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The foundation of developing drugs for retinal diseases by pharmaceutical drug-repositioning screening based on the distribution manner via the blood-retinal barrier

Research Project

Project/Area Number 16H05110
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionUniversity of Toyama

Principal Investigator

Hosoya Ken-ichi  富山大学, 大学院医学薬学研究部(薬学), 教授 (70301033)

Co-Investigator(Kenkyū-buntansha) 赤沼 伸乙  富山大学, 大学院医学薬学研究部(薬学), 助教 (30467089)
Research Collaborator MATSUYA Yuji  
ABE Hajime  
ANDO Tsugunobu  
KUBO Yoshiyuki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords血液網膜関門 / カチオン性薬物輸送 / 薬物輸送担体 / 内側血液網膜関門 / ドラッグリポジショニング / 網膜毛細血管内皮細胞 / カチオン性薬物輸送機構 / スクリーニング / 網膜疾患
Outline of Final Research Achievements

The purpose of this study was to establish the foundation of retinal drug discovery based on the cationic drug transport systems at the blood-retinal barrier. To evaluate the transport of drugs as candidates for the use of retinal diseases, the labeling reaction of cyanocobalamin, a model compound, with a fluorescent substrate was tested. Since receptor-mediated transcytosis manner of fluorescent cyanocobalamin was observed, it is indicated that the optimization of this labeling reaction with a fluorescent substrate is completed. Through the pharmaceutical drug-repositioning screening, several kinds of candidates for the treatment of retinal diseases were discovered. We continue to perform the pharmacological and pharmaceutical studies to judge whether these drugs could be applied for the retinal diseases.

Academic Significance and Societal Importance of the Research Achievements

ヒット薬物について、本報告書提出時点にて追加での薬理学的・薬物動態学的な評価を継続している。本評価が完了することで、革新的な網膜疾患治療薬が世に出るものと期待される。また、その薬物について治療標的を発見するための実験系構築に向けた各種検討結果も成果として挙げており、今後の創薬に向けた基礎の一部を本課題は築いたと言える。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (41 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 5 results) Presentation (28 results) (of which Int'l Joint Research: 11 results,  Invited: 4 results) Remarks (1 results)

  • [Int'l Joint Research] University of Kentucky(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Organic anion-transporting polypeptide 1a4–mediated heterogeneous distribution of sulforhodamine-101 in rat hepatic lobules2019

    • Author(s)
      Akanuma S、Kida R、Tsuchiyama A、Tachikawa M、Kubo Y、Hosoya K
    • Journal Title

      Drug Metabolism and Pharmacokinetics

      Volume: 34 Issue: 4 Pages: 239

    • DOI

      10.1016/j.dmpk.2019.04.001

    • NAID

      50014558511

    • URL

      https://pure.teikyo.jp/en/publications/6668560e-6e37-427e-9657-241b72376233

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple Cellular Transport and Binding Processes of Unesterified Docosahexaenoic Acid in Outer Blood–Retinal Barrier Retinal Pigment Epithelial Cells2018

    • Author(s)
      Tachikawa M、Akanuma S、Imai T、Okayasu S、Tomohiro T、Hatanaka Y、Hosoya K
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 41 Issue: 9 Pages: 1384-1392

    • DOI

      10.1248/bpb.b18-00185

    • NAID

      130007479893

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2018-09-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recent advances in drug and nutrient transport across the blood-retinal barrier2018

    • Author(s)
      Kubo Y、Akanuma S、Hosoya K
    • Journal Title

      Expert Opinion on Drug Metabolism & Toxicology

      Volume: 14 Issue: 5 Pages: 513

    • DOI

      10.1080/17425255.2018.1472764

    • URL

      https://localhost/en/publications/6ae32164-8fc0-4a32-9da8-46b2cc8d7f80

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of L-type amino acid transporter 1 at the inner blood-retinal barrier in the Blood-to-Retina Transport of Gabapentin2018

