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

• Project/Area Number: 20K16136
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Toho 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: ¥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。

Research Products

• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [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 dogs (2023)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts (2022)
  • 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
  • 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 model (2022)
  • 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
  • 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 model (2022)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of clinically-reported, memantine-induced cardiovascular adverse responses using the halothane-anesthetized dogs: Reverse translational study (2022)
  • 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
  • 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 fibrillation (2021)
  • 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
  • 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 analyses (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Cardiohemodynamic and arrhythmogenic effects of the anti-atrial fibrillatory compound vanoxerine in halothane-anesthetized dogs (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halothane-anesthetized dogs (2021)
  • 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
  • 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 ones (2021)
  • 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
  • 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 dogs (2021)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] Onset Mechanisms of Imatinib-Induced Heart Failure and QT-Interval Prolongation in the Halothane-Anesthetized Dogs (2023)
  • Author(s): Kambayashi Ryuichi, Matsumoto Akio, Sugiyama Atsushi
  • Organizer: 第87回日本循環器学会学術集会
• [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
• [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
• [Presentation] Analysis of electropharmacological effects of TASK-1 inhibitor doxapram along with anti-atrial fibrillatory action using the intact and chronic atrioventricular block dogs (2022)
  • 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
• [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
• [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
• [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
• [Presentation] Electrophysiological analysis of the anti-atrial fibrillatory action of oseltamivir using the paroxysmal atrial fibrillation canine model (2021)
  • 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
• [Presentation] How the Deuteration of Dronedarone Can Modify its Cardiovascular Profile: a New Strategy for Optimizing Efficacy and Adverse Effects (2020)
  • 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