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Effects of deuterium modification on the electropharmacological profile of anti-atrial fibrillatory drug

Research Project

Project/Area Number 20K16136
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionToho University

Principal Investigator

Kambayashi Ryuichi  東邦大学, 医学部, 助教 (70837492)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords重水素化 / 抗不整脈薬 / 心房細動 / 病態モデル / QT延長 / 心室不整脈 / 心房有効不応期 / 心室再分極 / 心血管
Outline of Research at the Start

抗不整脈薬dronedaroneは、心房細動に対し高い有効性を示す一方で、心不全および致死性心室不整脈といった有害作用のリスクを増加させることからその安全性には課題が残る。本研究では、dronedaroneの有害作用を減弱させるための手段として、薬物の薬理学的特性を変化させ得る重水素化に着目した。しかしながら、重水素化がdronedaroneの心血管系に対する多様な薬理作用に及ぼす影響を十分には解明できていない。そこで、臨床予測性が高く、薬物の循環薬理作用を多角的に評価可能であるin vivoモデルを用いて、重水素化がdronedaroneの循環薬理作用に与える影響を解明する。

Outline of Final Research Achievements

To investigate how deuteration can modify electropharmacological effects of antiarrhythmic drug, we assessed the effects of deuterated analogue of dronedarone, poyendarone, using the canine atrial fibrillation models, which were compared with those of dronedarone. The deuteration might enhance the drug-induced prolongation of atrial effective refractory period at high frequency of depolarization observed during AF episode, which can potentiate the inhibitory action on the paroxysmal atrial fibrillation. Meanwhile, the deuteration would hardly affect the defibrillation effect on the persistent atrial fibrillation, whereas it can attenuate the risk for QT prolongation and ventricular arrhythmias. Poyendarone would have more potent anti-atrial fibrillatory action and favorable cardiovascular safety profile than dronedarone, and therefore is a promising anti-atrial fibrillatory drug candidate.

Academic Significance and Societal Importance of the Research Achievements

心房細動の治療に使用される既存の抗不整脈薬は、心房組織への選択性または心房細動の病態に対する特異性が低く、心室組織に対しても電気生理学的作用を示し、致死性心室不整脈を誘発する可能性がある。本研究は、その有害作用を減弱する手段として重水素化に着目し、重水素化は抗不整脈薬の心房細動に対する有効性を増強し、心室不整脈の誘発リスクを減弱することを示した。それゆえ、重水素化が抗不整脈薬の循環薬理作用を修飾する上で有益な手段となる可能性を見出した。既存薬dronedaroneの重水素化誘導体poyendaroneは、より有効かつ安全な治療薬として心房細動患者の薬物治療に貢献できると考える。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (25 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (3 results) Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 13 results) Presentation (9 results)

  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Both osmolality-dependent and independent mechanisms are associated with acute hyperglycemia-induced cardiovascular adverse reactions: Analysis of the mutual interactions leading to cardiovascular phenotypes in dogs2023

    • Author(s)
      Kambayashi Ryuichi, Izumi-Nakaseko Hiroko, Goto Ai, Takei Yoshinori, Matsumoto Akio, Lorch Ulrike, Taubel Jorg, Sugiyama Atsushi
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 48 Issue: 3 Pages: 169-178

    • DOI

      10.2131/jts.48.169

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.2023

    • Author(s)
      Goto Ai, Kambayashi Ryuichi, Izumi-Nakaseko Hiroko, Shinozaki Makoto, Takei Yoshinori, Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: - Issue: 4 Pages: 201-209

    • DOI

      10.1016/j.jphs.2023.05.003

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors.2022

    • Author(s)
      Chiba Koki, Kambayashi Ryuichi, Onozato Mayu, Goto Ai, Izumi-Nakaseko Hiroko, Takei Yoshinori, Matsumoto Akio, Tanaka Koichiro, Kanda Yasunari, Fukushima Takeshi, Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 150 Issue: 3 Pages: 154-162

