Development of anti arrhythmia drug targeting cardiac adenylyl cyclase.

• Project/Area Number: 18K15013
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Yokohama City University
• Principal Investigator: Nakamura Takashi 横浜市立大学, 医学部, 助教 (30772371)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 抗不整脈薬 / アデニル酸シクラーゼ / 心房細動 / 心室性不整脈 / 水溶性誘導体 / 静脈内投与 / 経静脈内投与 / 不整脈 / cAMP

Outline of Final Research Achievements

Vidarabine , which is cardiac adenylyl cyclase inhibitor, has been shown to have anti-arrhythmic effects. However, since vidarabine is poorly water-solubility, it is likely to cause worsening of heart failure and central nervous system damage. Therefore, it is an obstacle to clinical application. We have developed a water-soluble vidarabine derivate V2E, which is 3-5 times more soluble in water than vidarabine. In this application, we examined the effect of water-soluble vidarabin derivate V2E on atrial fibrillation and ventricular tachyarrhythmia. Water-soluble vidarabine derivate V2E showed anti-arrhythmic effect on atrial fibrillation and ventricular tachyarrhythmia model in mice.

Academic Significance and Societal Importance of the Research Achievements

従来の交感神経遮断薬であるベータ受容体遮断薬は抗不整脈効果を有するが、心機能抑制や糖尿病および喘息の悪化などの副作用があることが問題となる。そこで、我々はベータ受容体遮断薬に代わる、安全な抗不整脈薬の開発を目指している。その候補の一つが心臓型アデニル酸シクラーゼ阻害薬である。臨床応用可能な心臓型アデニル酸シクラーゼを開発することで、ベータ受容体遮断薬が使用困難な患者に対しても安全に抗不整脈治療が可能になる可能性が高い。今後さらなる安全性の高い治療薬を開発することで、より多くの不整脈患者に貢献できるものと考える。

Research Products

• [Journal Article] Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice (2019)
  • Author(s): Prajapati R, Fujita T, Suita K, Nakamura T, Cai W, Hidaka Y, Umemura M, Yokoyama U, Knollmann BC, Okumura S, Ishikawa Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 295-303
  • DOI: 10.1253/circj.CJ-18-0743
  • NAID: 130007557004
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research