Analysis of patho-pharmacological significance of prolongation of atrial effective refractory period for treating atrial fibrillation.

• Project/Area Number: 19K16505
• 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: 長澤 美帆子 (萩原美帆子) 東邦大学, 医学部, 助教 (80804418)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Discontinued (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心房細動 / 心房有効不応期 / 抗心房細動薬 / 有効不応期 / 心房/心室作用選択性 / 病態薬理学

Outline of Research at the Start

心房細動治療において薬物療法と非薬物療法の併用は単独の治療と比較して心房細動の再発率を下げることが予想されるが、既存の抗心房細動薬は心房/心室非選択性であるために致死的な有害事象を引き起こすことが懸念されており、心房選択的な治療薬の開発に期待が寄せられている。前臨床試験では、心房有効不応期延長作用は臨床効果を定性的に予測する指標として用いられるが、定量的に予測する基準は存在しない。そこで、心房選択的な有効不応期延長作用を有する薬物を患者の病態を反映したin vivo心房細動モデルに投与し、心房有効不応期延長作用がどの程度発現すれば抗心房細動効果を発現するのか、その定量的な関係性を明らかにする。

Outline of Annual Research Achievements

2019年度：発作性心房細動犬モデル：慢性房室ブロック犬の心房を電気刺激し、有効不応期および心房内伝導時間を測定した。右心房を刺激周期10 msで高頻度刺激して心房細動を誘発し、持続時間を測定した。ドロネダロン（0.3および3 mg/kg/30 s, n=4）、オセルタミビル（3および30 mg/kg/10 min, n=4）、ラノラジン（0.3および3 mg/kg/10 min, n=4）の投与は、心房有効不応期を延長し、心房細動持続時間を短縮した。両者の変化の程度には相関が認められた。さらにピルジカイニド（1および3 mg/kg/10min, n=2）およびM201-A（0.3および3 mg/kg, n=2）を投与した。
2020年度：発作性心房細動犬モデル：2019年度と同用量のピルジカイニド（n=2）およびM201-A（n=1）を投与した。ピルジカイニドおよびM201-Aは心房有効不応期を延長し、心房細動持続時間を短縮した。両者の変化の程度には相関が認められた。持続性心房細動犬モデル：オセルタミビル（30 mg/kg/10 min, n=7）およびピルジカイニド（3 mg/kg/10min, n=8）を投与して心房細動停止に要した時間を測定した。オセルタミビルは7例中6例で、ピルジカイニドは8例中2例で心房細動を停止した。
2021年度：持続性心房細動犬モデル：M201-A（3 mg/kg/10 min, n=4）、ドロネダロン（3 mg/kg/30 s, n=4）およびラノラジン（3 mg/kg/10 min, n=1）を投与し、同様に測定を行った。M201-Aは4例中1例において心房細動を停止した。この結果は既存の抗不整脈薬と同程度の効果であった。致死性心室不整脈の発生は認められなかった。ドロネダロンは4例中2例で、ラノラジンは1例中0例で心房細動を停止した。

