人工酸素運搬体及び類縁体を用いた呼吸・循環器不全に対する実験的治療

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15H02569
• Research Institution: Tokai University
• Principal Investigator: 川口 章 東海大学, 医学部, 教授 (30195052)
• Co-Investigator(Kenkyū-buntansha): 根矢 三郎 千葉大学, 大学院薬学研究院, 教授 (10156169) ; 猪口 貞樹 東海大学, 医学部, 教授 (60160008) ; 北岸 宏亮 同志社大学, 理工学部, 准教授 (60448090) ; 山野 眞利子 大阪府立大学, 総合リハビリテーション学部, 客員研究員 (80192409) ; 奥 直人 静岡県立大学, 薬学部, 教授 (10167322)
• Project Period (FY): 2015-04-01 – 2020-03-31
• Keywords: 人工酸素運搬体 / 臓器虚血 / 再灌流障害

Outline of Annual Research Achievements

本研究は、1)リポゾーム封入タクロリスム(LET/静岡県立大)、2)コバルトヘム(CoHeme/千葉大）、3) Hemo-Cyclodextrin(HemoCD/同志社大）及び下記の国際連携(4－8)をふまえて、循環・呼吸に起因する広汎で多様な病態に最適な人工酸素運搬体を開発することを基本課題としている。
2016年度は、1）LETを用いた全脳虚血、2)コバルトヘムの改変の検討を行い、3)HemoCD3の量産が可能となり、4)SanguinateTMを用いた心筋梗塞、脳梗塞、肺高血圧症の実験的検討を開始した。また、方法論として、生体内酸素代謝動態の検出法として、A)近赤外光を用いた組織内酸素状態検出装置を作成し、悪性腫瘍での酸素化を証明し（村山、PLOS1）、非侵襲性を活かして健常者や脳卒中患者に応用できる診断装置を試作した。また、B)超小型人工心肺システムを作製して体外循環充填液としての効果・有用性の検討を開始した。一方、人工酸素運搬体を用いた臨床的使用法の実験的検討として、α)脳梗塞後の脳還流障害の緩和、β)糖尿病動物における創傷治癒の改善、γ)虚血骨格筋における効果、および、δ)正常動物における運動負荷時の心肺機能への効果を報告した。

4) Prolong Pharmaceuticals社(米)のPEGylated CarboxyHemoglobin Bovine(Sanguinate)、5) Hemarina社(仏)の海洋生物由来の酸素運搬体のHemoxcel およびHemo2Life、6) Texas-Tech大(米)のATP-Hemoglobin-PEG、7) Loyola大(米)のPEG-Hemoglobin Bovine、
8) Charite・Humboldt大(独)のHemoglobin Based Oxygen Carrier(HBOX)

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究では、薬学・理工学の研究者と協力し、国際的連携（前述の1～８）をふまえて、循環および呼吸に起因する広汎で多様な病態それぞれに最適な性能を有する人工赤血球及び酸素代謝改善薬を開発する。この目的で、共同研究ベースでそれぞれの特性を検討する契約を交わし、サンプルを用いて実験的検討にかかっている（先述の1～５）。また共同研究を予定している（先述の６－８）状況である。

Strategy for Future Research Activity

研究方針として、上記の人工酸素運搬体およびその類縁体を用いて、呼吸・循環機能のうち、酸素摂取の「肺」、ポンプとしての「心臓」、回路としての「血管」に対する従来の直接治療と異なり、そこを流れる「血液」の側からの新たな体系的なアプローチを行う。それぞれの機能不全、すなわち呼吸不全、心不全、還流不全のモデルで検討し、従来の治療法と併用して相乗効果も期待できる革新的な治療体系の構築を目指す。

