WO2002080973A1 - Composition pouvant etre utilisee pour le traitement d'un tissu dur de mammifere et methode therapeutique correspondante - Google Patents

Composition pouvant etre utilisee pour le traitement d'un tissu dur de mammifere et methode therapeutique correspondante Download PDF

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Publication number
WO2002080973A1
WO2002080973A1 PCT/JP2002/003348 JP0203348W WO02080973A1 WO 2002080973 A1 WO2002080973 A1 WO 2002080973A1 JP 0203348 W JP0203348 W JP 0203348W WO 02080973 A1 WO02080973 A1 WO 02080973A1
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WO
WIPO (PCT)
Prior art keywords
canine
bone
group
hard tissue
interferon
Prior art date
Application number
PCT/JP2002/003348
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English (en)
Japanese (ja)
Inventor
Masato Kuwabara
Masayoshi Yukawa
Original Assignee
Nihon University School Juridical Person
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nihon University School Juridical Person filed Critical Nihon University School Juridical Person
Publication of WO2002080973A1 publication Critical patent/WO2002080973A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • composition for treating mammalian hard tissue and method for treating the same
  • the present invention relates to a composition for treating hard tissue in mammals and a method for treating the same, and more particularly to a composition for treating hard tissue in animals, including a composition for treating joint disease, and a method for treating the same.
  • pannus granuloma-like tissue under the synovium
  • QOL quality of life
  • Rheumatoid arthritis in humans is a chronic inflammatory disease mainly associated with synovial inflammation of the joints and accompanied by a more or less diverse systemic symptom, together with the pathology of progressive osteoarthritis.
  • the histopathological image of a joint lesion in rheumatoid arthritis is composed of villous proliferation of the synovium of the pannus, neovascularization, infiltration of plasma cells of lymphocytes, cartilage and bone destruction by the pannus, and gradually cartilage. And absorb bone.
  • Human topa It has been reported that the presence of Nunnus can be diagnosed by MRI (supervised by Kazuo Sugimura: MRI of bone and soft tissue, Medical View, 67-68 (2000)).
  • Pharmacotherapy has been used as a treatment method for human rheumatoid arthritis.
  • Analgesic for pain Prescription of acidic non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory action, but only symptomatic treatment, multiple prescriptions may lead to more side effects than to enhancement There is also.
  • NSAID non-steroidal anti-inflammatory drug
  • an object of the present invention is to solve the above-mentioned problems of the prior art, and to provide a therapeutic composition and a method for treating a bone lesion effective for rheumatoid arthritis, a disease in animal hard tissue. .
  • canine chronic joint disease is a disease related to bone resorption and bone formation. Reached.
  • the “animal” used in the present application means an animal subject to veterinary medicine.
  • composition comprising a hard tissue absorption inhibitor and a hard tissue formation inhibitor.
  • the mammalian hard tissue is a bone or a tooth.
  • the mammal is a veterinary animal It is characterized by.
  • the mammal is a dog.
  • a method for treating mammalian hard tissue which comprises administering a hard tissue absorption inhibitor and a hard tissue formation inhibitor.
  • the hard tissue of the mammal is a bone or a tooth.
  • the mammal is a veterinary animal.
  • the mammal is a dog.
  • composition for treating a chronic joint disease of a dog comprising a bone resorption inhibitor and an osteogenesis inhibitor.
  • the composition comprises: internuferon as the bone resorption inhibitor; and an organic germanium compound as the bone formation inhibitor.
  • the canine interferon is canine interferon / ⁇ /.
  • the canine interferon is a recombinant interferon-T / described in SEQ ID NO: 1.
  • the organic germanium compound is represented by the following formula (1).
  • 1 1 to 1 3 is a hydrogen atom or the same or different methyl group, a lower alkyl group such as E methyl group, or an unsubstituted or substituted Fuyuniru group
  • X is a hydrogen group, O- lower alkyl group
  • Y represents a salt represented by OY, wherein Y represents a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid.
