containing an PDKs inhibitor as an active ingredient A cosmetic composition and a health functional food for preventing or treating an allergic disease.

Mast cells (mast cells; MC) has a major role in the direct allergic reaction (immediate-allergic reactions) as immune derived from hematopoietic precursor cells (hematopoietic precursors) cells ^1-3. Aggregation of high affinity IgE receptors (FcεRI) and stimulation by neuropeptides in mast cells is associated with histamine, protease, newly synthesized inflammatory mediators (eg, prostaglandin D2 PGD _2), leukotriene C4 (LTC ₄₎ and results in the release of mediators such as various cytokines) ^4-7. Mast cells are the only cells that store the formed TNF (tumor necrosis factor), and the formed TNF is released at a rapid rate and affects the collection and activation of T-cells ^{9 , 10} . The ability of mast cells to release multiple mediators helps mast cells to interact with other cells in the environment and participate in the development of mast cell-related diseases. Ultimately, the activation of mast cells hypersensitivity (anaphylaxis), asthma (asthma), rhinitis (rhinitis), life-threatening, such as atopic dermatitis (atopic dermatitis), or it can lead to several types of diseases that directly cause allergic reactions ^{3 , 11-15} . Therefore, inhibition of mast cell activation is strongly suggested as a potential treatment.

The mitochondrial pyruvate dehydrogenase (PDH) complex is a gatekeeping enzyme that binds the citric acid cycle in the cell metabolism and the next step, oxidative phosphorylation, through the glucose uptake process. Play a major role ¹⁶ . This enzymatic activity has been shown to have positional specificity at three serine residues (Ser ²³² , Ser ²⁹³ and Ser ³⁰⁰ ) of the E1 alpha subunit catalyzed by pyruvate dehydrogenase kinases 1-4 (PDK1-4) Phosphorylation / dephosphorylation. Four kinases have different reactivity for each of the three positions, and phosphorylation at all positions leads to the control of PDH activity. Many paper, adjust disabilities arm of PDH / PDK system, and demonstrated that metabolic disease, causes the onset of many diseases, including inflammation, presenting the opinion that part of having a potential treatment that PDK can suppress these diseases ^{17 -19} .

Dichloroacetate (DCA), on the other hand, is a general pharmacological inhibitor of isoform PDK, which has potential therapeutic effects on many diseases ²⁰ . For example, DCA has been proven that the role the in vitro and vivo cancer or for sensitizing tumor diseases, such as lung or breast cancer ^21-23. Another paper by DCA is by stimulating glucose oxidation in the heart ischemia model as well as eoteul indicate a protective effect inhibiting ^24, PDK4 up-regulation and glucose oxidation using FOXO1, sikindaneun consequently improve right ventricular function in the right ventricular hypertrophy ²⁵ proved that. Although no specific signaling pathway has been proposed, Marina et al. Have shown that DCA inhibits airway inflammation and hyperactivity in asthmatic mouse models ²⁶ . Recently, our researchers have reported that up-regulation of PDK4 induces the promotion of vascular calcification through SMAD1 / 5/8 phosphorylation and that DCA improves vascular calcification by modulating PDK4 ²⁷ . In addition, pharmacological inhibition of PDK caused by DCA is to suppress the CFA-induced inflammation have shown the importance of the lactic acid from inflammatory pain PDK- relationship ^28. DCA has been extensively studied in many disease models, including asthma, but no studies have examined whether DCA has antiallergic effects in in vitro and in vivo IgE / antigen-induced allergic response models.

The object of the present invention is to provide a pharmaceutical composition, a cosmetic composition and a health functional food for the prevention or treatment of allergic diseases containing an inhibitor of PDKs as an active ingredient.

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating an allergic disease comprising an inhibitor of PDKs (pyruvate dehydrogenase kinases) as an active ingredient.

It is preferred that the PDKs inhibitor is DCA (dichloroacetate) or a pharmaceutically acceptable salt thereof.

The allergic diseases are selected from the group consisting of edema, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, Rheumatoid arthritis, food allergies, and drug allergies.

The active ingredient of the present invention preferably inhibits degranulation of bone marrow derived mast cells (BMMC).

It is preferable that the active ingredient of the present invention inhibits the secretion of? -Hexosaminidase of BMMC.

The present invention also provides a cosmetic composition for preventing or ameliorating an allergic disease containing an inhibitor of PDKs as an active ingredient.

The PDKs inhibitor is preferably DCA or a pharmaceutically acceptable salt thereof.

The allergic disease is selected from the group consisting of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies desirable.

It is preferable that the active ingredient of the present invention inhibits the degranulation of BMMC.

The active ingredient of the present invention preferably inhibits the secretion of? -Hexosaminidase from BMMC.

