WO2007105910A1 - A pharmaceutical composition for the treatment of allergic diseases and chronic inflammatory diseases, and a method for treatment of allergic diseases and chronic inflammatory diseases - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients for treating allergic diseases and chronic inflammatory diseases. The present invention also provides a use of the above composition for a manufacture of medicament for treating allergic diseases and chronic inflammatory diseases. Further, the present invention provides a method of treating allergic diseases and chronic inflammatory diseases which comprises administrating the above pharmaceutical composition to a mammal. Therefore, even the patients with refractory allergic diseases and chronic inflammatory diseases who could not be sufficiently improved by treatments with standard pharmacological therapy can be effectively improved if the treating method using the above pharmacological composition of the present invention is applied.

Description

[DESCRIPTION]

[Invention Tit Ie]

A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALLERGIC DISEASES AND CHRONIC INFLAMMATORY DISEASES, AND A METHOD FOR TREATMENT OF ALLERGIC DISEASES AND CHRONIC INFLAMMATORY DISEASES

[Technical Field]

<ι> The present invention relates to a pharmaceutical composition for treatment of allergic diseases and chronic inflammatory diseases, a kit for treating allergic diseases and chronic inflammatory diseases, a use of the above said compositions for a manufacture of medicament for treating allergic diseases and chronic inflammatory diseases, and a method of treating allergic diseases and chronic inflammatory diseases.

[Background Art]

<2> Allergic diseases are a kind of chronic inflammatory diseases showing chronic inflammation of skin, airway mucosa or eye mucosa induced by hypersensitive immune response (allergic reaction) to external environmental antigen causing allergic reaction (allergen). Allergic diseases generally include atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, and bronchial asthma (Bierman CW, et al. (eds.) Allergy, asthma, and immunology from infancy to adulthood, page xvii, Saunders, Philadelphia, 1996). Besides, the above allergic diseases have been shown to be developed by the similar pathogenetic mechanisms although their clinical characteristics are differently expressed. Accordingly, there are many patients who are suffering from more than 2 kinds of above allergic diseases at the same time.

<3> Currently, allergic diseases can be improved by avoiding an exposure to a causative external allergen or by allergen-immunotherapy administering the causative allergen to the patients with allergic diseases from the small dose to increasing dose at regular intervals by subcutaneous injection and resulted in a decreased hypersensitivity reaction to the causative allergen if a relevant causative allergen to the patient can be identified. Currently, systemic or local administration of corticosteroids or systemic administrations of pharmaceutical compositions including antihistamines and anti-IgE antibody are known to simultaneously improve the most of clinical symptoms related to different allergic diseases, even if the patients have more than 2 kinds of allergic diseases.

<4> However, current pharmacological therapy can improve the clinical symptoms and physiological functions only during the continuous administration of medication and is not yet proven to fundamentally improve the allergic diseases. Besides, a causative external allergen frequently can not be detected in a significant proportion of patients with bronchial asthma, chronic rhinitis, chronic urticaria, and atopic dermatitis even after the extensive diagnostic tests. These patients are known to be clinically more severe, but therapeutic drugs or treatment methods that can effectively improve their clinical symptoms or can modify the long-term natural course of diseases with etiological treatment have not been developed yet. o> In the current academic society, the above allergic diseases are known to be induced by the chronic inflammation of skin, mucosa, and airway tissue due to hypersensitive immune response to external antigens. However, other chronic inflammatory diseases such as rheumatoid arthritis or osteoarthritis are also classified as autoimmune diseases because these diseases are believed to be induced by the chronic inflammation of synovial tissues or cartilage tissue surrounding the joint due to immune response to self-antigen in the body (autoantigen) (Davidson, A. et al., N Engl J Med 2001; 345:340- 350). Because, tee mechanism responsible for the development of chronic inflammatory diseases including rheumatoid arthritis has not been completely determined yet, a fundamental treatment based on the primary cause of diseases is not possible yet. Accordingly, the chronic inflammatory diseases often can not be appropriately controlled by current pharmacological therapy including corticosteroids, non-steroidal ant i-inflammatory drugs, methotrexate, hydroxychloroquine, sufasalazine, and immunomodulating drugs including cyclosporin A. <6> In 1951, Parrot and Laborde developed a new treatment method administering a complex of histamine and normal human serum gammaglobulin to restore the ability to block the biologic activity of histamine (histaminopexy) that is decreased in the patients with allergic diseases (J Physiol 1951:40:885-9). A complex of histamine/human gammaglobulin has been widely used in many countries including Japan and Europe for the treatment of allergic diseases such as allergic rhinitis, bronchial asthma, atopic dermatitis, and chronic urticaria (Yoshii H, et al . J Allergy Clin Immunol 1997:100:809-16). Injection of histamine-immunoglobulin complex to allergy animal model induced reductions of allergic inflammatory reaction and also showed immunomodulating effects resulting in reductions of the serum levels of TNF-alpha, IL-4 and allergen-specific IgE antibodies (Ayoub M, et al. Int Immunopharmacol 2003:3:523-539). The ant i-inflammatory effect of a complex of histamine/immunoglobulin was not produced when the same amount of histamine or immunoglobulin alone was administered to the animal model of allergy (Yoshii H, et al . J Allergy Clin Immunol 1997:100:809-16). Accordingly, some interaction between histamine and immunoglobulin has been supposed to be important in the pharmacological efficacy of this histamine/immunoglobulin complex on the treatment of allergic diseases. However, the treatment using histamine-immunoglobulin complex is not recommended as a standard pharmacological treatment in the current international guidelines for the treatment of allergic diseases because the clinical effectiveness of histamine-immunoglobulin complex is not currently regarded to be significantly better than other current standard pharmacological treatments by current academic society (Hanifin JM, et al . J Am Acad Dermatol 2004:50:391-404).

<7> A pharmaceutical formulation comprising human placenta extract for injection has been used for restoring a liver function in patients with liver diseases including liver cirrhosis and liver dysfunction in many countries including Japan, Korea, and Europe since the first development at Japan (Nakayama S, et al. Nippon Yakur igaku Zasshi 1989:94:289-97). A few clinicians in some portion of Asian countries including Japan has insisted that treatment with placenta extract is also effective for chronic refractory diseases including atopic dermatitis, bronchial asthma, and rheumatoid arthritis (Nishimura, et al . The Allergy in Practice 1986:6:437-440). However, those clinical efficacies of placenta extract have rarely been proved with systematic clinical trials by multiple clinical investigators. Moreover, the biological mechanism responsible for a pharmaceutical efficacy of placenta extract has not been completely determined yet.