  • 11 to 1 to 3 are hydrogen atoms and X is a hydroxyl group, and is an organic germanium compound.
  • the method is achieved by a method for treating chronic joint disease in dogs, which comprises administering a bone resorption inhibitor and a bone formation inhibitor.
  • inuinterfuron as the bone resorption inhibitor and an organic germanium compound as the bone formation inhibitor are administered.
  • the canine interferon is administered by injection into a joint cavity.
  • the canine interferon is administered to the dog at least once per 1 S to 0.8 to 2.0 million units / joint.
  • the canine interferon comprises at least It is also characterized by being administered to dogs 0.85 to 1.150,000 units / joint once a day.
  • the canine interferon is administered at least once a day to dogs in an amount of 0.9 to 11,000 units / joint.
  • the ininterferon is canine interferon- ⁇ described in SEQ ID NO: 1.
  • the canine interferon-1 ⁇ is a recombinant interferon-1y.
  • the organogermanium compound is orally administered.
  • the organic germanium compound is represented by the following formula (1).
  • R 1 to R 3 are a hydrogen atom or a lower alkyl group such as the same or different methyl group or ethyl group, or an unsubstituted or substituted fuunyl group;
  • X is a hydrogen group, an O-lower alkyl group, an amino group, or OY
  • Y represents a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid.
  • scale 1 to scale 3 water It is characterized in that the element is an organic germanium compound in which X is a hydroxyl group.
  • the organogermanium compound is orally administered at least once a day at a power of 10 mg / kg per body weight, or 100 mg / kg.
  • the organogermanium compound is orally administered at least once a day at a dose of 20 mg / kg to 80 mg / kg of body weight.
  • the organogermanium compound is orally administered at least once a day at a dose of 30 mg / kg to 75 mgZkg per body weight.
  • a preferred embodiment of the present invention is characterized by comprising a second monitoring step of monitoring a serum bone type alkaline phosphatase value as a bone formation marker and a urinary deoxypyridinoline value as a bone resorption marker.
  • the serum bone type al lipophosphatase value is at least 17% (MSC) at the start of administration (MSC) (abbreviation of minimum significant change, and is an index of a significant minimum change; MS C ”).
  • the urinary deoxypyridinoline level is reduced by at least 22.5% (MSC) at the start of administration.
  • a therapeutic composition comprising canine interferon- ⁇ as a bone resorption inhibitor and an organic germanium compound as an osteogenesis inhibitor is effective for treating rheumatoid arthritis in dogs. It is.
  • the effect of the present invention is that canine interferon-gamma is injected into a joint, and an organic germanium compound is orally administered, and also used in combination, effectively improves rheumatoid arthritis in dogs.
  • dog includes a canine family, and specifically refers to a family that includes a canine, a cocote, an okami, and a fox.
  • FIG. 1 is a diagram showing the results of changes over time in bone metabolic markers and C-reactive protein in Example 1 of the present invention, wherein ( ⁇ ) shows serum CRA values, and ( ⁇ ) shows serum levels. (C) shows the change in urinary DPD value.
  • FIG. 2 is a diagram showing the results of changes over time in bone metabolic markers and C-reactive protein in Example 2 of the present invention, wherein (A) shows serum CRA value, (B) shows serum BAP value, (C) shows the change in urinary DPD value.
  • A shows serum CRA value
  • B shows serum BAP value
  • C shows the change in urinary DPD value.
  • the present inventors have focused on bone lesions in rheumatoid arthritis, which is one of the chronic joint diseases in dogs.
  • the present invention is based on the finding that the treatment of rheumatism must suppress not only bone resorption but also concurrent bone formation. In other words, bone resorption and bone formation are progressing simultaneously in rheumatoid arthritis, and it is considered that rheumatoid arthritis cannot be cured without suppressing both.
  • Bone is a typical example of hard tissue, but bone resorption inhibitors include interferon, disodium fumidronate, alendronate, and dalcosamine. And chondroitin sulfate are known.