    • DOI

      10.1016/j.jphs.2022.07.008

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts2022

    • Author(s)
      Karkhanis Aneesh V.、Venkatesan Gopalakrishnan、Kambayashi Ryuichi、Leow Jacqueline Wen Hui、Han Marcus Qingrui、Izumi-Nakaseko Hiroko、Goto Ai、Pang Jeremy Kah Sheng、Soh Boon Seng、Kojodjojo Pipin、Sugiyama Atsushi、Chan Eric Chun Yong
    • Journal Title

      Acta Pharmaceutica Sinica B

      Volume: - Issue: 10 Pages: 3905-3923

    • DOI

      10.1016/j.apsb.2022.03.008

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Roles of IK,ACh for perpetuating atrial fibrillation: effects of atrial-selective K+ channel inhibitor AVE0118 and class I drugs on the persistent atrial fibrillation canine model2022

    • Author(s)
      Kambayashi Ryuichi、Goto Ai、Izumi-Nakaseko Hiroko、Takei Yoshinori、Matsumoto Akio、Kawai Shinichi、Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: - Issue: 4 Pages: 175-178

    • DOI

      10.1016/j.jphs.2022.05.004

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model2022

    • Author(s)
      Kambayashi Ryuichi、Goto Ai、Onozato Mayu、Izumi-Nakaseko Hiroko、Takei Yoshinori、Matsumoto Akio、Kawai Shinichi、Fukushima Takeshi、Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 148 Issue: 1 Pages: 179-186

    • DOI

      10.1016/j.jphs.2021.11.002

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of clinically-reported, memantine-induced cardiovascular adverse responses using the halothane-anesthetized dogs: Reverse translational study2022

    • Author(s)
      Kambayashi Ryuichi、Goto Ai、Hagiwara-Nagasawa Mihoko、Izumi-Nakaseko Hiroko、Shinozaki Makoto、Kawai Shinichi、Matsumoto Akio、Takei Yoshinori、Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 148 Issue: 4 Pages: 343-350

    • DOI

      10.1016/j.jphs.2022.01.011

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An exploratory analysis of effects of poyendarone, a deuterated analogue of dronedarone, on the canine model of paroxysmal atrial fibrillation2021

    • Author(s)
      Ryuichi Kambayashi, Ai Goto, Yoshio Nunoi, Mihoko Hagiwara-Nagasawa, Hiroko Izumi-Nakaseko, Gopalakrishnan Venkatesan, Yoshinori Takei, Akio Matsumoto, Eric Chun Yong Chan, Atsushi Sugiyama
    • Journal Title

      Naunyn-Schmiedeberg's archives of pharmacology

      Volume: - Issue: 6 Pages: 1103-1112

    • DOI

      10.1007/s00210-020-02047-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Translational studies on anti-atrial fibrillatory action of oseltamivir by its in vivo and in vitro electropharmacological analyses2021

    • Author(s)
      Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Ai Goto, Kazuya Tsurudome, Hironori Ohshiro, Taku Izumi, Mihoko Hagiwara-Nagasawa, Koki Chiba, Ryota Nishiyama, Satomi Oyama, Yoshio Nunoi, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
    • Journal Title

      Frontiers in Pharmacology

      Volume: 12

    • DOI

      10.3389/fphar.2021.593021

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardiohemodynamic and arrhythmogenic effects of the anti-atrial fibrillatory compound vanoxerine in halothane-anesthetized dogs2021

    • Author(s)
      Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Ai Goto, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
    • Journal Title

      Cardiovascular Toxicology

      Volume: 21 Issue: 3 Pages: 206-215

    • DOI

      10.1007/s12012-020-09612-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halothane-anesthetized dogs2021

    • Author(s)
      Ai Goto, Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Shinichi Kawai, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
    • Journal Title

      Heart and Vessels

      Volume: 36 Issue: 3 Pages: 424-429

    • DOI

      10.1007/s00380-020-01716-8

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones2021

    • Author(s)
      Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Ai Goto, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Koki Chiba, Takeshi Wada, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
    • Journal Title