<s> The clinical efficacy of placenta extract injection is not currently regarded to be significantly better than other current standard pharmacological treatments for allergic diseases and chronic inflammatory diseases and the treatment with placenta extract is not currently regarded as standard treatment method for the above diseases by the international academic society. For example, treatment with placenta extract is not currently regarded as a standard treatment method in the international standard treatment guideline for atopic dermatitis (Hanifin JM, et al . J Am Acad Dermatol 2004:50:391-404). [Disclosure] [Technical Problem]

<9> The disease prevalence of allergic diseases such as bronchial asthma, atopic dermatitis, allergic rhinitis, chronic urticaria and chronic inflammatory diseases including rheumatoid arthritis is known to rapidly increase over past 50 years (Bach JF. N Engl J Med 2002:347:911-20). Development of effective preventive methods or treatment methods or drugs that can fundamentally treat the above diseases has not been possible because the reasons for rapid increases of prevalence or precise etio-pathogenetic mechanisms of the above diseases have not been determined yet.

<ιo> Currently, significant numbers of patients with allergic diseases and chronic inflammatory diseases could not experience sufficient clinical improvements by the current standard pharmaceutical treatments. Accordingly, significant numbers of patients with allergic diseases and chronic inflammatory diseases are seeking possible helps from the alternative medicine or complementary medicine and this trend is world-wide phenomenon (Passalacqua G, et al . J Allergy Clin Immunol 2006; 117; 1054-62). The patients with refractory allergic diseases or chronic inflammatory diseases could be clinically improved if corticosteroids or immunosuppressants are administered. However the above drugs could not be used for a longtime because of a high probability of developing systemic side effects in cases of long term medications (Larche M, et al . Nature Med 2005;S69-S76) . So, developments of a new pharmaceutical composition with higher safety and efficacy than currently existing drugs and new treatment methods that can fundamentally improve the allergic diseases and chronic inflammatory diseases are urgently needed nowadays.

<ii> The present inventors made great efforts to develop a new therapeutic drug and a treatment method that could effectively improve the patients with refractory allergic diseases and chronic inflammatory diseases that had not been controlled by current pharmaceutical treatments.

<i2> Involvements of immune response to self proteins (autoimmunity) in the pathogenetic mechanisms has been proposed in the significant portions of patients with previously known as allergic diseases such as bronchial asthma, chronic rhinitis, chronic urticaria, and atopic dermatitis and also in patients with chronic inflammatory diseases including rheumatoid arthritis and the autoimmune mechanisms in the pathogenesis of these diseases have been demonstrated by various in vitro studies or animal models (Rottem M, et al . Int Arch Allergy Immunol 2003:132:210-214; Greaves M. Clin Rev Allergy Immunol 2002;23: 171-83; Schmid-Gredelmeier P, et al. J Allergy Clin Immunol 2005; 115: 1068-75; Davidson A, et al . N Engl J Med 2001:345:340-50). Autoantigen-specific immunotherapy inducing specific immune tolerance by an administration of the identified autoantigen in the forms of peptides has been suggested to be effective in various animal models (Larche M, et al . Nature Med 2005;S69-S76) . Accordingly, autoantigen-specific immunotherapy using human autoantigenic proteins has a possibility to show beneficial effect in the treatment of allergic diseases and chronic inflammatory diseases in which autoimmune pathogenetic mechanism has a role. Unfortunately, administration of specific autoantigens or autoantigenic peptides through oral or injection route has been rarely demonstrated to have significant clinical efficacy in human subjects suffering from allergic diseases and chronic inflammatory diseases. The present inventors believe that current autoantigen-specific immunomodulat ing therapies are ineffective for treating chronic inflammatory diseases in which autoimmune mechanism is involved in the pathogenesis because the target autoantigenic proteins contributing to the developments of tissue inflammation and clinical manifestations are multiple (epitope spreading phenomenon; Larche M, et al . Nature Med 2005;S69-S76) . It has been reported that patients with allergic diseases and chronic inflammatory diseases show autoimmune response to multiple human proteins in each individuals. Accordingly, present investigator judged that injection of a mixture containing multiple human proteins has an advantage in the autoantigenic protein-specific immunotherapy for patients with allergic diseases and chronic inflammatory diseases who show autoimmune phenomenon. However, developments of a new human protein therapeutic drug containing a mixture of multiple human proteins accompany difficulties in time, technique, and costs in the process of proving their safety. Accordingly, the present inventors had searched for a pre-existing pharmaceutical composition containing many human proteins with documented safety for administration to human and we found human placenta extract has been used safely as a therapeutic drug for injection during past 50 years in Japan, Korea, and some countries of Europe (Nakayama S, et al . Nippon Yakur igaku Zasshi 1989:94:289-97; Liu KX, et al . Biol Pharm Bull 1998:21:44-9). And the present inventors tried to use the placenta extract as a material containing multiple various human autoantigenic proteins for the autoantigen- specific immunotherapy. Past researchers reported that implantation of refrigerated or frozen stored human placenta tissue into the subcutaneous tissue after incision of skin (so called "placenta implantation") resulted in marked therapeutic effects in patients with severe refractory asthma and rheumatoid arthritis (de Mesquita HF. Hospital (Rio J) 1968:74:755-7). However, the "placenta implantation" therapy is rarely practiced nowadays because the therapeutic efficacy has not been clearly demonstrated by multiple researchers and because the procedure is relatively invasive and there is a possibility of viral transmission as a complication of that procedure. [Technical Solution]

<i3> The present inventors had tried to treat patients with refractory chronic urticaria, severe refractory atopic dermatitis, severe asthma, and severe refractory rheumatoid arthritis who could not be sufficiently improved by current standard pharmaceutical therapy with injections of placenta extract on the basis of previous reports on their efficacy for the allergic diseases including bronchial asthma by Japanese doctor (Nishimura, et al. The Allergy in Practice 1986:6:437-440). However, the present inventors could not archive significant clinical improvements in the above patients even after continuous treatment with placenta extract for 2-3 months. So, the present inventors judged that treatment with placenta extract in the currently available pharmaceutical formulations could not effectively improve the patients with allergic diseases and chronic inflammatory diseases that autoimmune mechanism is involved in the pathogenetic mechanism.