The present invention also provides a health functional food for preventing or ameliorating an allergic disease containing an inhibitor of PDKs as an active ingredient.

The PDKs inhibitor is preferably DCA or a pharmaceutically acceptable salt thereof.

The allergic disease is selected from the group consisting of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies desirable.

It is preferable that the active ingredient of the present invention inhibits the degranulation of BMMC.

The active ingredient of the present invention preferably inhibits the secretion of? -Hexosaminidase from BMMC.

The PDKs inhibitor as an active ingredient of the present invention exhibits an antiallergic effect similar to that of cromolyn, a commercially available mast cell stabilizer. Therefore, it can be used as a drug, a cosmetic, and a health functional food for the prevention or treatment of allergic diseases High value.

Figure 1 shows the degranulation inhibition of IgE / antigen stimulated BMMCs by DCA or cromolyn,
Figure 2 shows the effect of DCA or cromolyn in an IgE / antigen stimulated PCA reaction.

Hereinafter, the present invention will be described in detail.

The inventors of the present invention evaluated the anti-allergic effect of DCA, an inhibitor of PDKs, using an in vivo β-hexosaminidase secretion assay as an early marker of mast cell activation and through an IgE / antigen-induced manual skin anaphylaxis (PCA) mouse model . Furthermore, since cromolyn is a mast cell stabilizer that can be obtained commercially and medically, ²⁹ , the antiallergic effect of DCA and cromolyn was compared to confirm the anti-allergic effect of PDKs inhibitor, thereby completing the present invention.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating an allergic disease containing an inhibitor of PDKs as an active ingredient.

The PDKs inhibitor is preferably DCA or a pharmaceutically acceptable salt thereof.

The allergic diseases are selected from the group consisting of edema, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, Rheumatoid arthritis, food allergies, and drug allergies.

The active ingredient of the present invention preferably inhibits degranulation of bone marrow derived mast cells (BMMC).

It is preferable that the active ingredient of the present invention inhibits the secretion of? -Hexosaminidase of BMMC.

The pharmaceutical composition of the present invention may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, injections or creams of sterilized injection solutions, lotions, etc. And external preparations for skin, and may be administered by various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical or skin application. Such pharmaceutical compositions may further comprise carriers, excipients or diluents, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, But are not limited to, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, And the like. In addition, the pharmaceutical composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

In a preferred embodiment, the effective amount of the active ingredient of the pharmaceutical composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 5,000 mg, preferably 100 to 3,000 mg per day, It can be administered every other day or one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like. The pharmaceutical composition of the present invention can be administered to a subject through various routes. All modes of administration may be expected, for example, by injection into the skin, oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections. &Quot; Administration "in the present invention means providing the patient with the desired material in any suitable manner, and the route of administration of the pharmaceutical composition of the present invention may be applied through any general route as long as it can reach the target tissue, Or parenterally. The composition of the present invention may also be administered using any device capable of delivering an effective ingredient to a target cell. In the present invention, the term "object" includes, but is not limited to, human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig , Preferably a mammal, more preferably a human.

The present invention also provides a cosmetic composition for preventing or ameliorating an allergic disease containing an inhibitor of PDKs as an active ingredient.

The PDKs inhibitor is preferably DCA or a pharmaceutically acceptable salt thereof.

The allergic disease is selected from the group consisting of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies desirable.

It is preferable that the active ingredient of the present invention inhibits the degranulation of BMMC.

The active ingredient of the present invention preferably inhibits the secretion of? -Hexosaminidase from BMMC.

The components contained in the cosmetic composition of the present invention include conventional auxiliary agents and carriers conventionally used in cosmetic compositions, in addition to PDKs inhibitors as effective ingredients.

The cosmetic composition for preventing or ameliorating allergic diseases according to the present invention may be prepared in any formulations conventionally produced in the art and may be in the form of solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a sun cream, a flexible lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

The present invention also provides a health functional food for preventing or ameliorating an allergic disease containing an inhibitor of PDKs as an active ingredient.

The PDKs inhibitor is preferably DCA or a pharmaceutically acceptable salt thereof.

The allergic disease is selected from the group consisting of edema, hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies desirable.

It is preferable that the active ingredient of the present invention inhibits the degranulation of BMMC.

The active ingredient of the present invention preferably inhibits the secretion of? -Hexosaminidase from BMMC.