Research Products

• [Journal Article] Effects of mechanical ventilation with expiratory negative airway pressure on porcine pulmonary and systemic circulation: mechano-physiology and potential application (2021)
  • Author(s): Hagiwara-Nagasawa M, Kambayashi R, Goto A, Chiba K, Wada T, Nunoi Y, Izumi-Nakaseko H, Takei Y, Matsumoto A, Lurie KG, Sugiyama A
  • Journal Title: The Journal of Physiological Sciences Volume: 71 Issue: 1
  • DOI: 10.1186/s12576-021-00801-5
  • 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] 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] 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] 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] 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
• [Journal Article] In vivo comparison of dl-sotalol-induced electrocardiographic responses among halothane anesthesia, isoflurane anesthesia with nitrous oxide, and conscious state (2021)
  • Author(s): Hiroyuki Saito, Ryuichi Kambayashi, Mihoko Hagiwara-Nagasawa, Yoshio Nunoi, Ai Goto, Hiroko Izumi-Nakaseko, Shinichi Kawai, Yoshinori Takei, Akio Matsumoto, Kiyotaka Hoshiai, Yasuki Akie, Atsushi Sugiyama
  • Journal Title: Journal of Pharmacological Sciences Volume: 145 Issue: 1 Pages: 16-22
  • DOI: 10.1016/j.jphs.2020.10.001
  • Peer Reviewed / Open Access
• [Journal Article] In vivo analysis of concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables in dogs (2021)
  • Author(s): Hiroyuki Saito, Ryuichi Kambayashi, Ai Goto, Mihoko Hagiwara-Nagasawa, Kiyotaka Hoshiai, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Yasuki Akie, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
  • Journal Title: Journal of Pharmacological Sciences Volume: 145 Issue: 3 Pages: 268-272
  • DOI: 10.1016/j.jphs.2020.12.010
  • 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] Analysis of electropharmacological effects of AVE0118 on the atria of chronic atrioventricular block dogs: characterization of anti-atrial fibrillatory action by atrial repolarization-delaying agent (2020)
  • Author(s): Ryuichi Kambayashi, Mihoko Hagiwara-Nagasawa, Tomoaki Ichikawa, Ai Goto, Koki Chiba, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Akio Matsumoto, Akira Takahara, Atsushi Sugiyama
  • Journal Title: Heart and Vessels Volume: 35 Issue: 9 Pages: 1316-1322
  • DOI: 10.1007/s00380-020-01612-1
  • Peer Reviewed / Open Access
• [Journal Article] Risperidone alone did not induce torsade de pointes: Experimental evidence from the chronic atrioventricular block model dogs (2020)
  • Author(s): Yoshio Nunoi, Koki Chiba, Mihoko Hagiwara-Nagasawa, Ai Goto, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akio Matsumoto, Yoshinori Watanabe, Atsushi Sugiyama
  • Journal Title: Journal of Pharmacological Sciences Volume: 143 Issue: 4 Pages: 330-332
  • DOI: 10.1016/j.jphs.2020.05.008
  • Peer Reviewed / Open Access
• [Journal Article] Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes (2020)
  • Author(s): Goto Ai, Sakamoto Kengo, Hagiwara-Nagasawa Mihoko, Kambayashi Ryuichi, Chiba Koki, Nunoi Yoshio, Izumi-Nakaseko Hiroko, Matsumoto Akio, Sugiyama Atsushi
  • Journal Title: Journal of Pharmacological Sciences Volume: 142 Issue: 4 Pages: 172-175
  • DOI: 10.1016/j.jphs.2019.12.007
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of microminipig as a laboratory animal for pharmacological study by analyzing bepridil-induced cardiovascular responses (2020)
  • Author(s): Nunoi Yoshio, Hagiwara-Nagasawa Mihoko, Kambayashi Ryuichi, Goto Ai, Chiba Koki, Wada Takeshi, Izumi-Nakaseko Hiroko, Matsumoto Akio, Watanabe Yoshinori, Sugiyama Atsushi
  • Journal Title: Journal of Pharmacological Sciences Volume: 143 Issue: 1 Pages: 56-59