<i4> Accordingly, the present inventors hypothesized that a simultaneous administration of mixture of placenta extract and histamine-immunoglobulin complex could improve the patients with refractory allergic diseases and refractory chronic inflammatory diseases and this clinical efficacy would be superior than the administration of placenta extract alone because histamine- immunoglobulin complex was used as an immuno-modulating adjuvant on the basis of previous reports observed the therapeutic efficacy for allergic diseases and proved immuno-modulating effects (suppression of TNF-alpha and IL-4) in animal model (Ayoub M, et al. Int Immunopharmacol 2003:3:523-539). And the present inventors hypothesized that the above mixture of placenta extract and histamine-immunoglobulin complex could be developed as a new pharmaceutical composition for the treatment of allergic diseases and chronic inflammatory diseases.

<ι^> According to the above hypothesis, the present inventors completed the present invention by demonstrating a therapeutic effect of pharmaceutical composition of the present invention comprising a mixture of histamine, immunoglobulin, and placenta extract for the allergic diseases and chronic inflammatory diseases in the examples of present invention.

O6> In the examples of the present invention, the present inventors could confirm the unexpected excellent therapeutic efficacy of simultaneous administration of a mixture comprising histamine, immunoglobulin, and placenta extract for patients with refractory allergic diseases and rheumatoid arthritis compared to the administrations of either histamine- immunoglobulin complex alone or placenta extract alone. The present inventors also discovered that simultaneous administration of a mixture comprising histamine, immunoglobulin, and placenta extract was significantly more effective for the clinical improvement of patients with refractory allergic diseases than administrations of placenta extract and histamine- immunoglobulin complex by injecting the each of two drugs separately to two different sites of body. So, the present inventors judge that synergistic interactions among histamine, immunoglobulin, and placenta extract produced excellent therapeutic effects to the patients with refractory allergic diseases and refractory chronic inflammatory diseases.

^i7-> So, the present inventors demonstrated that a pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract had a therapeutic effect for the patients with refractory allergic diseases and refractory chronic inflammatory diseases who could not be improved by current standard pharmaceutical treatments and thereby the present inventors developed a new treatment method for allergic diseases and chronic inflammatory diseases by using the therapeutic pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract . [Advantageous Effects]

<M<X> If the pharmaceutical composition of the present invention is administered to the patients with allergic diseases and chronic inflammatory diseases, marked clinical improvements can be obtained compared to the current standard pharmaceutical treatments. Therefore, allergic diseases and chronic inflammatory diseases can be significantly improved without side effects even in the patients with refractory allergic diseases and refractory chronic inflammatory diseases who could not be sufficiently improved by treatment with standard pharmaceutical treatment if the pharmaceutical composition, its use for treating allergic diseases and chronic inflammatory diseases, or the treatment method using the above compositions of the present invention was applied. [Description of Drawings]

<i^{>-> Fig. 1 shows the result of SDS-PAGE and protein staining of histamine- immunoglobulin complex and human placenta extract used in the examples of the present invention. Lane 1: molecular weight markers; lane 2: commercially available purified human IgG antibody for intravenous administration (IV

TM TM globulin ; Green Cross Co., Korea); lane 3: human placenta extract (Laennec ; GCJBP, Korea); lane 5 and lane 6: commercially available human immunoglobulin

TM for intramuscular administration (Gamma globulin ; Green Cross Co., Korea);

TM lane 7 and lane 8: histamine-immunoglobulin complex (Histobulin ; Green

Cross Co., Korea); lane 9: molecular weight markers. [Best Mode]

-■-<>> The present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients. The present invention also provides a pharmaceutical composition for treating allergic diseases and chronic inflammatory diseases comprising histamine, immunoglobulin and placenta extract as active ingredients. oi> In an embodiment of the present invention, the allergic diseases and chronic inflammatory diseases include atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, bronchial asthma, degenerative arthritis, and rheumatoid arthritis.

<22> Also, the present invention provides a kit for treating allergic diseases and chronic inflammatory diseases comprising: a first container containing histamine; a second container containing immunoglobulin; and a third container containing placenta extract.

<23> The present invention also provides a kit for treating allergic diseases comprising: a first container containing one or more ingredients selected from a group consisting of histamine, immunoglobulin and placenta extract; and a second container containing other remaining ingredient(s) .

<24> The present invention provides the use of a composition comprising histamine, immunoglobulin and placenta extract as active ingredients for the manufacture of medicament for treating allergic diseases.

<25> The present invention provides a method of treating allergic diseases and chronic inflammatory diseases which comprises administrating to a mammal a pharmaceutical composition comprising a therapeutically effective amount of histamine, immunoglobulin and placenta extract.

<26> Further, the present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients, a kit for treating allergic diseases containing the above components, the use of the above said composition for the manufacture of medicament for treating allergic diseases and chronic inflammatory diseases, and a method of treating allergic diseases and chronic inflammatory diseases by administering the above said pharmaceutical composition.

<27> The present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients.

<2x> The pharmaceutical composition comprising histamine, immunoglobulin and placenta extract can be used for the treatment of allergic diseases and chronic inflammatory diseases, too. So, the present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients for treating allergic diseases.

-29> An active ingredient, "histamine" in the composition of the present invention is a compound of formula C5H9N3, which is broadly present within living bodies. It is formed from decarboxylation of histidine in protein by putrefactive bacterium or enteric bacterium. It is regarded that histamine is present in tissues as inactive form which is bonded with tissue protein, but when allergic reaction or anaphylaxis is developed by antigen-antibody reaction, the inactive histamine become to be active form by certain action, thereby the activated histamine acts to organs or tissues. Histamine used in the present composition can be chemically prepared by well known methods in the art, or can be a selling good obtained from the art.