The health functional food of the present invention can be used variously in foods and beverages effective for preventing or improving allergic diseases. Examples of foods containing the active ingredient of the present invention include various foods, beverages, gums, tea, vitamin complex, health supplement foods and the like, and they can be used in the form of powder, granule, tablet, capsule or beverage . The active ingredient of the present invention may generally be added in an amount of 0.01 to 15% by weight of the total food, and the health beverage composition may be added in a proportion of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml. The health functional food of the present invention may contain, as an essential ingredient, the above-mentioned active ingredient in a prescribed ratio, as well as a food-acceptable food supplementary additive such as natural carbohydrate and various flavoring agents as an additional ingredient. Examples of the natural carbohydrate include sugar sugars such as glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of the flavor agent include tau martin, rebaudioside A, glycyrrhizin, saccharin, and aspartame. The proportion of the above-mentioned flavoring agent is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the health functional food of the present invention. In addition to the above, the health functional food of the present invention may contain various kinds of nutrients, vitamins, minerals, flavors such as synthetic flavors and natural flavors, colorants and heavy stabilizers, pectic acid and its salts, alginic acid and its salts, Thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain flesh for producing natural fruit juice, fruit juice drink, vegetable drink and the like. These components may be used independently or in combination. The proportion of such additives is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the active ingredient of the present invention.

Hereinafter, the present invention will be described in more detail with reference to specific examples.

[Example]

1. Materials and Methods

1.1. Experimental animal

A 6-week-old uncontrolled female C57bl / 6 mouse from birth was purchased from Coatec (Korea). All experimental methods were approved by Kyungpook National University Animal Experimental Ethics Committee.

1.2. Generation of BMMC

Bone marrow cells were inhaled from 4-8 weeks old C57BL6 mice and cultured in RPMI 1640 medium (Thermo Fisher Scientific, Waltham, Mass.). The medium was supplemented with 10% FBS, 100 U / mL penicillin (Thermo Fisher Scientific), 10 mmol / L HEPES (Sigma-Aldrich, St. Louis), 100 mmol / L non-essential amino acid solution (Invitrogen, New York Grand Island) A pokeweed mitogen spleen cell-conditioned medium was included as a source of IL-3. After 4 to 8 weeks, more than 99% of the cells were positive for c-kit and FcεRI.

1.3. Degranulation analysis

BMMC (10 ⁶ cells / mL) were sensitized with 500 ng / mL mouse anti-DNP IgE (Sigma) overnight and stimulated at appropriate intervals using DNP-human serum albumin (HAS; Sigma-Aldrich). The supernatant or total cell lysate was loaded onto a 96-well plate together with 2.5 mM 4-nitrophenyl-N-acetyl-D-glucosaminide (Sigma) and solubilized in 0.04M citrate buffer solution adjusted to pH 4.5 with sodium phosphate . After incubation at 37 ° C for 60 minutes, 50 μl of 0.2 M glycine solution adjusted to pH 10.7 with sodium hydroxide was added to terminate the reaction. The colored product was measured at 405 nm with a microplate reader (BMG Labteck, Oppenberg, Germany). For the secretion of β-hexosaminidase in BMMC To examine the effect of 25 [mu] M DCA (Sigma) or cromolyn (Sigma) DNP-HSA was added 1 hour before the injection.

1.4. IgE mediated passive skin hypersensitivity

Anti-DNP IgE (80 ng / 20 μl, Sigma) was injected into the ear skin of a 6-week-old male mouse from birth. After 24 hours, DCA 100 mg / kg (Sigma) was administered once to the oral cavity. One hour later, 60 μg / 200 μl DNP-HSA was injected intravenously with PBS (200 μl) containing 2% Evans Blue (Sigma). After 1 hour treatment with DNP-HSA, the mice were euthanized and the ears removed and dissolved in 500 ul of the oligonucleotide dimethylformamide (JUNSEI, Japan) at 37 ° C. The extracellular flux of the dye was measured at 650 nm using a microplate reader (BMG Labtech).

1.5. Statistical analysis

All data are expressed as means ± SD and represent at least 3 experiments. The significance of the results was tested using the Student's Student t test using GraphPad Prism 5. P <0.05 was found to be significant.

2. Results and Discussion

2.1. Inhibition of PDKs Inhibitor DCA In Vitro BMMC IgE / Antigen Stimulation β-Hexosaminidase Emission Inhibition

Hypersensitivity induced by cross-linking of specific IgE bound to FceRI due to allergen induces antigen induces multiple signaling pathways resulting in degranulation, PGD ₂ , leukotriene synthesis, and the production of various cytokines and chemokines ³⁰ . In MC activation due to IgE / antigen stimulation, deagglomeration of MC occurs at a rapid rate, so the extent of granule component release can be determined. The inventors of the present invention investigated β-hexa minidase as an IgE / antigen stimulus as to whether DCA inhibits degranulation of BMMC. Since chromolin, widely known as a mast cell stabilizer, has been used in rats to investigate the biological role of mast cells in vitro and in vivo, the inhibitory effect of DCA or cromolyne on the release of? -Hexosaminidase from IgE / Were compared.

