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Preparation of Polymer Conjugated Bilirubin Oxidase and Development of Therapeatic Method for Jaundice.

Research Project

Project/Area Number 63870032
Research Category

Grant-in-Aid for Developmental Scientific Research (B).

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionKumamoto University

Principal Investigator

MAEDA Hiroshi  Kumamoto Univ. Med. School. Dept. Microbiol., Professor, 医学部, 教授 (90004613)

Co-Investigator(Kenkyū-buntansha) KOJIMA Yuichiro  Kumamoto Univ. Med. School, Dept. Microbiol., Assist., 医学部, 助手 (50215258)
松村 保広  熊本大学, 医学部, 助手 (90209619)
井上 正康  熊本大学, 医学部, 助教授 (80040278)
佐々木 征治  天野製薬研究所, 主任研究員
小田 達也  熊本大学, 医学部, 講師 (60145307)
Project Period (FY) 1988 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1990: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1989: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1988: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsBilirubin / Jaundice / Kernicterus / Bilirubin oxidase / Polyethylene glycol conjugate / Fluminant hepatitis / Hepatitis / Liver function / 黄疽 / 肝硬変 / ポリエチレングリコ-ル結合型酵素 / 肝不全 / 新生児核黄疸 / 減黄療法 / ポリエチレングリコール結合型酵素製剤 / PEG結合酵素
Research Abstract

The clinical cause of jaundice is known to be due to elevated plasma level of bilirubin, and its removal is a critical factor. We have elucidated that bilirubin is toxic to even cells in culture in that it suppress DNA, RNA and protein syntheses and membrane transport. A microbial enzyme called bilirubin oxidase can detoxify all these toxic effects. The degradation products of bilirubin by this enzyme were found to be excreted from the kidney, thus, transhepatic elimination is not required for detoxification. Polymer conjugated bilirubin oxidase does the same job as expected in vitro. When rats were artificially made jaundice by ligating and cutting the bile duct and then, they were treated with polymer-conjugated bilirubin oxidase by intravenous (i. v.) injection. The result was that the polymer conjugate exhibited a pronounced reduction in the plasma bilirubin level to the normal upto 48hr after injection, whereas the native oxidase did so only a little at 30 min post injection only. Furthermore immunological problems associated with injection with native bilirubin oxidase was removed more than 95% in the polymer conjugated one. There was little toxicity observed upon i. v. injection of this polymer-enzyme conjugate at the therapeutic dose. Thus, its clinical application appears feasible.

Report

(4 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • 1988 Annual Research Report
  • Research Products

    (55 results)

All Other

All Publications (55 results)