<30> Another active ingredient, "immunoglobulin" in the composition of the present invention is defined as "glycoprotein" having important role in immunity and acting as antibody, among serum components. Immunoglobulin is a term indicating a specifically definable group of "glycoprotein" which can be clearly characterized and differentiated from other kinds of proteins by a common 3 dimensional structure on X-ray crystal lographic analysis, a common migration pattern on electrophoresis, and common constant amino acid sequences on amino acid sequence analysis. Basic structure of immunoglobulins consists of a pair of L chain (light chain) having molecular weight of about 23,000 and a pair of H chain (heavy chain) having molecular weight of about 50,000 to 70,000, wherein the L chain and H-chain are linked to each other by S-S bond. Immunoglobulins are classified to IgG, IgA, IgM, IgD, IgE according to the kinds of H chain, i.e., _Y, α, μ, δ, ε. The immunoglobulin used in the present composition can be IgG, IgA, IgM, IgD, IgE or their mixture thereof, their fragments having biologically equal activity or the mixture of the fragments. Also, the immunoglobulin used in a composition of the present invention can comprise non-specific immunoglobulin or specific immunoglobulin to specific antigen (example, autoantigen). The immunoglobulin used in the present composition can be isolated from plasma of human or animal. Generally, the immunoglobulin used in a composition of the present invention can be formulated by plasma fractionation, or prepared by well-known genetic engineering technique (Vaughan TJ, et al. Nature Biotech 1998:16:535-539).

<^i> The other active ingredient "placenta extract" in the present composition indicates a complex containing fragments and peptides of water soluble or organic solvent-soluble proteins extracted from mammal placenta including cord tissue and chorionic tissue by the known arts in the current pharmaceutical industries (example, U.S. Patent 4,054,648). The "placenta extract" of the present invention can be a form of a composition comprising human placenta tissue hydrolysate made from the processing of human placenta material by steps of treatment with acetone for removal of lipids and extensive hydrolysis with pepsin and hydrochloride to prevent a formation of incomplete hydrolysates as described in the drug information sheet of commercially available human placenta extract for injection (GCJBP, Korea) used in the examples in an embodiment of the present invention. The placenta for manufacturing a pharmaceutical composition comprising placenta extract of the present invention could be obtained from mammal tested for the absence of known infectious agents (including virus, bacteria, and prion) to minimize the transmission of infection. Furthermore, placenta material for manufacturing a pharmaceutical composition would be recommended to be obtained from homologous mammal species that will be treated with the placenta extract to minimize a possible side effect due to allergic reaction to heterologous protein. However, the placenta tissue from other mammals besides human (including pig) could be also used for the manufacturing a pharmaceutical composition of the present invention to overcome the disadvantage of ethical problem and amounts of supplies to obtain human placenta.

<-32> In an embodiment of the present invention, this invention also provides a kit for treating allergic diseases and chronic inflammatory diseases comprising: a first container containing histamine; a second container containing immunoglobulin; and a third container containing placenta extract. Otherwise, the present invention provides a kit for treating allergic diseases and chronic inflammatory diseases comprising: a first container containing one or more ingredient(s) selected from a group consisting of histamine, immunoglobulin and placenta extract; and a second container containing remaining components of the above 3 ingredients.

<VΪ> The present invention provides use of a composition comprising histamine, immunoglobulin and placenta extract as active ingredients for the manufacture of medicament for treating allergic diseases. The pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract as active ingredients can be used for the manufacture of medicament for treating allergic diseases and chronic inflammatory diseases.

<?4> Also, the present invention provides a method of treating allergic diseases and chronic inflammatory diseases that comprises administrating a pharmaceutical composition comprising therapeutically effective amounts of histamine, immunoglobulin and placenta extract to a mammal.

--^> The method for treating allergic diseases in the present invention can be performed by using the said pharmaceutical composition. The dosage of the present pharmaceutical composition can be decided by considering the dosage of histamine-immunoglobulin complex used in non-specific immunotherapy using histamine-immunoglobulin complex or dosage of placenta extract used in injection therapy with placenta extract. Although the dosage of general pharmaceutical composition can be decided depending on severity of the clinical symptoms, age, weight of the patient, etc., the dosage of the present composition should be also decided by considering patient's sensitivity to the placenta extract and/or patient's sensitivity for histamine or immunoglobulin, as well as the above conditions.

<36> When the pharmaceutical composition of the present invention comprising histamine, immunoglobulin and placenta extract is administrated at once, a dosage of histamine can be 0.05 to 2.5//g, preferably 0.1 to l.Oμg, and a dosage of immunoglobulin can be 0.05 to 50mg, preferably 12 to 36mg as a protein amount, and a dosage of placenta extract can be 50/zg to 50 mg/in-C , preferably 100 to 1000/-g/m4 as a protein amount in the buffer for injection. Preferably, histamine, immunoglobulin and placenta extract can be combined as a form of lyophilized powder contained in a sterile and sealed glass vial and then dissolved in 0.5 to 2ml of buffer for one injection just before administrat ion.

<37> The advantages and features of the present invention and the method of revealing them will be explicit from the following examples described in detail. However, it is to be distinctly understood that the present invention is not limited thereto but may be otherwise variously embodied and practiced. It is obvious that the following examples are to complete the disclosure of the invention and to indicate the scope of the present invention to a skilled artisan completely, and the present invention will be defined only by the scope of the claims. [Mode for Invention]

<3S> Examples

<3o> [Example 1]

<4o> Example of formulation 1:

<4i> Human immunoglobulin 24mg

<42> Histamine dichloride 0.30_/zg

<43> Sodium chloride 8mg

<44> Amino acetic acid 90mg

<45> D-ma.nitol 8mg

<46> Sodium hydroxide - an appropriate amount

<47> Aluminum hydroxide 0.001-2mg

<48> Placenta extract 2 mg (as a protein amount)

<49> Solution for injection 4ml (supplied as another vial from the above ingredients)

<50> oi> The above example of formulation 1 is a pharmaceutical formulation designed on the basis of amounts of histamine, immunoglobulin, and placenta extract administered to the patients with allergic diseases and chronic inflammatory diseases at one administration for the treatment of the diseases in the examples of the present invention. Immune response enhancers (adjuvant) including aluminum hydroxide that is commonly used in the field of art can be added to the pharmaceutical formulation of the present invention as in the above example of formulation 1. The dosage and ratio of the ingredients in the above example of formulation 1 can be appropriately changed according to the clinical severity of diseases for treatment, age of the patient, weight of the patient, and other accompanied diseases in the patients.