  • the bone formation inhibitor include organic germanium compounds; dexamethasone sodium phosphate; dexamethasone; dexamethasone V-xyl; dexamethasone acetate; And the like.
  • One active ingredient of the therapeutic composition for canine chronic joint disease according to the present invention is preferably V-type, and in particular, canine interferon- ⁇ is effective.
  • V-type canine interferon- ⁇
  • the recombinant type was produced by the method described in JP-A-9-123485.
  • a canine interferon having an amino acid sequence represented by SEQ ID NO: 1 is known, and in the present invention, a particularly favorable therapeutic effect can be obtained.
  • the interferon used in the present invention is administered by injection into a dog joint. Where to administer it, it is preferable to administer it in the joint where Pannus will break down. As observed in human chronic joint diseases, the presence of the pannus can be confirmed by the MRI method according to a known method.
  • the dose of dog interferon is 10,000 units per dog joint. 20,000 units Intra-Z joint administration induces cytokines as a side effect.
  • an organic germanium compound is another active ingredient of the composition for canine chronic joint disease of the present invention.
  • the organic germanium compound include a compound represented by the following formula (1).
  • R 3 is a hydrogen atom or a lower alkyl group such as the same or different methyl group or ethyl group, or an unsubstituted or substituted phenyl group is a hydrogen group, an O-lower alkyl group, an amino group or OY.
  • Y represents a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid.
  • organic germanium compound used in the present invention include the following.
  • a method for treating canine chronic joint disease comprises administering a composition comprising canine interferon and an organogermanium compound.
  • the present invention is based on the finding that canine rheumatoid arthritis is a disease in which bone resorption and bone formation are related.
  • the present invention also provides a method for treating rheumatoid arthritis, which suppresses both processes.
  • the bone metabolic markers include serum bone type alkaline phosphatase (hereinafter referred to as “BAPj”) as a bone formation marker and urinary deoxypyridinoline (hereinafter “DPD”) as a bone resorption marker. ) Is known.
  • BAP is used as a bone formation marker
  • DPD is used as a bone resorption marker.
  • Healthy dogs that is, dogs without rheumatoid arthritis, have a normal BAP value of 11.7 uZ1 or less and a normal DPD value of 5.6 to 2.1 nM / mMCr. These values were used as a reference value and used as a scale for rheumatoid arthritis.
  • CRP C-reactive protein
  • Changes in each bone metabolic marker for the treatment of rheumatoid arthritis in dogs are determined by monitoring serum BAP and urinary DPD, as well as CRP levels. be able to.
  • the CRP value is improved after the start of administration, and thereafter, the serum BAP value is reduced by at least 17% (MSC), or the urinary DPD value is reduced. Drop by 22.5% (MS C) It has been found that Setsu Ryumachi is heading for the better.
  • Case 1 showed Canine RA (hereinafter referred to as “CRA”) grade III (X-ray findings based on the clinical staging of rheumatoid arthritis). And destruction of bones are observed).
  • the organic germanium compound Ge 132 manufactured by biremo f was orally administered once a day at 50 mg / kg per dog body weight.
  • the serum CRP value once increased slightly, but the serum CRP value and BAP value decreased.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pouvant être utilisée pour le traitement d'un tissu dur de mammifère, laquelle composition présente la particularité de comprendre un agent inhibiteur destiné à la résorption du tissu dur et un agent inhibiteur destiné à la formation du tissu dur. L'invention concerne également une méthode thérapeutique consistant à administrer une composition destinée au traitement d'un tissu dur, laquelle composition comprend un agent inhibiteur destiné à la résorption du tissu dur et un agent inhibiteur destiné à la formation du tissu dur. La composition et la méthode thérapeutique susmentionnées conviennent tout particulièrement au traitement d'un tissu dur de mammifère.