Research Products

• [Journal Article] HemoCD as a Totally Synthetic Artificial Oxygen Carrier: Improvements in the Synthesis and O2/CO Discrimination (2017)
  • Author(s): H. Kitagishi, Q. Mao, N. Kitamura, T. Kita
  • Journal Title: Artificial Organs Volume: 41(4) Pages: 372-380
  • DOI: 10.1111/aor.12870
  • Peer Reviewed
• [Journal Article] Preoperative Risk Levels and Vascular Access in Transcatheter Aortic Valve Implantation-A Single-Institute Analysis. (2017)
  • Author(s): Kawaguchi AT, Collet JP, Cluzel P, Makri R, Laali M, DeFrance C, Furuya H, Murakami A, Leprince P.
  • Journal Title: Artif Organs Volume: 41 Pages: 130,138
  • DOI: 10.1111/aor.12754.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Monitoring mitochondrial complex-I activity using novel PET probe 18F-BCPP-EF allows early detection of radiotherapy effect in murine squamous cell carcinoma. (2017)
  • Author(s): Murayama C, Kawaguchi AT, Kamijo A, Naito K, Kanazawa M, Tsukada H (BCPPef).
  • Journal Title: PLOS ONE Volume: - Pages: -
  • DOI: 10.1371/journal.pone0170911
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke. (2017)
  • Author(s): Fukuta T, Asai T, Yanagida Y, Namba M, Koide H, Shimizu K, Oku N.
  • Journal Title: The FASEB Journal Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1096/fj.201601209R
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inducibility of Ventricular Arrhythmia 1 Year Following Treatment with Heavy Ion Irradiation in Dogs with Myocardial Infarction. (2017)
  • Author(s): Amino M, Yoshioka K, Furusawa Y, Tanaka S, Kawabe N, Hashida T, Tsukada T, Izumi M, Inokuchi S, Tanabe T, Ikari Y
  • Journal Title: Pacing and Clinical Electrophysiology Volume: 40 Pages: 379,390
  • DOI: 10.1111/pace.13031
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel CPR system that predicts return of spontaneous circulation from amplitude spectral area before electric shock in ventricular fibrillation. (2017)
  • Author(s): Nakagawa Y, Amino M, Inokuchi S, Hayashi S, Wakabayashi T, Noda T.
  • Journal Title: Resuscitation Volume: 113 Pages: 8,12
  • DOI: 10.1016/j.resuscitation.2016.12.025
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Detection of synthetic cannabinoids using GC-EI-MS, positive GC-CI-MS, and negative GC-CI-MS. (2017)
  • Author(s): Umebachi R, Saito T, Aoki H, Namera A, Nakamoto A, Kawamura M, Inokuchi S.
  • Journal Title: International Journal of Legal Medicine Volume: 131 Pages: 143,152
  • DOI: 10.1007/s00414-016-1428-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Utility of heme analogues to intentionally modify heme-globin interactions in myoglobin. (2016)
  • Author(s): Neya S, Nagai M, Nagatomo S, Hoshino T, Yoneda T, Kawaguchi AT.
  • Journal Title: Biochimica et Biophysica Acta Volume: 1857 Pages: 582,588
  • DOI: 10.1016/j.bbabio.2015.09.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthesis of type III isomers of diacetyldeutero-, hemato-, and protoporphyrins with the use of Knorr's pyrrole. (2016)
  • Author(s): Neya S, Yoneda T, Hoshino T, Kawaguchi AT, Suzuki M
  • Journal Title: Tetrahedron Volume: 27 Pages: 4022,4026
  • DOI: 10.1016/j.tet.2016.05.030