<52>

<?3> Example of formulation 2-1: histamine-immunoglobulin complex o4> An injection formulation for histamine-immunoglobulin complex

TlI

(Histobulin , Green cross PBM, Korea) contained 12 mg of human immunoglobulin and 0.15//g of histamine dichloride as described in the product information sheet provided by the manufacturer. The above formulation is provided as two vials comprising one vial containing the above active ingredients in a lyophilized form and another vial containing 2 ml of distilled water for injection and the manufacturer recommends to mix the contents of two vials using an injection syringe immediately before the each injections and dissolve the active ingredients well and inject 2ml of this mixture subcutaneousIy. When the contents of IgG, IgM, IgA and albumin concentration in the above histamine-immunoglobulin complex injection solution were determined by nephelometry analyzer (COBAS INTEGRA, Roche Diagnostics GmbH, Germany), the 11.0 mg of human IgG and 0.24mg of human IgA were contained in the above formulation, but IgM or albumin was not detected in the above formulation because their concentrations were below the lowest detection limits of the above analyzer (IgM <0.037mg/ml, albumin <0.09mg/ml) . o5> o6> Example of formulation 2-2: injection solution of placenta extract

•o7> In the embodiment of present invention, the inventors used an injection

TM solution of placenta extract (Laennec ; GCJBP, Korea; Technical collaboration for production with Japanese Biological Product Company, Tokyo, Japan) containing human placenta chorial tissue hydrolysate as described in the product information sheet provided by manufacturer. One vial of the above injection solution containing placenta extract contained 2ml of yellowish brown colored solution with 500 μg/ml of the total protein concentration quantified by Bradford's method. Accordingly, 1 vial of the above injection solution of placenta extract used in the examples of the present invention contained about lmg protein extracted from human placenta. An the above 2ml of placenta extract is recommended to be administered through subcutaneous injection or intramuscular injection and maximally 3 vials(6 ml) of the placenta extract can be administered for 1 day according to the product information sheet provided by the manufacturer. o8> To evaluate the protein or peptide compositions contained in the histamine-immunoglobulin complex (the example of formulation 2-1) and placenta extract (the example of formulation 2-2) used in the examples of the present invention, analysis using sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS-PAGE) and protein staining was performed with the above two formulations. On the SDS-PAGE analysis, IgG antibody consisting of 50-kDa heavy chain and 25-kDa light chain was a major component of the above histamine-immunoglobulin complex and fragments and peptides of human proteins with molecular weight sizes less than 20-kDa were major components of the above placenta extract (Fig. 1). Accordingly, the pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract can be identified with analysis of the constituting components by simple electrophoresis (SDS-PAGE, etc) and protein staining.

<6o> [Example 2] Proving a clinical efficacy of the pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract in patients with refractory allergic diseases and refractory chronic inflammatory diseases who can not be improved by current standard pharmacological treatments. «>2> Example 2-1: An example of a patient with refractory atopic dermatitis who had not been clinically improved by histamine-immunoglobulin complex treatment but showed a marked clinical improvement after treatment with the pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract

<63> A 47-year old female patient visited the clinic for typical symptoms of atopic dermatitis including erythematous skin eruptions, itching sensation, dryness of skin, and scaling of skin predominantly involving facial area especially around the eyes that had lasted for the past 5 years. Although the patient continuously received various medical treatments at many clinics, the patient did not experience any clear improvements in her clinical symptoms and the patient had not been satisfied by the any past treatments. On the allergy skin prick test with common inhalant and food allergens, she showed negative response to all tested allergens. She was diagnosed as intrinsic atopic dermatitis. And then the above patient received standard pharmacological treatment with oral antihistamine, low dose oral corticosteroid, topical corticosteroid and topical immunomodulating agent (tacrolimus) for 2 months but any significant improvement of atopic dermatitis symptoms could not be observed in the above patients during and after those treatments. And then the above patient additionally received treatment with 1 vial (2ml) of histamine-immunoglobulin complex of the above example of formulation 2-1 at weekly interval for 2 months but the patients experienced frequent recurrences of clinical symptoms. Accordingly, the present inventors subcutaneousIy injected a mixture of histamine- immunoglobulin complex (the above example of formulation 2-1) 1 vial (2ml) and placenta extract (the above example of formulation 2-2) 2 vials to the above patients at a weekly interval for 4 weeks. After treatments with the above injection treatment for 4 weeks, the above patient experienced complete disappearance of clinical symptoms related to atopic dermatitis and discontinued pharmacological treatment and did not used topical agents also. -w> After complete discontinuation of the any treatment for 1 month, the above patient experienced a gradual aggravation of skin symptoms and the patient wanted to continue the injection treatment with a decreased dose. Therefore, the above patient only received injection of the placenta extract (the above example of formulation 2-2) 2 vials (total 4ml) at a weekly interval for 4 weeks without administration of histamine-immunoglobulin complex (the above example of formulation 2-1). However, the above patient experienced gradual recurrences of erythematous skin eruptions and itching sensation of facial skin and these skin symptoms could be only controlled by continuous regular ingestions of oral corticosteroid. Therefore, the above patient received a mixture of placenta extract and histamine-immune complex made by direct mixing and dissolving of placenta extract solution (lvial=2ml) with lyophilized powder of histamine-immunoglobulin complex (1 vial) to reduce the volume of injection at weekly interval for 4 weeks. After treatments with the above injection solution containing a mixture of the above two formulation for 4 weeks, the above patient experienced complete disappearance of clinical symptoms related to atopic dermatitis including erythematous skin eruptions, itching sensation, and dryness of facial skin and discontinued pharmacological treatment and did not used topical agents also. The above patient reported that the clinical severity of atopic dermatitis were significantly improved more than 70% compared to the baseline clinical severity before the start of the above combination treatment of the above two pharmaceutical formulations when judged by the patient's own subjective assessment and any abnormality of skin could not be observed on the physical examination by physician. No case of side effect was observed in the above patient after subcutaneous injections of the above composition comprising histamine, immunoglobulin, and placenta extract in this example 2- 1 except transient localized pain at the injection site.

<6?> The above example 2-1 provides evidence that a pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract is significantly more effective for the clinical improvement of a patient with refractory atopic dermatitis than either one of placenta extract or histamine-immunoglobulin complex and with excellent therapeutic efficacy and safety. So₁ the pharmaceutical composition of present invention comprising histamine, immunoglobulin, and placenta extract provides a new therapeutic composition and a new treatment method for atopic dermatitis.