    • Author(s)
      Akanuma Shin-ichi、Yamakoshi Atsuko、Sugouchi Takeshi、Kubo Yoshiyuki、Hartz Anika M. S.、Bauer Bjoern、Hosoya Ken-ichi
    • Journal Title

      Molecular Pharmaceutics

      Volume: 15 Issue: 6 Pages: 2327-2337

    • DOI

      10.1021/acs.molpharmaceut.8b00179

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Investigation of Receptor-Mediated Cyanocobalamin (Vitamin B <sub>12</sub> ) Transport across the Inner Blood-Retinal Barrier Using Fluorescence-Labeled Cyanocobalamin2018

    • Author(s)
      Kinoshita Yuri, Nogami Kagayaki, Jomura Ryuta, Akanuma Shin-ich, Abe Hajime, Inouye Masahiko, Kubo Yoshiyuki, Hosoya Ken-ichi.
    • Journal Title

      Molecular Pharmaceutics

      Volume: 15 Issue: 8 Pages: 3583

    • DOI

      10.1021/acs.molpharmaceut.8b00617

    • URL

      https://pure.teikyo.jp/en/publications/1c6d18fd-9db8-4219-ac4e-36bf445fdf59

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of cationic drug-sensitive transport systems at the blood-cerebrospinal fluid barrier in para-tyramine elimination from rat brain2018

    • Author(s)
      Akanuma S., Yamazaki Y., Kubo Y., Hosoya K.
    • Journal Title

      Fluids Barriers CNS

      Volume: 15 Issue: 1 Pages: 1

    • DOI

      10.1186/s12987-017-0087-9

    • URL

      https://localhost/en/publications/000629ff-58c1-449e-86fc-c28bb38a0e39

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression and function of connexin 43 protein in mouse and human retinal pigment epithelial cells as hemichannels and gap junction proteins2018

    • Author(s)
      Akanuma S., Higashi H., Maruyama S., Murakami K., Tachikawa M., Kubo Y., Hosoya K.
    • Journal Title

      Exp. Eye Res.

      Volume: 168 Pages: 128

    • DOI

      10.1016/j.exer.2018.01.016

    • URL

      https://localhost/en/publications/201cd638-6f83-4208-be82-8f3897eb5ac8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blood-to-Retina Transport of Fluorescence-Labeled Verapamil at the Blood-Retinal Barrier2018

    • Author(s)
      Kubo Yoshiyuki、Nakazawa Ayumi、Akanuma Shin-ichi、Hosoya Ken-ichi
    • Journal Title

      Pharmaceutical Research

      Volume: 35 Issue: 5 Pages: 93-93

    • DOI

      10.1007/s11095-018-2384-7

    • URL

      https://localhost/en/publications/46c3415f-18f9-4175-819b-a1f73fbc29a2

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Retina-to-Blood Transport of 1-Methyl-4-Phenylpyridinium Involves Carrier-Mediated Process at the Blood-Retinal Barrier2017

    • Author(s)
      Kubo Yoshiyuki、Yamamoto Masakazu、Matsunaga Kensuke、Usui Takuya、Akanuma Shin-ichi、Hosoya Ken-ichi
    • Journal Title

      Journal of Pharmaceutical Sciences

      Volume: 106 Issue: 9 Pages: 2583

    • DOI

      10.1016/j.xphs.2017.04.028

    • URL

      https://localhost/en/publications/41eb95dc-f65d-4013-a810-f56f4e116271

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants2017

    • Author(s)
      Kubo Yoshiyuki、Akanuma Shin-ichi、Hosoya Ken-ichi
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 8 Pages: 1139-1145

    • DOI

      10.1248/bpb.b17-00090

    • NAID

      130005876324

    • ISSN
      0918-6158, 1347-5215
    • URL

      https://localhost/en/publications/f01492df-d0b0-4df1-8648-178065e1a344

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood–Retinal Barrier and in the Liver2016

