WO2007105910A1 - Composition pharmaceutique pour le traitement de maladies allergiques et de maladies inflammatoires chroniques, et procédé de traitement de maladies allergiques et de maladies inflammatoires chroniques - Google Patents

Composition pharmaceutique pour le traitement de maladies allergiques et de maladies inflammatoires chroniques, et procédé de traitement de maladies allergiques et de maladies inflammatoires chroniques Download PDF

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WO2007105910A1
WO2007105910A1 PCT/KR2007/001251 KR2007001251W WO2007105910A1 WO 2007105910 A1 WO2007105910 A1 WO 2007105910A1 KR 2007001251 W KR2007001251 W KR 2007001251W WO 2007105910 A1 WO2007105910 A1 WO 2007105910A1
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Prior art keywords
immunoglobulin
histamine
diseases
treatment
chronic inflammatory
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PCT/KR2007/001251
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English (en)
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Sook-Yeong Jeon
Dong-Ho Nahm
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Sook-Yeong Jeon
Dong-Ho Nahm
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Priority claimed from KR1020070024402A external-priority patent/KR100756974B1/ko
Application filed by Sook-Yeong Jeon, Dong-Ho Nahm filed Critical Sook-Yeong Jeon
Priority to JP2009500292A priority Critical patent/JP2009530269A/ja
Publication of WO2007105910A1 publication Critical patent/WO2007105910A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • chronic inflammatory diseases including rheumatoid arthritis
  • a fundamental treatment based on the primary cause of diseases is not possible yet.
  • 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.
  • histamine-immunoglobulin complex 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.
  • 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).
  • 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).
  • those clinical efficacies of placenta extract have rarely been proved with systematic clinical trials by multiple clinical investigators.
  • the biological mechanism responsible for a pharmaceutical efficacy of placenta extract has not been completely determined yet.
  • 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.
  • 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.
  • 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 .
  • placenta extract was used as a material containing multiple various human autoantigenic proteins for the autoantigen- specific immunotherapy.
  • placenta implantation implantation of refrigerated or frozen stored human placenta tissue into the subcutaneous tissue after incision of skin
  • ⁇ 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.
  • 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.
  • 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.
  • 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 .
  • the therapeutic pharmaceutical composition of the present invention comprising histamine, immunoglobulin, and placenta extract .
  • 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
  • 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.
  • the allergic diseases and chronic inflammatory diseases include atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, bronchial asthma, degenerative arthritis, and rheumatoid arthritis.
  • 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.
  • 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) .
  • 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical composition comprising histamine, immunoglobulin and placenta extract as active ingredients.
  • 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.
  • 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.
  • Immunoglobulin 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 , ⁇ , ⁇ , ⁇ , ⁇ .
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • placenta tissue from other mammals besides human 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a dosage of histamine can be 0.05 to 2.5//g, preferably 0.1 to l.O ⁇ g
  • a dosage of immunoglobulin can be 0.05 to 50mg, preferably 12 to 36mg as a protein amount
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 ⁇ g/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.
  • 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.
  • formulation 2-1 histamine-immunoglobulin complex
  • placenta extract the example of formulation 2-2
  • SDS-PAGE sodium dodecyl sulphate/polyacrylamide gel electrophoresis
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • placenta extract solution lastodian
  • histamine-immunoglobulin complex (1 vial)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • histamine-immunoglobulin complex the above example of formulation 2-1
  • placenta extract the above example of formulation 2-2
  • total 4ml total 4ml
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Group 2 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.
  • 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.
  • ⁇ 9i> 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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 ii ⁇ >
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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]
  • 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.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Reproductive Health (AREA)
  • Pregnancy & Childbirth (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant de l'histamine, de l'immunoglobuline et de l'extrait de placenta comme ingrédients actifs pour le traitement de maladies allergiques et de maladies inflammatoires chroniques. L'invention concerne également une utilisation de la composition précitée pour la fabrication d'un médicament destiné au traitement de maladies allergiques et de maladies inflammatoires chroniques. En outre, l'invention concerne un procédé de traitement de maladies allergiques et de maladies inflammatoires chroniques, procédé consistant à administrer la composition pharmaceutique précitée à un mammifère. Il en résulte que même les patients souffrant de maladies allergiques réfractaires et de maladies inflammatoires chroniques, qui ne peuvent être suffisamment améliorés par des traitements par thérapie pharmacologique standard, peuvent être efficacement améliorés si l'on applique le procédé de traitement utilisant la composition pharmacologique précitée conforme à l'invention.
PCT/KR2007/001251 2006-03-16 2007-03-14 Composition pharmaceutique pour le traitement de maladies allergiques et de maladies inflammatoires chroniques, et procédé de traitement de maladies allergiques et de maladies inflammatoires chroniques WO2007105910A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2009500292A JP2009530269A (ja) 2006-03-16 2007-03-14 アレルギー疾患及び慢性炎症性疾患の治療の為の薬学的組成物及びアレルギー疾患及び慢性炎症性疾患の治療方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR20060024143 2006-03-16
KR10-2006-0024143 2006-03-16
KR20060042449 2006-05-11
KR10-2006-0042449 2006-05-11
KR10-2007-0024402 2007-03-13
KR1020070024402A KR100756974B1 (ko) 2006-03-16 2007-03-13 알레르기 질환 및 만성염증성 질환의 치료를 위한 약학적 조성물 및 키트

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WO2007105910A1 true WO2007105910A1 (fr) 2007-09-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109475304A (zh) * 2016-07-14 2019-03-15 皇家飞利浦有限公司 用于监测哮喘症状的系统和方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3584117A (en) * 1967-11-07 1971-06-08 Minna Granirer Medicinal products from placenta tissue and processes of preparing same
WO2001001995A2 (fr) * 1999-07-06 2001-01-11 Nutricology, Inc. Methode de traitement de l'asthme

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3584117A (en) * 1967-11-07 1971-06-08 Minna Granirer Medicinal products from placenta tissue and processes of preparing same
WO2001001995A2 (fr) * 1999-07-06 2001-01-11 Nutricology, Inc. Methode de traitement de l'asthme

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AYOUB M. ET AL.: "Modulation of the Th1/Th2 bias by an immunoglobulin histamine complex in the ovalbumin allergy mouse model", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 3, 2003, pages 523 - 539 *
YOSHII H. ET AL.: "A complex of histamine/mouse gamma-globulin preferentially inhibits allergen-induced peritoneal accumulation of eosinophils, but not neutrohils, in mouse", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 100, no. 6, PART 1, December 1997 (1997-12-01), pages 809 - 816, XP000876581 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109475304A (zh) * 2016-07-14 2019-03-15 皇家飞利浦有限公司 用于监测哮喘症状的系统和方法

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