  • [Publications] H.Maeda,T.Oda,Y.Natsumura and M.Kimura: "Improvement of pharmacological properties of proteinーdrugs by tailoring with synthetic polymers." J.Bioactive and Compatible polymers. 3. 27-43 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] M.Kimura,Y.Matsumura,Y.Miyauchi and H.Maeda: "A new tactic for the treatment of jaundice:An injectable polymerーconjugated bilirubin oxidase." proc.Soc.Exp.Biol.Med.188. 364-369 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩: "制癌性物質の化学修飾による効果の向上 ー高分子化制癌剤ー" 蛋白質・核酸・酵素. 33. 211-216 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩: "タンパク性医薬とプロテインテ-ライング 「創薬のための分子設計」" 化学増刊. 116. 41-54 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] H.Maeda Y.Matsumura: "Tumoritropic and Iymphotropic principles of macromolecular drugs." Critical Reviews in Therapeutic Drug Carrier Systems. 6. 193-210 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] M.Kimura,Y.Matsumura,T.Konno,Y.Miyauchi and H.Maeda: "Enzymatic removal bilirubin toxicity by bilirubin oxidase in vitro and excretion or degradation products in vivo." Proc.Soc.Biol.Med.195. 64-69 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩: "細菌性プロテア-ゼの病原性ー分子レベルにおける多面的病因作用機構ー(総説)" 生化学. 63. 14-21 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 小嶋 祐一,前田 浩: "SODの高分子化学修飾とその薬理動態" 治寮. 73. 47-56 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 鎌田 龍二,宮川 真一,岡村 良一,前田 浩: "難治性周辺部角膜潰瘍に対する蛋白分解酵素阻害剤オボマクログロブリンの点眼治寮効果" 臨床眼科. (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 稲田 祐二,前田 浩: "続タンパク質ハイブリッド これからの化学修飾:ハイブリッド型酵素医薬" 共立出版, (274)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] T.Oda,T.Akaike,T.Hirano and H.Maeda(eds.O.Hayaishi,E.Niki,M.Kondo and T.Yoshikawa).: "Medical,Biochemical and Chemical Aspects of Free RAdicals" Elsevier Science, (747)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] K.Kitagawa,M.Matsumoto,T.Oda,H.Maeda,N.Handa,R.Fukunaga,K.Kimura and T.Kamada: "Medical,Biochemical and Chemical Aspects of Free Radicals." Elsevier Science, (665)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩,赤池 孝章: "Cu,ZuーSOD構造,機能と治寮への試み,2.ウイルス感染における病因論としての活性酸素系と持続型SODによるその治寮.谷口直之編 「SODの新知見」" メディカルトリビュ-ン社, (146)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩,宮本 洋一: "DDSの開発及び実用化の現状と問題点,4.高分子医薬品と油性化製剤の特微と問題点,嘉 悦勲 編「DDS 技術の進歩」" (社)日本工業技術振興協会, (232)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 前田 浩,赤池 孝章: "呼吸器疾患と活性酸素,ウイルス性肺炎における活性酸素の関与.井上正康編 「活性酸素の病態と疾患」" 学会出版センタ-,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] H.Maeda,M.Kimura,I.Sasaki,Y.Hirose and T.Konno: "Biochemical Application of PEC Chemistry.(M.Harris ed.)" Plenum Pub.Corp.,N.Y.,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] H.Maeda: "A Comprehensive Guide to Medical and Pharmaceutical Applications.(ed.M.Szycher)." Technomic Pub.Co.Inc.Lancaster,P.A.,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hiroshi Maeda: "Improvement of pharmacological properties of protein-drugs by tailoring with synthetic polymers." J. Bioactive and Compatible Polymers. 3. 27-43 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Masami kimura: "A new tactic for the treatment of jaundice : An injectable polymer conjugated bilirubin oxidase." Proc. Soc. Exp. Biol. Med.188. 364-369 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hiroshi Maeda: "Tumoritropic and lymphotropic principles of macromolecular drugs." Critical Rev. in Therapeutic Drug Carrier Systems. 6. 193-210 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Masami Kimura: "Enzymatic removal of bilirubin toxicity by bilirubin oxidase in vitro and excretion of degradation products in vivo." Proc. Soc. Exp. Biol. Med.195. 64-69 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tatsuya Oda: "Therapeutic effect of pyran-copolymer conjugated SOD on the mouse influenza virus infection. (eds. O. Hayaishi, E. Niki, M. Kondo and T. Yoshikawa.)" Elsevier Science Publishers. 747-750 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kazuo Kitagawa: "Protective effect of pyran-conjugated superoxide dismutase on experimental cerebral ischemia. (eds. O. Hayaishi, E. Niki, M. Kondo and T. Yoshikawa.)" Elsevier Science Publishers. 655-658 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hiroshi Maeda: Technomic Pub. Corp.Protein drugs tailored with synthetic polymers, Enhanced plasma-half-life and efficient delivery to tumor and inflammatory sites. (ed. M. Szycher)., (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hiroshi Maeda: Plenum. Pub. Corp.,. Toxicity of bilirubin and detoxification by PEG-bilirubin oxidase conjugate : A new tactic for treatment of jaundice. (M. Harris ed.), (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] H.Maeda,T.Oda,Y.Matsumura and M.Kimura: "Improvement of pharmacological properties of proteinーdrugs by tailoring with synthetic polymers." J.Bioactive and Compatible Polymers. 