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Liposome-Encapsulated Hemoglobin Improves Tumor Oxygenation as Detected by Near-Infrared Spectroscopy in Colon Carcinoma in Mice. (2016)
  • Author(s): Kawaguchi F, Kawaguchi AT, Murayama C, Kamijo A, Haida M.
  • Journal Title: Artif Organs Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/aor.12825.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of Heme Electronic Structure and Distal Polar Interaction on Functional and Vibrational Properties of Myoglobin (2016)
  • Author(s): Yuki Kanai, Ryu Nishimura, Kotaro Nishiyama, Tomokazu Shibata, Sachiko Yanagisawa, Takashi Ogura, Takashi Matsuo, Shun Hirota, Saburo Neya , Akihiro Suzuki, and Yasuhiko Yamamoto.
  • Journal Title: Inorg. Chem. Volume: 55 Pages: 1613,1622
  • DOI: 10.1021/acs.inorgchem.5b02520
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] [62] Tetradecaphyrin and its mono - and bis - Zn(II) complexes (2016)
  • Author(s): Tomoki Yoneda, Takanori Soya, Saburo Ney a, and Atsuhiro Osuka
  • Journal Title: Chemistry A European Journal Volume: 22 Pages: 14518,14522
  • DOI: 10.1002/chem.201603121
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intramolecular Oxidative O-Demethylation of an Oxoferryl Porphyrin Complexed with a Per-O-methylated β-Cyclodextrin Dimer (2016)
  • Author(s): H. Kitagishi, S. Kurosawa, K. Kano
  • Journal Title: Chemistry An Asian Jouranl Volume: 11 Pages: 3213,3219
  • DOI: 10.1002/asia.201601097
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Feedback Response to Selective Depletion of Endogenous Carbon Monozide in the Blood (2016)
  • Author(s): H. Kitagishi, S. Minegishi, A. Yumura, S. Negi, S. Taketani, Y. Amagase, Y. Mizukawa, T. Urushidani, Y. Sugiura, K. Kano
  • Journal Title: Journal of the American Chemical Society Volume: 138 Pages: 5417,5425
  • DOI: 10.1021/jacs.6b02211
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The metabolism of methazolamide in immortalized human keratinocytes, HaCaT cells. (2016)
  • Author(s): Sasabe T, Maeda S, Kishida K, Yamano M, Miwa Y, Sugiyama T.
  • Journal Title: Drug Metabolism Letters Volume: 10 Pages: 295,305
  • DOI: 10.2174/1872312811666170127160931
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-1 activity (2016)
  • Author(s): Tatsuya Fukuta, Tomohiro Asai, Takayuki Ishii, Hiroyuki Koide, Chiaki Kiyokawa, Masahiro Hashimoto, Takashi Kikuchi, Kosuke Shimizu, Norihiro Harada, Hideo Tsukada, Naoto Oku
  • Journal Title: Scientific Reports Volume: 6 Pages: -
  • DOI: 10.1038/srep30127
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil (2016)
  • Author(s): Tatsuya Fukuta, Tomohiro Asai, Akihiko Sato, Mio Namba, Yosuke Yanagida, Takashi Kikuchi, Hiroyuki Koide, Kosuke Shimizu, Naoto Oku
  • Journal Title: International Journal of Pharmaceutics Volume: 506 Pages: 129,137
  • DOI: 10.1016/j.ijpharm.2016.04.046
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical characteristics of α-pyrrolidinovalerophenone (α-PVP) poisoning. (2016)
  • Author(s): Umebachi R, Aoki H, Sugita M, Taira T, Wakai S, Saito T, Inokuchi S.
  • Journal Title: Clinical Toxicology Volume: 54 Pages: 563,567
  • DOI: 10.3109/15563650.2016.1166508
