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Basic study of novel adrenomedullin derivatives to develop as a pharmaceutical drug of cardiovascular diseases

Research Project

Project/Area Number 18H02810
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionUniversity of Miyazaki

Principal Investigator

KITAMURA KAZUO  宮崎大学, 医学部, 教授 (50204912)

Co-Investigator(Kenkyū-buntansha) 山崎 基生  宮崎大学, 医学部, 特任教授 (30796983)
永田 さやか  宮崎大学, 医学部, 助教 (00452920)
鶴田 敏博  宮崎大学, 医学部, 准教授 (10389570)
加藤 丈司  宮崎大学, フロンティア科学総合研究センター, 教授 (20274780)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsアドレノメデュリン(AM) / PEG化AM / AM誘導体 / 高血圧症 / 心不全 / 脳血管性認知症 / AM受容体 / cAMP / 非臨床試験 / cAMP
Outline of Final Research Achievements

Adrenomedullin (AM) is a possible drug for cardiovascular disorders. We have developed a PEGylated AM derivative (PEG-AM) for clinical application because AM has a short half-life in the blood. We assessed the in vitro and in vivo activities of PEG-AM. The PEG-AM activated the AM receptors, in the similar manner to those of native AM, and the addition of PEG did not influence the receptor selectivity. The acute hypotensive effect of PEG-AM was much weaker than AM after bolus injection in rats. However, single subcutaneous injection of PEG-AM inhibited blood pressure increase in spontaneously hypertensive rats which were loaded with high salt diet. In four-vessel occlusion model rats, which exhibit vascular dementia, a single subcutaneous injection of PEG-AM reduced the escape latency in the hidden platform test. PEG-AM is a possible candidate compound for the treatment of cardiovascular diseases.

Academic Significance and Societal Importance of the Research Achievements

アドレノメデュリン(AM)はわが国で発見された重要な生理活性ペプチドであり、循環器疾患治療薬として有望である。しかし、ペプチドであるため半減期が短く、経静脈持続投与が必要なため利便性が悪い。本研究では研究代表者が発明したPEG化AMの循環器疾患治療薬としての基礎的研究を行った。PEG化AMが慢性心不全・難治性高血圧や脳血管性認知症の治療薬として有望であることが明らかになった。PEG化AMが将来循環器疾患の治療薬として実用化されれば、高齢化社会でさらに増加する循環器疾患の制圧にもつながり、医学の発展ばかりでなく医療の発展にも貢献できるため社会的な意義も大きい。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (18 results)

All 2021 2020 2019 2018

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 5 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Development of a novel human adrenomedullin derivative: human serum albumin-conjugated adrenomedullin2021

    • Author(s)
      Kuroishi Nobuko、Nagata Sayaka、Akashi Emiko、Ashizuka Shinya、Kato Johji、Yamasaki Motoo、Kitamura Kazuo
    • Journal Title

      The Journal of Biochemistry

      Volume: 26(5) Issue: 4 Pages: 479-484

    • DOI

      10.1093/jb/mvab057

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial.2021

    • Author(s)
      Kita T, Ashizuka S, Ohmiya N, Yamamoto T, Kanai T, Motoya S, Hirai F, Nakase H, Moriyama T, Nakamura M, Suzuki Y, Kanmura S, Kobayashi T, Ohi H, Nozaki R, Mitsuyama K, Yamamoto S, Inatsu H, Watanabe K, Hibi T, Kitamura K.
    • Journal Title

      J Gastroenterol

      Volume: 56 Issue: 2 Pages: 147-157

    • DOI

      10.1007/s00535-020-01741-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a novel AlphaLISA ImmunoAssay for Big angiotensin‐252020

    • Author(s)
      Nagata Sayaka、Fukuda Akihiro、Kikuchi Masao、Sato Yuji、Nagatomo Masanao、Aburaya Junko、Fujimoto Shouichi、Kitamura Kazuo
    • Journal Title

      Nephrology

      Volume: 26 Issue: 5 Pages: 479-484

    • DOI

      10.1111/nep.13845

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thrombin rapidly digests adrenomedullin: Synthesis of adrenomedullin analogs resistant to thrombin2020