  • DOI: 10.1016/j.jphs.2020.01.010
  • Peer Reviewed / Open Access
• [Journal Article] How the deuteration of dronedarone can modify its cardiovascular profile: In vivo characterization of electropharmacological effects of poyendarone, a deuterated analogue of dronedarone (2020)
  • Author(s): Kambayashi Ryuichi, Hagiwara-Nagasawa Mihoko, Kondo Yoshiki, Yeo Zhi Jie, Goto Ai, Chiba Koki, Nunoi Yoshio, Izumi-Nakaseko Hiroko, Leow Jacqueline Wen Hui, Venkatesan Gopalakrishnan, Matsumoto Akio, Chan Eric Chun Yong, Sugiyama Atsushi
  • Journal Title: Cardiovascular Toxicology Volume: － Issue: 4 Pages: 339-350
  • DOI: 10.1007/s12012-019-09559-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Electropharmacological characterization of aciclovir in the halothane-anesthetized dogs: A proposal of evaluation method for cardiovascular safety pharmacology of anti-virus drugs (2020)
  • Author(s): Kondo Yoshiki, Hagiwara-Nagasawa Mihoko, Kambayashi Ryuichi, Goto Ai, Chiba Koki, Nunoi Yoshio, Izumi-Nakaseko Hiroko, Matsumoto Akio, Sugiyama Atsushi
  • Journal Title: Cardiovascular Toxicology Volume: － Issue: 4 Pages: 419-426
  • DOI: 10.1007/s12012-020-09568-4
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological β-adrenoceptor blockade can augment torsadogenic action of IKr inhibitor: Comparison of proarrhythmic effects of d-sotalol and dl-sotalol in the chronic atrioventricular block dogs (2019)
  • Author(s): Goto Ai, Hagiwara-Nagasawa Mihoko, Chiba Koki, Kambayashi Ryuichi, Nunoi Yoshio, Izumi-Nakaseko Hiroko, Matsumoto Akio, Kanda Yasunari, Sugiyama Atsushi
  • Journal Title: Journal of Pharmacological Sciences Volume: 141 Issue: 1 Pages: 86-89
  • DOI: 10.1016/j.jphs.2019.09.009
  • Peer Reviewed / Open Access
• [Journal Article] Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium (2019)
  • Author(s): Kambayashi Ryuichi, Hagiwara-Nagasawa Mihoko, Goto Ai, Chiba Koki, Izumi-Nakaseko Hiroko, Naito Atsuhiko T., Matsumoto Akio, Sugiyama Atsushi
  • Journal Title: Heart and Vessels Volume: 35 Issue: 4 Pages: 593-602
  • DOI: 10.1007/s00380-019-01521-y
  • Peer Reviewed / Open Access
• [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 R, Izumi-Nakaseko H, Goto A, Hagiwara-Nagasawa M, Nunoi Y, Takei Y, Matsumoto A, Kawai S, Sugiyama A
  • Organizer: 第67回日本不整脈心電学会学術大会
• [Presentation] アルツハイマー型認知症治療薬memantineによる心血管系有害作用の解析：ハロセン麻酔犬を用いたreverse-translational研究 (2021)
  • Author(s): 神林 隆一, 後藤 愛, 長澤（萩原） 美帆子, 中瀬古（泉） 寛子, 武井 義則, 松本 明郎, 川合 眞一, 杉山 篤
  • Organizer: 第144回日本薬理学会関東部会
• [Presentation] カンゾウ（甘草）による心臓作用の電気生理学的評価：ヒトiPS細胞由来心筋細胞シートおよび慢性房室ブロック犬モデルを併用したリバーストランスレーショナル研究 (2021)
  • Author(s): 中瀨古（泉） 寛子, 千葉 浩輝, 後藤 愛, 神林 隆一, 長澤（萩原） 美帆子, 松本 明郎, 武井 義則, 川合 眞一, 杉山 篤
  • Organizer: 第28回HAB研究機構学術年会
• [Presentation] 心機能および心室再分極過程に対する高血糖の作用：イソフルラン麻酔犬での検討. (2020)
  • Author(s): 廣川佳貴, 長澤（萩原）美帆子, 神林隆一, 後藤愛, 布井啓雄, 中瀬古（泉）寛子, 松本明郎, 武井義則, 川合眞一, 杉山篤
  • Organizer: 第143回日本薬理学会関東部会
• [Presentation] 抗心房細動薬の有効性と安全性の向上を目的とした重水素化誘導体の循環薬理学的検討 (2020)
  • Author(s): 神林隆一，長澤（萩原）美帆子
  • Organizer: 第156回東邦医学会例会
• [Presentation] 抗インフルエンザ薬oseltamivirの抗心房細動効果：持続性心房細動モデル犬、ハロセン麻酔犬およびパッチクランプ法による電気薬理学的評価 (2020)
  • Author(s): 神林隆一, 布井啓雄, 長澤（萩原）美帆子, 後藤愛, 西山良太, 大山聡美, 廣川佳貴, 中瀬古（泉）寛子, 武井義則, 松本明郎, 川合眞一, 杉山篤
  • Organizer: 第143回日本薬理学会関東部会
• [Presentation] Analysis of in vivo electropharmacological effects of vanoxerine. (2020)
  • Author(s): 長澤(萩原)美帆子, 神林隆一, 後藤愛, 千葉浩輝, 布井啓雄, 和田剛, 中瀬古(泉)寛子, 松本明郎, 杉山篤
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Effect of negative expiratory airway pressure on the systemic circulation: A new strategy to salvage patients with cardiogenic shock. (2020)
  • Author(s): Hagiwara-Nagasawa Mihoko, Kambayashi Ryuichi, Matsumoto Akio, Sugiyama Atsushi
  • Organizer: 第84回日本循環器学会学術集会