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduced Immunocompetent B Cells and Increased Secondary Infection in Elderly Patients With Severe Sepsis. (2016)
  • Author(s): Suzuki K, Inoue S, Kametani Y, Komori Y, Chiba S, Sato T, Inokuchi S, Ogura S.
  • Journal Title: Shock Volume: 46 Pages: 270,278
  • DOI: 10.1097/SHK.0000000000000619
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] βモノアザポルフィリンのpHに依存した吸光変化解析 (2017)
  • Author(s): 根矢 三郎・星野忠次・米田 友貴
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2017-03-24 – 2017-03-27
• [Presentation] 水溶性のシトクロムcオキシダーゼ活性中心モデル錯体 (2017)
  • Author(s): 下司大貴，北岸宏亮
  • Organizer: 日本化学会第97春季年会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川県横浜市)
  • Year and Date: 2017-03-18 – 2017-03-18
• [Presentation] Characterization of Complexes between Hemes and Parallel G-Quadruplex DNAs (2016)
  • Author(s): Yasuhiko Yamamoto, Tomokazu Shibata,Yuya Katahira, Yusaku Nakayama, Hulin Tai, Toru Matsui, Kenji Morihashi, Akari Watanabe, Tomomi Nakao, Sachiko Yanagisawa, Takashi Ogura, Akihiro Suzuki, Saburo Neya.
  • Organizer: 8th Asian Biological Inorganic Chemistry Conference.
  • Place of Presentation: University of Auckland(Auckland, New Zealand)
  • Year and Date: 2016-12-04 – 2016-12-09
  • Int'l Joint Research
• [Presentation] 血中に存在する内因性COの選択的除去により引き起こされる生体内反応 (2016)
  • Author(s): 峯岸彩夏，北岸宏亮
  • Organizer: 第２３回日本血液代替物学会年次大会
  • Place of Presentation: 早稲田大学西早稲田キャンパス(東京都新宿区)
  • Year and Date: 2016-11-24 – 2016-11-24
• [Presentation] Development of synthetic polymer nanoparticles interacting with HMGB1 for the treatment of cerebral ischemia/reperfusion injury (2016)
  • Author(s): C. Kiyokawa, H. Koide, K.J. Shea, N. Oku
  • Organizer: 2016 AAPS Annual Meeting and Exposition Final Program
  • Place of Presentation: Colorado Convention Center (Denver, USA)
  • Year and Date: 2016-11-15 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Combination therapy with liposomal neuroprotective agents plus tissue plasminogen activator for the treatment of ischemic stroke (2016)
  • Author(s): T. Fukuta, Y. Yanagida, T. Asai, N. Oku
  • Organizer: 2016 AAPS Annual Meeting and Exposition Final Program
  • Place of Presentation: Colorado Convention Center (Denver, USA)
  • Year and Date: 2016-11-14 – 2016-11-14
  • Int'l Joint Research
• [Presentation] Induction of HO-1 Expression by Selective Removal of Endogenous CO (2016)
  • Author(s): Hiroaki Kitagishi, Koji Kano
  • Organizer: 9th International Conference on Heme Oxygenase
  • Place of Presentation: Purkyne Institute(Prague, Czech Republic)
  • Year and Date: 2016-09-17 – 2016-09-17
  • Int'l Joint Research
• [Presentation] ヘムタンパク質の構造解析のための対称的天然型ポルフィリンの新規合成法 (2016)
  • Author(s): 根矢 三郎、米田 友貴、星野 忠次、鈴木 優章
  • Organizer: 錯体化学会第66回討論会
  • Place of Presentation: 福岡大学七隈キャンパス(福岡県福岡市)
  • Year and Date: 2016-09-10 – 2016-09-12
• [Presentation] 13C標識メチル化シクロデキストリンによる生体内類似環境での包接現象の観測 (2016)
  • Author(s): 北岸宏亮 , 齋藤真依, 根木 滋, 喜里山暁子, 加納航治
  • Organizer: 第３３回シクロデキストリンシンポジウム
  • Place of Presentation: かがわ国際会議場(香川県高松市)
  • Year and Date: 2016-09-09 – 2016-09-09
• [Presentation] メゾアリール ベータアルキルハイブリッド型ペンタフィリンの合成とその物性 (2016)
  • Author(s): 米田友貴、星野忠次、根矢三郎
  • Organizer: 第27回基礎有機化学討論会