    • Author(s)
      Kubo Y, Akanuma S, Hosoya K
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 12 Pages: 1903-1911

    • DOI

      10.1248/bpb.b16-00597

    • NAID

      130005171493

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] ラット血液脳関門を介したimipramine輸送機構解明2019

    • Author(s)
      韓 明来、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 血液脳関門nicotineインフラックス輸送系への中枢神経系疾患治療薬認識性2018

    • Author(s)
      細谷 健一、山﨑 雄平、手賀 悠真、赤沼 伸乙、久保 義行
    • Organizer
      日本薬剤学会第33年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Expression and localization of creatine synthesizing enzyme and monocarboxylate transporter 12 in rat brain and retina2018

    • Author(s)
      Jomura R, Tanno Y, Akanuma S, Tachikawa M, Kubo Y, Hosoya K
    • Organizer
      The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characteristics of imipramine transport at the blood-brain barrier2018

    • Author(s)
      Han M, Akanuma S, Kubo Y, Hosoya K
    • Organizer
      The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Study of receptor-mediated cyanocobalamin (vitamin B12) transport at the blood-retinal barrier with Cy5-labeled cyanocobalamin2018

    • Author(s)
      Kubo Y, Kinoshita Y, Nogami K, Jomura R, Akanuma S, Abe H, Inouye M, Hosoya K
    • Organizer
      2018 International Meeting on 22nd MDO and 33rd JSSX
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Localization of monocarboxylate transporter 12 as a facilitative creatine transporter in rat choroid plexus and retinal pigment epithelium2018

    • Author(s)
      Jomura R, Tanno Y, Akanuma S, Tachikawa M, Kubo Y, Hosoya K
    • Organizer
      2018 International Meeting on 22nd MDO and 33rd JSSX
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血液脳関門におけるimipramine輸送特性解明2018

    • Author(s)
      韓 明来、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会北陸支部第130回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 血液脳関門モデル細胞におけるnicotine輸送に対する中枢神経系疾患治療薬の影響2018

    • Author(s)
      細谷 健一、山﨑 雄平、赤沼 伸乙、久保 義行
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ラット網膜色素上皮細胞におけるchloroquine過剰蓄積によるlysosome空胞化2018

    • Author(s)
      牧野 令奈、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 内側血液網膜関門カチオン性薬物輸送に対する酸性小胞内蓄積機構の寄与2018

    • Author(s)
      粉川 紗季、久保 義行、赤沼 伸乙、細谷 健一
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 内側血液網膜関門におけるcyanocobalamin輸送機構の解明2017

    • Author(s)
      木下 由梨、野上 暁生、阿部 肇、井上 将彦、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会第137年会 (仙台)
    • Place of Presentation
      仙台市 (宮城県)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] Involvement of lysosomal trapping in verapamil transport across the blood-retinal barrier2017

    • Author(s)
      Ken-ichi Hosoya, Ayumi Nakazawa, Shin-ichi Akanuma, Yoshiyuki Kubo
    • Organizer
      International Symposium on Drug Delivery and Pharmaceutical Sciences: Beyond the History
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2017-03-09
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 内側血液網膜関門を介したcyanocobalamin取り込み輸送機構2017

    • Author(s)
      久保 義行、木下 由梨、野上 暁生、阿部 肇、井上 将彦、赤沼 伸乙、細谷 健一
    • Organizer
      日本薬剤学会 第32年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 血液脳関門nicotine輸送と神経作用薬の相互作用2017

    • Author(s)
      細谷 健一、手賀 悠真、赤沼 伸乙、久保 義行
    • Organizer
      第39回生体膜と薬物の相互作用シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 網膜毛細血管内皮細胞における酸性小胞内蓄積機構とカチオン性薬物輸送への影響2017

