Establishment of the molecular basis for the safety of tadalafil administration for fetal growth retardation.

• Project/Area Number: 19K09800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Mie University
• Principal Investigator: Ikeda Tomoaki 三重大学, 医学系研究科, 教授 (80202894)
• Co-Investigator(Kenkyū-buntansha): 田中 博明 三重大学, 医学部附属病院, 講師 (30727996) ; 田中 佳世 三重大学, 医学系研究科, 助教 (60812310) ; 真木 晋太郎 三重大学, 医学部附属病院, 助教 (90794371)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); 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: 胎児発育不全 / 胎児発育遅延

Outline of Research at the Start

基礎的研究、並びに臨床試験を進め、タダラフィルの胎児発育不全（FGR）の著しい改善と胎児・新生児・乳児死亡率が明確に減少するを確認した。一方、オランダにおいて実施された臨床試験（PDE5阻害薬の1つであるシルデナフィルをFGRに投与する試験）において、シルデナフィル投与群に肺高血圧に関連した新生児死亡が著しく増加し、臨床試験が中止となった。本研究では、シルデナフィルとタダラフィルのFGRへの作用の相違点についてFGRモデルマウスを用いた動物実験で詳細に検証し、その知見を考慮してFGRに対するタダラフィルの第Ⅲ相試験への円滑な移行を研究グループ全体で慎重に検討する。

Outline of Final Research Achievements

In this study, we investigated the effect of tadalafil on placental mTOR signaling. tadalafil treatment of mice with L-NAME-induced FGR resulted in a significant decrease in p-mTOR expression in FGR mice on day 13 postpartum, but by day 17 after tadalafil treatment but recovered to the same level as controls by day 17 after tadalafil administration. This result was also true for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) proteins, which act downstream of the mTOR signaling pathway. We demonstrated that tadalafil treatment of FGR in mice improves placental mTOR signaling and promotes fetal growth.

Academic Significance and Societal Importance of the Research Achievements

タダラフィルがmTORシグナルを変化させ、胎盤における胎児胎盤循環の促進を介して胎児の発育を促進することを示した。今後は、タダラフィルの詳細な作用機序をさらに解明し、臨床試験を通じてFGRおよびPE治療におけるmTORシグナルへの役割を確認することが重要である。そして、臨床試験での実証は、様々な問題を抱えるFGRによって出生した児の、予後の改善に繋がるという社会的意義を有する。

Research Products

• [Journal Article] Tadalafil Treatment of Mice with Fetal Growth Restriction and Preeclampsia Improves Placental mTOR Signaling (2022)
  • Author(s): Tanaka Kayo、Tanaka Hiroaki、Tachibana Ryota、Yoshikawa Kento、Kawamura Takuya、Takakura Sho、Takeuchi Hiroki、Ikeda Tomoaki
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 3 Pages: 1474-1474
  • DOI: 10.3390/ijms23031474
• [Journal Article] Developmental Evaluation of Infants Who Have Received Tadalafil in Utero for Fetal Growth Restriction (2020)
  • Author(s): Maki Shintaro、Kato Ineko、Enomoto Naosuke、Takakura Sho、Nii Masafumi、Tanaka Kayo、Tanaka Hiroaki、Hori Shinsuke、Matsuda Kana、Ueda Yukito、Sawada Hirofumi、Hirayama Masahiro、Sudo Akihiro、Ikeda Tomoaki
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 5 Pages: 1448-1448
  • DOI: 10.3390/jcm9051448
  • Peer Reviewed
• [Journal Article] Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial (2019)
  • Author(s): Maki Shintaro、Tanaka Hiroaki、Tsuji Makoto、Furuhashi Fumi、Magawa Shoichi、Kaneda Michiko K.、Nii Masafumi、Tanaka Kayo、Kondo Eiji、Tamaru Satoshi、Ogura Toru、Nishimura Yuki、Endoh Masayuki、Kimura Tadashi、Kotani Tomomi、Sekizawa Akihiko、Ikeda Tomoaki
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 6 Pages: 856-856
  • DOI: 10.3390/jcm8060856
  • Peer Reviewed
• [Journal Article] Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions. (2019)
  • Author(s): Tachibana Ryota, Umekawa Takashi, Yoshikawa Kento, Owa Takao, Magawa Shoichi, Furuhashi Fumi, Tsuji Makoto, Maki Shintaro, Shimada Kyoko, Kaneda K. Michiko, Nii Masafumi, Tanaka Hiroaki, Tanaka Kayo, Kamimoto Yuki, Kondo Eiji, Kato Ineko, Ikemura Kenji, Okuda Masahiro, et al.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 234-234
  • DOI: 10.1038/s41598-018-36084-x
  • Peer Reviewed / Open Access / Int'l Joint Research