<66>

67-. Examp1e 2-2•' An example of a patient with severe refractory rheumatoid arthritis who had not been clinically improved by standard pharmacological treatment but showed significant clinical improvement after treatment with the pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract

<68>

^69> A 47-year old female patient visited the clinic for multiple joint swelling and pain symmetrically involving fingers, elbows and knees lasted for more than 3 years. The patient also complained stiffness of joints in the morning lasting more than one hour. Although the patient continuously received various medical treatments at many clinics under the diagnosis of rheumatoid arthritis, the patient did not experienced any clear improvements in her clinical symptoms and the patient had not been satisfied by past treatments. On the blood test, rheumatoid factor was positive and erythrocyte sedimentation rate was markedly increased above the normal limit. On the basis of above clinical features and laboratory findings, she was diagnosed as severe rheumatoid arthritis. And then the above patient received standard pharmacological treatment with oral non-steroidal ant i-inflammatory drugs and low dose oral corticosteroid, and anti-rheumatic drugs for more than 6 months but any significant improvement of clinical symptoms related to rheumatoid arthritis could not be observed in the above patients by the above treatments and the persistent clinical symptoms significantly limited her daily living.

<7o> Accordingly, the present inventors subcutaneousIy injected a mixture of histamine-immunoglobulin complex (the above example of formulation 2-1) 1 vial (2ml) and placenta extract (the above example of formulation 2-2) 2 vials (4ml) to the above patients at a weekly interval for 4 weeks. After treatments with the above injection treatment for 4 weeks, the above patient experienced a significant decrease of subjective clinical symptoms related to rheumatoid arthritis and she reported that she experienced no limitation of her daily living even she reduced the doses of her regular oral medication to half doses for last 2 weeks.

<7i> The above example 2-2 provides evidence that the treatment with pharmaceutical composition of the present invention comprising a mixture of histamine, immunoglobulin, and placenta extract can provide marked clinical improvement in the patients with chronic inflammatory diseases including refractory rheumatoid arthritis that can not be controlled by standard pharmacological treatments.

<⁷2> So, a pharmaceutical composition of the present invention for treating allergic diseases and chronic inflammatory diseases comprising histamine, immunoglobulin and placenta extract can provides a new effective pharmaceutical composition and a new effective treatment method for treating chronic inflammatory diseases including refractory rheumatoid arthritis.

<73>

<74> Example 2-3: An example of a patient with severe refractory asthma and chronic rhinitis who had not been clinically improved by standard pharmacological treatment but showed significant clinical improvement after treatment with the pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract

<⁷?> A 50-year old female patient visited the clinic for persistent coughing and breathlessness for last 10 years. On the medical history of the patient, she continuously received current standard pharmacological treatments including inhalation therapy with combination of corticosteroid and long- acting beta-agonist, and oral medications for the past 2 years. However, she had experienced a severe asthmatic attack and admitted to hospital after endotracheal intubation at 2 years ago and she also had admitted to hospital due to severe asthmatic attack at 1 year ago. She also showed clinical features of chronic rhinitis including persisting runny nose, sneezing, and nasal obstruction. On physical examination, she showed clinical features including moon face, facial flushing, and central obesity compatible with iatrogenic Cushing syndrome due to long term oral corticosteroid ingestions. On auscultation, wheezing sound was audible in both lower lung fields. On the pulmonary function test, the value of forced expiratory flow volume in one second (FEVl) was 39% of expected value and showed a significant reversibility of airway obstruction showing more than 30% increase of FEVl value compared to baseline FEVl value when measured after inhalation of bronchodilator . She showed negative results for all tested allergen on an allergy skin prick test with common inhalant allergens and this result was compatible with non-atopic asthma and rhinitis. The patient was diagnosed as severe refractory asthma and chronic rhinitis. The patient received daily inhaled treatment with combination of corticosteroid and long acting beta- agonist, daily oral corticosteroid (prednisolone 20mg/day), and daily oral theophylline (200mg/day). Her clinical symptoms of bronchial asthma including coughing, breathlessness, wheezing and symptoms of chronic rhinitis including runny nose, sneezing, nasal obstruction were not improved and continued and FEVl was 42% of expected value without significant improvement after 6 months of the above pharmacological treatment. Accordingly, the patient received subcutaneous injections of histamine-immunoglobulin complex (the above example of formulation 2-1) 1 vial (2ml) and placenta extract (the above example of formulation 2-2) 2 vials (total 4ml) to the separate sites of the body at a monthly interval. At one month after the initiation of the above injection treatment, the FEVl was significantly increased to 56% of expected value and the patient expressed that the degree of coughing and breathlessness was decreased to 50% compared to before the initiation of the above injection treatment even after decreasing the daily dose of oral corticosteroid to prednisolone lOmg/day. Therefore, the above patient received a simultaneous subcutaneous injection of a composition comprising placenta extract and histamine-immune complex made by direct mixing and dissolving of placenta extract solution (lvial=2ml) with lyophilized powder of histamine-immunoglobulin complex to reduce the volume of injection at a monthly intervals. At the 2 months after monthly injections of the above mixture, the FEVl was significantly increased to 66% of expected value and the patient expressed that the degree of coughing and breathlessness was decreased to more than 70% compared to before the initiation of the above injection treatments with a mixture of the above example of formulation 2-1 and the above example of formulation 2-2 even after decreasing the daily dose of oral corticosteroid to prednisolone 2.5mg/day.

-76^ The inventors asked the above patient which one was her preferred administration method among administrating the two injection formulations of histamine-immunoglobulin complex (the above example of formulation 2-1) and placenta extract (the above example of formulation 2-2) to two separate sites of body or single injection of a mixture made of the above two formulations judged on the points of therapeutic efficacy and easiness of receiving injection. The above patient expressed that she preferred simultaneous single injection of the above two formulation in one site because it was more effective for the symptomatic improvement of bronchial asthma and chronic rhinitis and less painful at injection compared to two separate injections of the above two formulations. No case of side effect was observed in the above patient after subcutaneous injections of the above composition comprising histamine, immunoglobulin, and placenta extract in the above example 2-3 except transient localized pain at the injection site.

<⁷?> The above example 2-3 provides evidence that a pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract is significantly effective and safe for the clinical improvement of a patient with severe refractory asthma and can reduce the needs of long-term treatment with high dose oral corticosteroid and thereby reducing the risk of developing side effects due to oral corticosteroid in the patient. So, the above example 2-3 provides evidence that the pharmaceutical composition of present invention comprising histamine, immunoglobulin, and placenta extract provides a new therapeutic composition and a new treatment method with safety and excellent efficacy that can clinically improve a patient with severe refractory asthma and chronic rhinitis.