    • Author(s)
      粉川 紗季、赤沼 伸乙、久保 義行、細谷 健一 網膜毛細血管内皮細胞における酸性小胞内蓄積機構
    • Organizer
      日本薬学会北陸支部 第129回例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 網膜色素上皮細胞におけるchloroquineのlysosomal trappingと細胞障害作用2017

    • Author(s)
      牧野 令奈、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会北陸支部 第129回例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 中枢神経系疾患治療薬とin vitro血液脳関門ニコチン輸送との相互作用2017

    • Author(s)
      赤沼 伸乙、山﨑 雄平、久保 義行、細谷 健一
    • Organizer
      日本薬物動態学会 第32回年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 血液脳脊髄液関門を介した脳からのヒスタミン排出輸送:形質膜モノアミントランスポーター (PMAT) の役割2016

    • Author(s)
      臼井 拓也、中沢 亜弓、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      第38回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      名古屋市 (愛知県)
    • Year and Date
      2016-11-17
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血液網膜関門verapamil輸送におけるlysosomal trappingの関与2016

    • Author(s)
      細谷 健一、中沢 亜弓、赤沼 伸乙、久保 義行
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本市 (長野県)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] The role of blood-retinal barrier transporters in retinal drug delivery2016

    • Author(s)
      Ken-ichi Hosoya, Shin-ichi Akanuma, Yoshiyuki Kubo
    • Organizer
      XXII Biennial Meeting of the International Society for Eye Research
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Implications of the carrier-mediated transport of nicotine in lung and other tissues.2016

    • Author(s)
      Ken-ichi Hosoya
    • Organizer
      Workshop on Drug Transporters in the Lungs, Trinity College Dublin
    • Place of Presentation
      Dublin, Ireland
    • Year and Date
      2016-09-22
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Histamine elimination from the cerebrospinal fluid: involvement of plasma membrane monoamine transporter at choroid plexus epithelial cells.2016

    • Author(s)
      Takuya Usui, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya
    • Organizer
      The First International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Place of Presentation
      Toyama, Japan
    • Year and Date
      2016-09-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional expression of nicotine influx transporter driven by an outward H+ gradient in rat blood-brain barrier and liver.2016

    • Author(s)
      Yuma Tega, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya
    • Organizer
      The First International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Place of Presentation
      Toyama, Japan
    • Year and Date
      2016-09-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microdialysis for evaluating the efflux transport of drugs across the blood-retinal barrier.2016

    • Author(s)
      Ken-ichi Hosoya
    • Organizer
      8th International Symposium on Microdialysis
    • Place of Presentation
      Uppsala, Sweden
    • Year and Date
      2016-05-25
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 眼組織のトランスポーター2016

    • Author(s)
      細谷 健一
    • Organizer
      第36回 比較眼科学会年次大会
    • Place of Presentation
      東京都
    • Year and Date
      2016-05-21
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Transporter-mediated histamine elimination from cerebrospinal fluid: involvement of PMAT at the blood-cerebrospinal fluid barrier.2016

    • Author(s)
      Takuya Usui, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya
    • Organizer
      2016 China-Japan-Korea Joint Symposium, 20th Anniversary of Oriental Pharmaceutical Science
    • Place of Presentation
      Seoul, Korea
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 蛍光基質を用いた肝臓における有機アニオン輸送体organic anion-transporting polypeptide (Oatp) 1a4 の機能解析2016

    • Author(s)
      木田 凜太郎、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会北陸支部 第128回例会
    • Place of Presentation
      金沢市 (石川県)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血液網膜関門を介したcyanocobalamin輸送機構の解明2016

    • Author(s)
      木下 由梨、野上 暁生、阿部 肇、井上 将彦、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会北陸支部 第128回例会
    • Place of Presentation
      金沢市 (石川県)
    • Related Report
      2016 Annual Research Report
  • [Remarks] 研究代表者主宰研究室webページ

    • URL

      http://www.pha.u-toyama.ac.jp/phaphzai/index-j.html

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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