      Naunyn-Schmiedeberg's archives of pharmacology

      Volume: 394 Issue: 4 Pages: 581-589

    • DOI

      10.1007/s00210-020-01997-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs2021

    • Author(s)
      Yoshio Nunoi, Ryuichi Kambayashi, Ai Goto, Mihoko Hagiwara-Nagasawa, Koki Chiba, Hiroko Izumi-Nakaseko, Shinichi Kawai, Yoshinori Takei, Akio Matsumoto, Yoshinori Watanabe, Atsushi Sugiyama
    • Journal Title

      Heart and Vessels

      Volume: - Issue: 7 Pages: 1088-1097

    • DOI

      10.1007/s00380-021-01830-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Onset Mechanisms of Imatinib-Induced Heart Failure and QT-Interval Prolongation in the Halothane-Anesthetized Dogs2023

    • Author(s)
      Kambayashi Ryuichi, Matsumoto Akio, Sugiyama Atsushi
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 心房細動の停止に有効なイオンチャネル遮断特性:発作性および持続性心房細動モデル犬を用いたoseltamivirの薬効評価2022

    • Author(s)
      神林隆一, 後藤愛, 中瀬古(泉) 寛子, 武井義則, 松本明郎, 杉山篤
    • Organizer
      第146回日本薬理学会関東部会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 早期(J-Tpeak)および後期(Tpeak-Tend)再分極時間の延長様式が引き続き発生する torsade de pointes 発作の開始様式と自然停止確率を予測する2022

    • Author(s)
      神林隆一, 後藤愛, 中瀬古(泉)寛子, 武井義則, 松本明郎, 杉山篤
    • Organizer
      第96回日本薬理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Analysis of electropharmacological effects of TASK-1 inhibitor doxapram along with anti-atrial fibrillatory action using the intact and chronic atrioventricular block dogs2022

    • Author(s)
      Kambayashi Ryuichi、Goto Ai、Izumi-Nakaseko Hiroko、Takei Yoshinori、Matsumoto Akio、Kawai Shinichi、Sugiyama Atsushi
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] TASK-1阻害薬doxapramのイソフルラン麻酔犬における電気薬理学的作用評価:抗心房細動薬としての可能性の検討2021

    • Author(s)
      神林隆一、後藤愛、中瀨古(泉)寛子、武井義則、松本明郎、川合眞一、杉山篤
    • Organizer
      第31回日本循環薬理学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Anti-atrial fibrillatory action of oseltamivir and its electrophysiological analysis using the paroxysmal and persistent atrial fibrillation models of dogs.2021

    • Author(s)
      Kambayashi Ryuichi、Izumi-Nakaseko Hiroko、Goto Ai、Hagiwara-Nagasawa Mihoko、Nunoi Yoshio、Takei Yoshinori、Matsumoto Akio、Kawai Shinichi、Sugiyama Atsushi
    • Organizer
      第67回日本不整脈心電学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 先行する早期(J-Tpeak)および後期(Tpeak-Tend)再分極時間の変化がtorsade de pointesの病態形成を担う2021

    • Author(s)
      神林隆一、後藤愛、布井啓雄、中瀬古(泉)寛子、松本明郎、杉山篤
    • Organizer
      心電学関連春季大会2021
    • Related Report
      2021 Research-status Report
  • [Presentation] Electrophysiological analysis of the anti-atrial fibrillatory action of oseltamivir using the paroxysmal atrial fibrillation canine model2021

    • Author(s)
      Ryuichi Kambayashi, Yoshio Nunoi, Ai Goto, Yoshiki Hirokawa, Hiroko Izumi-Nakaseko, Mihoko Hagiwara-Nagasawa, Yoshinori Takei, Akio Matsumoto, Shinichi Kawai, Atsushi Sugiyama
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] How the Deuteration of Dronedarone Can Modify its Cardiovascular Profile: a New Strategy for Optimizing Efficacy and Adverse Effects2020

    • Author(s)
      Ryuichi Kambayashi, Mihoko Hagiwara-Nagasawa, Akio Matsumoto, Atsushi Sugiyama
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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