    • Author(s)
      Nishimoto Yayoi、Nagata Sayaka、Akashi Emiko、Yamasaki Motoo、Kitamura Kazuo
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 529 Issue: 3 Pages: 778-783

    • DOI

      10.1016/j.bbrc.2020.06.057

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase I Clinical Trial2020

    • Author(s)
      T. Kita, T. Kaji, K. Kitamura
    • Journal Title

      Drug Design, Development and Therapy

      Volume: 14 Pages: 1-11

    • DOI

      10.2147/dddt.s225220

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adrenomedullin: A Novel Therapy for Intractable Crohn's Disease with a Loss of Response to Infliximab2019

    • Author(s)
      Ashizuka Shinya、Kuroishi Nobuko、Nakashima Koji、Inatsu Haruhiko、Kita Toshihiro、Kitamura Kazuo
    • Journal Title

      Internal Medicine

      Volume: 58 Issue: 11 Pages: 1573-1576

    • DOI

      10.2169/internalmedicine.1791-18

    • NAID

      130007658128

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2019-06-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Polyethylene glycol-conjugated human adrenomedullin as a possible treatment for vascular dementia.2019

    • Author(s)
      Nagata S, Yamasaki M, Kitamura K
    • Journal Title

      Peptides

      Volume: 121 Pages: 170133-170133

    • DOI

      10.1016/j.peptides.2019.170133

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Developments of human adrenomedullin-IgG1 Fc fusion proteins. J2019

    • Author(s)
      Nagata S, Yamasaki M, Kawano A, Kitamura K
    • Journal Title

      Biochem

      Volume: 78 Issue: 2 Pages: 129-134

    • DOI

      10.1093/jb/mvz023

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adrenomedullin: Continuing to explore cardioprotection.2018

    • Author(s)
      Tsuruda T, Kato J, Kuwasako K, Kitamura K
    • Journal Title

      Peptides

      Volume: in press Pages: 47-54

    • DOI

      10.1016/j.peptides.2018.03.012

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis2018

    • Author(s)
      Kinoshita Yuta、Arita Seiya、Murazoe Haruka、Kitamura Kazuo、Ashizuka Shinya、Inagaki-Ohara Kyoko
    • Journal Title

      Human Cell

      Volume: 32 Issue: 1 Pages: 12-21

    • DOI

      10.1007/s13577-018-0219-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] ヒトIgGのFc領域を融合したアドレノメデュリン誘導体の開発2020

    • Author(s)
      永田さやか、山﨑基生、北村和雄
    • Organizer
      第93回日本内分泌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ヒトIgGのFc領域を融合したAM誘導体の創製.Cardiovascular Translational Research Conference2020

    • Author(s)
      永田さやか、山﨑基生、北村和雄
    • Organizer
      第16回学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] C3腎症をターゲットとしたアドレノメデュリン誘導体の開発2020

    • Author(s)
      永田さやか、山﨑基生、北村和雄
    • Organizer
      第11回ペプチド・ホルモン研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] PEG化アドレノメデュリンの受容体に対する反応性の評価2020

    • Author(s)
      明石絵美子、永田さやか、山﨑基生、北村和雄
    • Organizer
      第11回ペプチド・ホルモン研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アドレノメデュリン(AM)とAM誘導体の新規降圧薬としての可能性2019

    • Author(s)
      北村和雄、永田さやか、北俊弘、加藤丈司
    • Organizer
      第42回日本高血圧学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Update in Cardiovascular and Hypothalamic Peptides2019

    • Author(s)
      北村和雄
    • Organizer
      第5回国際神経ペプチド学会日本支部シンポジウム
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Adrenomedullin (AM) and PEG-AM as a Potential therapeutic agent for inflammatory bowel diseases.2018

    • Author(s)
      Kitamura K, Shinjo H, Yamasaki M.
    • Organizer
      BIO 2018 International Convention Company Presentation.
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規アドレノメデュリン類縁体、その製造方法及びその医薬用途2020

    • Inventor(s)
      北村和雄
    • Industrial Property Rights Holder
      北村和雄
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-066608
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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