As shown in FIG. 1, when pre-cultured with DCA or chromolin, the release of β-hexosaminidase from the IgE / antigen-active BMMC was markedly inhibited and the absorbance was measured by IgE / Ag, DCA, (p <0.0001) were 1.96 ± 0.06, 0.49 ± 0.02, and 0.39 ± 0.01, respectively. Interestingly, the inhibitory effect of? -Hexosaminidase release due to DCA is similar to the inhibitory effect of cromolyne.

2.2. Inhibition of IgE / antigen stimulation in the body by PDKs inhibitor DCA and inhibition of passive skin hypersensitivity

DCA is an antidiabetic and hypolipidemic effect ^31, as well as cardiac and cerebrovascular ischemia potential therapeutic effects ^{32, 33} also are on, the incubation period and the acquired ^{34, 35} and born ³⁶ clinical ^- that is effective for the ³⁸ form lactic acidosis . When DCA is orally administered in the form of a sodium salt, it is rapidly absorbed and bioavailable, and the plasma half-life of the first 12.5-50 mg / kg DCA oral administration is up to 1 hour ^{32 , 39} . Monocarboxylate and pyruvate delivery systems pass plasma and mitochondrial membranes, respectively, to pass through blood primers and mitochondrion concentrations. When IgE / antigen-stimulated PCA reaction is induced in the mouse's ear, the Evans blue solution can be easily administered to the mouse to monitor the transient extravasation and efflux due to increased osmotic pressure in the skin ^40,41 . In other words, PCA can be used to study sensitivity to allergen-induced antigens and their response improvement.

Anti-allergic effects of DCA or cromolyn were examined using IgE / antigen-stimulated passive skin hypersensitivity mice. Similar to the in vitro effect of the β-hexosaminidase release assay, mice treated with DCA showed a significant reduction in Evans blue extravasation (FIGS. 2A and 2B, p <0.0001). More interestingly, the inhibitory effect of DCA on Evans blue extravasation was superior to that due to chromolin. The excretion of Evans blue solution was 5.02 ± 1.01, 1.14 ± 0.45, and 1.78 ± 0.58 in the rats treated with vehicle, DCA, and cromolyn, respectively.

The present invention demonstrated for the first time that the PDKs inhibitor DCA has an inhibitory effect on the β-hexosaminidase release of IgE / antigen-activated BMMCs, and that the inhibitory effect is similar or superior to that of chromolin . Therefore, the inventors of the present invention have confirmed that treatment with DCA successfully inhibits IgE / antigen-induced passive skin hypersensitivity and that the effect is comparable to chromolin. In the in vitro and in vivo IgE / antigen-stimulated PCA model, attempts to elucidate signaling pathways for anti-allergic effects using DCA as a mediator should be made in the future. Furthermore, this study has provided a basis for developing new DCA derivatives as potential antiallergic drugs.

Claims (15)

A pharmaceutical composition for the prevention or treatment of allergic diseases containing an inhibitor of pyruvate dehydrogenase kinases (PDKs) as an active ingredient. 2. The pharmaceutical composition according to claim 1, wherein the PDKs inhibitor is DCA (dichloroacetate) or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the allergic disease is selected from the group consisting of edema, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies. The pharmaceutical composition according to claim 1, which inhibits degranulation of bone marrow derived mast cells (BMMC). The pharmaceutical composition according to claim 1, which inhibits the secretion of? -Hexosaminidase of BMMC. A cosmetic composition for preventing or ameliorating allergic diseases containing an inhibitor of pyruvate dehydrogenase kinases (PDKs) as an active ingredient. 7. The cosmetic composition according to claim 6, wherein the PDKs inhibitor is DCA (dichloroacetate) or a pharmaceutically acceptable salt thereof. 7. The method of claim 6, wherein the allergic disease is selected from the group consisting of edema, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, wherein the composition is selected from the group consisting of atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies. The cosmetic composition according to claim 6, which inhibits degranulation of bone marrow derived mast cells (BMMC). The cosmetic composition according to claim 6, which inhibits secretion of? -Hexosaminidase of BMMC. A health functional food for preventing or ameliorating allergic diseases containing an active ingredient of an inhibitor of pyruvate dehydrogenase kinases (PDKs). 12. The health functional food according to claim 11, wherein the PDKs inhibitor is DCA (dichloroacetate) or a pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the allergic disease is selected from the group consisting of edema, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, pruritus, insect allergies, food allergies and drug allergies. 12. The health functional food according to claim 11, which inhibits degranulation of bone marrow derived mast cells (BMMC). 12. The health functional food according to claim 11, which inhibits the secretion of? -Hexosaminidase of BMMC.

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