3. 27-43 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] M.Kimura,Y.Matsumura,Y.Miyauchi and H.Maeda: "A new tactic for the treatment of jaundice:An injectable polymerーconjugated bilirubin oxidase." Proc.Soc.Exp.Biol.Med.188. 364-369 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩: "制癌性物質の化学修飾による効果の向上ー高分子化制癌剤ー" 蛋白質・核酸・酵素. 33. 211-216 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩: "タンパク性医薬とプロテインテ-ライング「創薬のための分子設計」" 化学増刊. 116. 41-54 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] H.Maeda and Y.Matsumura: "Tumoritropic and lymphotropic principles of macromolecular drugs." Critical Reviews in Therapeutic Drug Carrier Systems. 6. 193-210 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] M.Kimura,Y.Matsumura,T.Konno,Y.Miyauchi and H.Maeda: "Enzymatic removal of bilirubin toxicity by bilirubin oxidase in vitro and excretion of degradation products in vivo." Proc.Soc.Exp.Biol.Med.195. 64-69 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩: "細菌性プロテア-ゼの病原性ー分子レベルにおける多面的病因作用機構ー(総説)" 生化学. 63. 14-21 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 小嶋 祐一郎,前田 浩: "SODの高分子化学修飾とその薬理動態" 治療. 73. 47-56 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 鎌田 龍二,宮川 真一,岡村 良一,前田 浩: "難治性周辺部角膜潰瘍に対する蛋白分解酵素阻害剤オボマクログロブリンの点眼治療効果" 臨床眼科. (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 稲田 祐二,前田 浩: "続タンパク質ハイブリッド これからの化学修飾;ハイブリッド型酵素医薬" 共立出版, 274 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Oda,T.Akaike,T.Hirano and H.Maeda (eds.O.Hayaishi,E.Niki,M.Kondo and T.Yoshikawa).: "Medical,Biochemical and Chemical Aspects of Free Radicals" Elsevier Science, 747 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] K.Kitagawa,M.Matsumoto,T.Oda,H.Maeda,N.Handa,R.Fukunaga,K.Kimura and T.Kamada: "Medical,Biochemical and Chemical Aspects of Free Radicals." Elsevier Science, 665 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩,赤池 孝章: "Cu,ZnーSODの構造,機能と治療への試み,2.ウイルス感染における病因論としての活性酸素系と持続型SODによるその治療.谷口直之編「SODの新知見」" メディカルトリビュ-ン社, 146 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩,宮本 洋一: "DDSの開発及び実用化の現状と問題点,4.高分子医薬品と油性化製剤の特徴と問題点.嘉 悦勲編「DDS技術の進歩」" (社)日本工業技術振興協会, 232 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 前田 浩,赤池 孝章: "呼吸器疾患と活性酸素,ウイルス性肺炎における活性酸素の関与.井上正康編「活性酸素の病態と疾患」" 学会出版センタ-, (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] H.Maeda,M.Kimura,I.Sasaki,Y.Hirose and T.Konno: "Biochemical Application of PEG Chemistry.( M.Harris ed. )" Plenum Pub.Corp.,N.Y., in press (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] H.Maeda: "A Comprehensive Guide to Medical and Pharmaceutical Applications. ( ed.M.Szycher )." Technomic Pub.Co.Inc.Lancaster,P.A., in press (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.oda,T.Akaike,T.Hamamoto,F.Suzuki,T.Hirano and H.Maeda: "Involvement of activated Oxygen radicals in the Pathogenesis of influenza virus infection and theatment with tailor-made suberoxide dismutase" Scince. 244. 974-976 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] T.Akaike,M.Ando,T.Oda T.Doi,S.Ijiri,S.Araki and H.Maeda: "Dependence on O^-_2 generation by xanthine oxidase of pathogenesis of influenza virus infection in mice" J.Clin.Invest. 85. (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] H.Maeda and T.Akaike: "Oxygen radicals in infections diseases." Bioessays. (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] T.Oda,Y.Kojima,T.Akaike S.Ijiri,A.Molla and H.Maeda: "Inactivation of Chemotactic activity of C5a by serratial 56K Protease" Infec.Immun.59. (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] M.Kimura,Y.Matsumura,T.Konno,Y.Miyauchi and H.Maeda: "Enzymatic removal of bilirubin toxicity against neural cells by bilirubin oxidase in vitro and excretion of the degradation products in vivo." Proc.Soc.Exc.Med,Biol.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] 前田浩: "タンパク性医薬とプロテインテ-ラリング" 科学同人科学増刊:「創薬のための分子設計」. 116. 41-54 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] H.Maeda: "High Performace Biomaterials;A Comprehensive guide to medical and Pharmaceutical applications." Technomic Pub.Co,INC.Lancaster,PA,U.S.A, (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] M.Kimura;Y.Matsumura;Y.Miyauchi;H.Maeda: Proc.Soc.Exp.Biol.Med.188. 364-369 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] H.Maeda;T.Oda;Y.Matsumura;M.Kimura: J.Bioactive Compatible Polymers. 3. 27-43 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 木村正美,松村保広,今野俊光,前田浩,宮内好正: 日本外科学会雑誌第88回日本外科学会総会号. 臨時増巻. 229 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 前田浩: バイオインダストリー. 5. 499-505 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 稲田祐二,前田浩: "蛋白質ハイブリッド" 共立出版, 274 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 前田浩,松村保広,小田達也,佐々木一美: "食品・医薬品分野における蛋白質テーラリング" 学会出版センター, 318 (1988)

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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