  • Place of Presentation: 広島国際会議場(広島県広島市)
  • Year and Date: 2016-09-03 – 2016-09-03
• [Presentation] Practical Synthesis of Symmetric Isomers of Diacetyl-, Hemato-, and Protoporphyrins (2016)
  • Author(s): Saburo Neya, Tomoki Yoneda, Tyuji Hoshino, and Masaaki Suzuki.
  • Organizer: Ninth International Conference on Porphyrins and Phthalocyanines．
  • Place of Presentation: Nanjing, China
  • Year and Date: 2016-07-03 – 2016-07-08
  • Int'l Joint Research
• [Presentation] Conformational Fixation of a Rectangular Antiaromatic [28]Hexaphyrin Using Rationally Installed Peripheral Straps (2016)
  • Author(s): Tomoki Yoneda, Taeyeon Kim, Takanori Soya, Saburo Neya, Juwon Oh, Dongho Kin, Atsuhiro Osuka
  • Organizer: Ninth International Conference on Porphyrins and Phthalocyanines．
  • Place of Presentation: Nanjing, China.
  • Year and Date: 2016-07-03 – 2016-07-08
  • Int'l Joint Research
• [Presentation] ミオグロビンの機能調節におけるヘムの電子構造の変化と遠位アミノ酸変異による影響 (2016)
  • Author(s): 渡邉美帆、金井佑生、西村龍、柴田友和、松尾貴史、廣田俊、鈴木秋弘、根矢三郎、山本泰彦
  • Organizer: 第43回生体分子科学討論会
  • Place of Presentation: 名古屋大学 野依記念学術交流館(愛知県名古屋市)
  • Year and Date: 2016-06-25 – 2016-06-26
• [Presentation] ヘムタンパク質物理化学解析のための対称型ポルフィリンの新規合成法 (2016)
  • Author(s): 根矢 三郎、米田 友貴、星野 忠次、鈴木 優章
  • Organizer: 第26回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 北海道大学北海道大学学術交流会館 (北海道札幌市)
  • Year and Date: 2016-06-17 – 2016-06-18
• [Presentation] ヘムの化学修飾がメトアジドミオグロビンのスピン平衡に与える影響 (2016)
  • Author(s): 並木 孝介、柴田 友和、根矢 三郎、鈴木 秋弘、山本 泰彦
  • Organizer: 第26回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 北海道大学北海道大学学術交流会館 (北海道札幌市)
  • Year and Date: 2016-06-17 – 2016-06-18
• [Presentation] Liposome-Encapsulated Tacrolimus Ameliorates Total Brain Ischemia and Reperfusion Injury in the Rat. (2016)
  • Author(s): Kawaguchi AT, Endo H, Yamano M, Fukuta T, Ishii T, Oku N.
  • Organizer: ASAIO 62th conference
  • Place of Presentation: Hyatt Regency San Francisco, Embarcadero Center (SAN FRANCISCO, CA, USA)
  • Year and Date: 2016-06-16 – 2016-06-16
  • Int'l Joint Research
• [Presentation] Liposome-encapsulated Hemoglobin Protects Ischemic Myocardium by Preserving Hemodynamics and Oxygen Consumption in the Rat －A Concept of Biological Circulatory Support. (2016)
  • Author(s): Kawaguchi AT, Yamano M
  • Organizer: ASAIO 62th conference
  • Place of Presentation: Hyatt Regency San Francisco, Embarcadero Center (SAN FRANCISCO, CA, USA)
  • Year and Date: 2016-06-16 – 2016-06-16
  • Int'l Joint Research
• [Presentation] Oligoarginine-Conjugated Cyclodextrin as a Cell-Penetrating Host Molecule (2016)
  • Author(s): Hiroaki Kitagishi, Atsuki Nakagami, Koji Kano
  • Organizer: 18th International Cyclodextrin Symposium
  • Place of Presentation: Gainseville, FL, USA
  • Year and Date: 2016-05-19 – 2016-05-19
  • Int'l Joint Research
• [Presentation] Monitoring mitochondrial complex-I using novel PET probe allow early detection of radiosensitivity. (2016)
  • Author(s): Murayama C, Kawaguchi AT, Kamijyo A, Naito K, Kanazawa M, Tsukada H.
  • Organizer: 35th Congress of European Society for Radiotherapy & Oncology
  • Place of Presentation: Lingotto Fiere Via Nizza (Torino, Italy)
  • Year and Date: 2016-05-02 – 2016-05-02
  • Int'l Joint Research