<⁷,x>

-⁷9> [Example 3] Analysis of clinical efficacy of the pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract for the treatment of patients with refractory chronic urticaria

<xi-- The patients with chronic urticaria who showed typical clinical features including itching skin eruptions characterized by wheal and erythema lasting for more than 6 weeks and who were not improved sufficiently to be satisfied by himself or herself and experienced limitations in daily living even after receiving standard pharmacological treatments including oral antihistamines were treated by one of 3 treatment methods described in the below. Currently, chronic urticaria without an identifiable external cause is known to be mostly developed by autoimmune mechanism (Greaves M. Clin Rev Allergy Immunol 2002:23:171-83).

<82>

<-83> Group 1 (placenta extract treated group): The placenta extract of the above

TM example of formulation 2-2 (Laennec ) was administered with minor modifications in the intervals of administration recommended by manufacturer. Two vials of the above placenta extract formulation was administered simultaneously by subcutaneous injection at intervals of every one week for 8 weeks and then two times at 2 weeks interval from 8-12 weeks and monthly interval after 12 weeks.

<84>

<X5> Group 2 (histamine-immunoglobulin treated group): The histamine- immunoglobulin complex of the above example of formulation 2-1 (Histobulin , Green cross PBM, Korea) was administered with a slight modifications in the intervals of administration recommended by manufacturer. Two vials of the above histamine-immunoglobulin complex formulation were administered subcutaneousIy every one week for 8 weeks and then two times at 2 weeks interval from 8-12 weeks and monthly interval after 12 weeks.

<X6>

<X7> Group 3 (a combination treatment group with a mixture of histamine, immunoglobulin, and placenta extract): The treatment methods of group 1 and group 2 were simultaneously administered. To minimize the inconvenience of patients by injecting the two kinds of formulation separately in both arms, the 4 ml of injection solution containing the placenta extract was directly mixed to the 2 vials of lyophilized powder containing histamine- immunoglobulin complex and the mixture was rapidly dissolved and the above mixture was simultaneously administered by single subcutaneous injection. The above mixture containing histamine, immunoglobulin, and placenta extract was administered simultaneously by single subcutaneous injection at intervals of every one week for 8 weeks and then two times at 2 weeks interval from 8-12 weeks and monthly interval after 12 weeks.

<X8>

<X9> The clinical improvements of atopic dermatitis by above treatment methods were evaluated by combining the two criteria as described below.

<90>

<9i> (1) Subjective assessment of clinical improvement obtained by medical history of patients: The patients were asked to tell the subjective improvement of clinical symptoms related to chronic urticaria including degree and involved area of itching and skin eruptions (including wheal and erythema) at monthly interval from the beginning of treatment. Patients were educated to express the improvement as 100% if their symptoms were completely disappeared and 0% if their symptoms were not least improved or even aggravated and 50% if their symptoms were decreased to half compared to the baseline state before starting the treatment. The subjective improvements assessed by patients were recorded by physicians monthly and then analyzed.

<^l>2> (2) Global assessment of general severity of chronic urticaria on the basis of physical examination by physician: The physician involved in the patient care measured the clinical severity of chronic urticaria (comprehensively assessing degrees of wheal and erythema of skin and area of involvement) by physical examination of patients at a monthly interval using the investigator's global assessment (IGA) criteria as previously described (Gelmetti C, et al . Allergy 2004;59 (Suppl. 78): 61-65). The IGA scoring was made very severe (5), severe (4), moderate (3), mild (2), almost clear (1), and clear (0). The scoring was made monthly and recorded.

^c>4.> The above patients were continued the treatments for 3 months. The clinical improvement was analyzed using the mean improvement values calculated from the summation of improvements assessed by the above two methods. Assessment of clinical improvement was analyzed at 3 months after the start of the above treatments compared to the clinical severity before the start of the above treatments (Table 1).

<^> [Table 1]

<%> Analysis of clinical efficacy of a pharmaceutical composition comprising histamine, immunoglobulin, and placenta extract in patients with refractory chronic urt icaria

<97>

<^l)8>

* Fisher's exact test PO.05, it means statistically significant difference in the frequency of improvement more than 20% between group 1 and group 3.

<99> + Fisher's exact test P<0.05, it means statistically significant difference in the frequency of improvement more than 50% between group 1 and group 3 and between group 2 and group 3.

< 100> There was no statistically significant difference in the frequency of improvement more than 20% or 50% between group 1 and group 2 (Fisher's exact test P>0.05).

< 10 l > From the above analyzed results (Table 1), it could be confirmed that marked clinical improvements more than 50% compared to clinical severity before the start of the above treatments were significantly more frequently observed in the patient group treated by the pharmaceutical composition of the present invention comprising the above 3 active ingredients (group 3) compared to the patient groups treated by placenta extract alone (group 1) or histamine-immunoglobulin complex alone (group 2) at 3 months after the start of the above treatments (Table 1; pθ.05, Fisher's exact test). No case of generalized side effect was observed in the all above 3 treatment groups except for the transient localized pain at the injection site. Accordingly, a pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract provides a new safe pharmaceutical composition for the treatment of chronic urticaria having significantly higher efficacy than the current placenta extract alone or histamine- immunoglobulin complex alone (showing 75% of patients were clinically improved more than 50% compared to the baseline clinical severity before the start of the treatment).

<io2> Therefore, a pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract and the treatment method using the composition can provide an opportunity for significant marked clinical improvement (that can not be expected by the other treatments) to the large numbers of patients with refractory allergic diseases and refractory chronic inflammatory diseases including refractory chronic urticaria who could not be improved by current standard pharmaceutical treatments.

<1(H>

-io4> [Example 4] Examples that confirmed whether the therapeutic effect of the pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract for the treatment of allergic diseases is simply an additive effect of the two therapeutic formulations of placenta extract and histamine-immunoglobulin complex or a synergistic effect produced by a combination of the two therapeutic formulations.