PCT/JP2002/003348 2001-04-03 2002-04-03 Composition pouvant etre utilisee pour le traitement d'un tissu dur de mammifere et methode therapeutique correspondante WO2002080973A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2001104886 2001-04-03
JP2001-104886 2001-04-03
JP2001223538A JP2003002845A (ja) 2001-04-03 2001-07-24 哺乳類の硬組織治療用組成物及びその治療方法
JP2001-223538 2001-07-24

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WO2002080973A1 true WO2002080973A1 (fr) 2002-10-17

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4523762B2 (ja) * 2003-06-11 2010-08-11 学校法人日本大学 腫瘤形成抑制方法
CN108486127A (zh) * 2018-01-12 2018-09-04 中国农业科学院北京畜牧兽医研究所 犬干扰素-α6α7重组蛋白及其制备方法与应用
CN108424915A (zh) * 2018-01-12 2018-08-21 中国农业科学院北京畜牧兽医研究所 犬干扰素-α2重组蛋白的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4921697A (en) * 1985-05-30 1990-05-01 Boehringer Ingelheim International Gmbh IFN-gamma as an active substance for inhibiting and preventing degradation processes in bone
WO1994014842A1 (fr) * 1992-12-22 1994-07-07 The Procter & Gamble Company Derive de difluoro pentapeptide utile commes agent anti-inflammatoire
WO1995008115A1 (fr) * 1993-09-17 1995-03-23 Osteometer Biotech As Procede de dosage de fragments de collagene dans les liquides biologiques, materiel de test et moyens pour appliquer ce procede, et utilisation de ce procede pour diagnostiquer des troubles associes au metabolisme de collagene
JPH0892083A (ja) * 1994-09-27 1996-04-09 Asai Gerumaniumu Kenkyusho:Kk 破骨細胞による骨吸収活性抑制剤
JPH1192377A (ja) * 1997-09-18 1999-04-06 Nippon Boehringer Ingelheim Co Ltd 免疫調節用医薬組成物
JP2000136139A (ja) * 1998-10-30 2000-05-16 Sanwa Kagaku Kenkyusho Co Ltd 有機ゲルマニウム化合物を有効成分とするｍｃｐ−１受容体拮抗剤、及びｍｃｐ−１が関与する炎症性疾患及び臓器障害の発症予防または治療剤
JP2000316585A (ja) * 1998-06-09 2000-11-21 Toray Ind Inc イヌインターフェロン−γ変異体、インターフェロン−γの製造法、イヌの難治性皮膚炎治療剤および治療方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4921697A (en) * 1985-05-30 1990-05-01 Boehringer Ingelheim International Gmbh IFN-gamma as an active substance for inhibiting and preventing degradation processes in bone
WO1994014842A1 (fr) * 1992-12-22 1994-07-07 The Procter & Gamble Company Derive de difluoro pentapeptide utile commes agent anti-inflammatoire
WO1995008115A1 (fr) * 1993-09-17 1995-03-23 Osteometer Biotech As Procede de dosage de fragments de collagene dans les liquides biologiques, materiel de test et moyens pour appliquer ce procede, et utilisation de ce procede pour diagnostiquer des troubles associes au metabolisme de collagene
JPH0892083A (ja) * 1994-09-27 1996-04-09 Asai Gerumaniumu Kenkyusho:Kk 破骨細胞による骨吸収活性抑制剤
JPH1192377A (ja) * 1997-09-18 1999-04-06 Nippon Boehringer Ingelheim Co Ltd 免疫調節用医薬組成物
JP2000316585A (ja) * 1998-06-09 2000-11-21 Toray Ind Inc イヌインターフェロン−γ変異体、インターフェロン−γの製造法、イヌの難治性皮膚炎治療剤および治療方法
JP2000136139A (ja) * 1998-10-30 2000-05-16 Sanwa Kagaku Kenkyusho Co Ltd 有機ゲルマニウム化合物を有効成分とするｍｃｐ−１受容体拮抗剤、及びｍｃｐ−１が関与する炎症性疾患及び臓器障害の発症予防または治療剤

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