<io6> Example 4-1: Comparing the therapeutic effects of the treatment by simultaneously administrating a mixture of histamine, immunoglobulin, and placenta extract and the treatment with administrating placenta extract and histamine-immunoglobulin complex separately to two different sites of the body in patients with refractory chronic urticaria

<.1()7>

"io8> Two patients with chronic urticaria were treated by a mixture of histamine, immunoglobulin, and placenta extract as described in the group 3 of the above example 3 of the present invention for 3 months and the clinical symptoms of patients related to chronic urticaria had been improved more than 70% compared to the baseline clinical severity before the start of the above combination treatment after 3 months of the treatments. After getting agreements from two patients, two vials of histamine-immunoglobulin complex (the above example of formulation 2-1) and two vials of placenta extract (the above example of formulation 2-2) were separately administered to the 2 different arms at 2 weeks interval for 2 months. At two months after changing to the above treatment, clinical symptoms and objective findings of chronic urticaria were evidently aggravated more than 30% compared to before the changing to the above treatment as judged by both the patient's own subjective assessment and the physician's objective assessment. Then the patient received the administration of mixture comprising histamine, immunoglobulin, and placenta extract in the same doses and injection methods as described in the group 3 of the above example 3 of the present invention again. At two month after returning to the above treatment, the clinical symptoms related chronic urticaria were significantly improved more than 70% compared to the baseline clinical severity before the start of the initial treatment described in the group 3 of the above example 3 of the present invention again. The above two patients had not been improved sufficiently even after receiving continuous daily oral antihistamine before the start of the treatment, but the patients experienced controls of urticaria symptoms only requiring intermittent ingestion of oral antihistamine after treatment of continuous regular injections of the above pharmaceutical composition of the present invention.

< 109> oio> Example 4-2: Comparing the therapeutic effects of the treatment by simultaneously administrating a mixture of histamine, immunoglobulin, and placenta extract and the treatment by administrating placenta extract and histamine-immunoglobulin complex separately to two different sites in patients with severe refractory asthma iiι> Two patients with severe refractory asthma had not been controlled by current standard pharmaceutical treatments including daily inhaled treatments with combination of corticosteroid and long acting beta-agonist for more than 6 months and they had experienced continuously typical clinical symptoms of bronchial asthma including coughing, breathlessness, and wheezing. The above patients received administration of therapeutic composition comprising a mixture of histamine, immunoglobulin, and placenta extract as described in the group 3 of the above example 3 of the present invention for 3 months in addition to the above standard pharmaceutical treatments. At 3 month after receiving the above treatment, the clinical symptoms of patients related to bronchial asthma including frequencies of asthmatic attacks accompanying coughing and breathlessness were significantly decreased more than 50% compared to the baseline clinical assessment before the start of the above treatment as judged by both the patient's own subjective assessment and the physician's objective assessment based on the medical history of the patients. After getting agreements from the above two patients, two vials of histamine-immunoglobulin complex (the above example of formulation 2-1) and two vials of placenta extract (the above example of formulation 2-2) were separately administered to the 2 different arms (injection of same kinds of two vials to the same injection site) at 2 weeks interval for 2 months. At two months after changing to the above treatment of separate injections from the simultaneous single injection of a mixture of the above 3 active ingredients, the severities and frequencies of asthmatic attacks in the above patients were significantly increased more than 30% compared to before the changing to the above treatment (separate injections of the above two formulations) as judged by both the patient's own subjective assessment and the physician's medical history. Then the patient received the an administration of the mixture comprising histamine, immunoglobulin, and placenta extract in the same doses and injection methods as monthly maintenance treatment described in the group 3 of the above example 3 of the present invention again. At two months after returning to the above treatment, the severities and frequencies of asthmatic attacks in the above patients began to improve and the above patients experienced continuous improvements of clinical symptoms related to bronchial asthma including the frequencies of asthmatic attacks accompanying coughing and breathlessness more than 50% compared to the baseline clinical state before the start of the initial treatment described in the group 3 of the above example 3 of the present invention.

<ii2> Accordingly, the above example 4 demonstrates that the therapeutic efficacy of a pharmaceutical composition of the present invention and a treatment method with the composition comprising histamine, immunoglobulin, and placenta extract is not simply an additive effect of the two kinds of currently available therapeutic formulations including placenta extract or histamine-immunoglobulin complex but a synergistic effect produced by mixing the three major ingredients consisting of histamine, immunoglobulin, and placenta extract result in marked therapeutic efficacy. [Industrial Applicability]

<ii3> The present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients for treating allergic diseases and chronic inflammatory diseases. Accordingly, the pharmaceutical composition of the present invention can be used for the manufacture of medicament for treating allergic diseases and chronic inflammatory diseases as an industrial application. Also, the present invention provides a method of treating patients with allergic diseases and chronic inflammatory diseases by administrating the above pharmaceutical composition of the present invention that can produce a significantly better therapeutic efficacy compared to current standard pharmacological treatments. Therefore, even the patients with allergic diseases and chronic inflammatory diseases who could not be sufficiently improved by treatment with standard pharmacological treatments can be significantly improved without side effects if the pharmaceutical composition of the present invention, its manufacturing method, its use for treating allergic diseases and chronic inflammatory diseases, or a treatment method using the above composition of the present invention was applied.

Claims

[CLAIMS] [Claim 1]

<iiv> A pharmaceutical composition for treating allergic diseases and chronic inflammatory diseases comprising histamine, immunoglobulin and placenta extract as active ingredients.

[Claim 2] iuv> The pharmaceutical composition of claim 1, wherein the immunoglobulin is human immunoglobulin.

[Claim 3]

*-ii7^ The pharmaceutical composition of claim 1, wherein the placenta is human placenta.

[Claim 4]

-i!8> The pharmaceutical composition of claim 1, wherein the allergic diseases and chronic inflammatory diseases are atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, bronchial asthma or rheumatoid arthritis.

[Claim 5]

<-ii9> The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a kit for treating allergic diseases and chronic inflammatory diseases comprising: a first container containing histamine, immunoglobulin, and placenta extract; and a second container containing buffer for injection.

[Claim 6]

<i2o> A method of treating allergic diseases and chronic inflammatory diseases which comprises administrating to a mammal a pharmaceutical composition comprising a therapeutically effective amount of histamine, immunoglobulin, and placenta extract.

[Claim 7]

^i2i> The method of claim 6, wherein the immunoglobulin is human immunoglobulin.

[Claim 8] <i22> The method of claim 6, wherein the placenta is human placenta.

[Claim 9] i2^"!> The method of claim 6, wherein the allergic diseases and chronic inflammatory diseases are atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, bronchial asthma or rheumatoid arthritis.

[Claim 10] i24> A pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients.