Development of experimental prevention using Daikenchuto for extremely severe neonatal necrotizing enteritis

• Project/Area Number: 17K11515
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: University of Miyazaki (2019); Kagoshima University (2017-2018)
• Principal Investigator: Masuya Ryuta 宮崎大学, 医学部, 助教 (90448572)
• Co-Investigator(Kenkyū-buntansha): 家入 里志 鹿児島大学, 医歯学域医学系, 教授 (00363359) ; 大西 峻 鹿児島大学, 医歯学総合研究科, 客員研究員 (10614638) ; 川野 孝文 鹿児島大学, 医歯学総合研究科, 客員研究員 (40457651) ; 加治 建 鹿児島大学, 鹿児島大学病院, 特任教授 (50315420) ; 武藤 充 鹿児島大学, 医歯学域鹿児島大学病院, 講師 (70404522) ; 中目 和彦 宮崎大学, 医学部, 講師 (70448570) ; 町頭 成郎 鹿児島大学, 医歯学総合研究科, 客員研究員 (80404523) ; 矢野 圭輔 鹿児島大学, 鹿児島大学病院, 特任助教 (30757919)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 新生児壊死性腸炎 / モデルラット / 大建中湯 / IL-6 / 重症新生児壊死性腸炎 / 新生児壊死性腸炎スコアリング / 壊死性腸炎 / 動物モデル作成

Outline of Final Research Achievements

Neonatal necrotizing enterocolitis ("NEC") model rats were modified and severely affected, and Daikenchuto's Dosing protocols were determined for each dose. After that, actual dosing experiments were conducted. The intestinal tracts removed from rats after sacrifice death were analyzed histologically to determine the relationship between the severity of NEC and the dose of Daikenchuto. We also quantified the inflammatory cytokines and nuclear proteins in the tissues and assessed their correlation with the dose of Daikenchuto.
The results showed that (1) Daikenchuto administration reduced the grade of NEC based on histological evaluation tendency, and (2) high doses (1.0 g/kg/day) of Daikenchuto significantly reduced the incidence of NEC. improvement and (3) significantly reduced the incidence of IL-6-positive cells.

Academic Significance and Societal Importance of the Research Achievements

壊死性腸炎(NEC)は、腸管機能の未熟な低出生体重児に多く発症し、腸粘膜の虚血性壊死を主病変とする疾患である。新生児集中治療室における患児の1～5％に発症し、新生児その他の疾患に比較して高い死亡率を示す原因不明の疾患である。本研究では重症NECモデルラットに大建中湯を投与する実験を行い、大建中湯投与によってNECの重症度を低く抑えられること、大建中湯の高用量投与によってNECの発症率を有意に改善することが明らかになった。
この結果が臨床応用されることにより、低出生体重児の生存率の改善に大いに寄与新生児のintact survivalの改善、少子高齢化時代における貴重児の健全な成長が見込まれる。

Research Products

• [Journal Article] Morphometrical analyses on narrowing of portal veins and thickening of hepatic arteries in the liver of biliary atresia (2019)
  • Author(s): Masuya R, Muraji T, Ohtani H, Mukai M, Onishi S, Harumatsu T, Yamada K, Yamada W, Kawano T, Machigashira S, Nakame K, Kaji T, Ieiri S
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 5 Pages: 529-537
  • DOI: 10.1007/s00383-019-04459-4
  • Peer Reviewed / Open Access
• [Journal Article] Microvascular proliferation of the portal vein branches in the liver of biliary atresia patients at Kasai operation is associated with a better long-term clinical outcome. (2019)
  • Author(s): Harumatsu T, Muraji T, Masuya R, Ohtani H, Nagai T, Yano K, Onishi S, Yamada K, Yamada W, Matsukubo M, Muto M, Kaji T, Ieiri S.
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 12 Pages: 1437-1441
  • DOI: 10.1007/s00383-019-04579-x
  • Peer Reviewed / Open Access
• [Journal Article] Novel effect of glucagon-like peptide-2 for hepatocellular injury in a parenterally fed rat model of short bowel syndrome. (2019)
  • Author(s): Yano K, Kaji T, Onishi S, Machigashira S, Nagai T, Harumatsu T, Yamada K, Yamada W, Muto M, Nakame K, Mukai M, Ieiri S.
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 12 Pages: 1345-1351
  • DOI: 10.1007/s00383-019-04560-8
  • Peer Reviewed / Open Access
• [Journal Article] A Randomized Trial to Compare the Conventional Three-Port Laparoscopic Appendectomy Procedure to Single-Incision and One-Puncture Procedure That Was Safe and Feasible, Even for Surgeons in Training (2019)
  • Author(s): Moriguchi Tomoe、Machigashira Seiro、Sugita Koshiro、Kawano Masato、Yano Keisuke、Onishi Shun、Yamada Koji、Yamada Waka、Masuya Ryuta、Kawano Takafumi、Nakame Kazuhiko、Mukai Motoi、Kaji Tatsuru、Ieiri Satoshi
  • Journal Title: Journal of Laparoendoscopic & Advanced Surgical Techniques Volume: 29 Issue: 3 Pages: 392-395
  • DOI: 10.1089/lap.2018.0195
  • Peer Reviewed / Open Access
• [Journal Article] The long-term health-related quality of life in patients operated for choledochal cyst (2019)
  • Author(s): Baba Tokuro、Mukai Motoi、Masuya Ryuta、Kawano Masato、Yano Keisuke、Murakami Masakazu、Onishi Shun、Yamada Koji、Yamada Waka、Kawano Takafumi、Machigashira Seiro、Nakame Kazuhiko、Kaji Tatsuru、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 5 Pages: 539-546
  • DOI: 10.1007/s00383-019-04456-7
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Factors for Native Liver Survival in Patients With Biliary Atresia After Kasai Portoenterostomy (2018)
  • Author(s): 桝屋 隆太、家入 里志、連 利博、中目 和彦、川野 孝文、春松 敏夫、山田 和歌、町頭 成郎、向井 基、加治 建
  • Journal Title: Journal of the Japanese Society of Pediatric Surgeons Volume: 54 Issue: 7 Pages: 1324-1331
  • DOI: 10.11164/jjsps.54.7_1324
  • NAID: 130007535913
  • ISSN: 0288-609X, 2187-4247
  • Year and Date: 2018-12-20
  • Peer Reviewed / Open Access
• [Journal Article] Predictive factors affecting the prognosis and late complications of 73 consecutive cases of esophageal atresia at 2 centers (2018)
  • Author(s): Masuya Ryuta、Kaji Tatsuru、Mukai Motoi、Nakame Kazuhiko、Kawano Takafumi、Machigashira Seiro、Yamada Waka、Yamada Koji、Onishi Shun、Yano Keisuke、Moriguchi Tomoe、Sugita Koshiro、Kawano Masato、Noguchi Hiroyuki、Suzuhigashi Masaya、Muto Mitsuru、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 34 Issue: 10 Pages: 1027-1033
  • DOI: 10.1007/s00383-018-4326-1
  • Peer Reviewed / Open Access
• [Journal Article] GvHD仮説からみた成因と発症時期 (2018)
  • Author(s): 連 利博, 桝屋隆太, 向井 基、家入里志
  • Journal Title: 小児外科 Volume: 50 Pages: 16-20
• [Journal Article] The effect of intravenous lipid emulsions and mucosal adaptation following massive bowel resection (2018)
  • Author(s): Onishi Shun、Kaji Tatsuru、Machigashira Seiro、Yamada Waka、Masuya Ryuta、Nakame Kazuhiko、Kawano Masato、Yano Keisuke、Yamada Koji、Kawano Takafumi、Mukai Motoi、Yoshioka Takako、Tanimoto Akihide、Ieiri Satoshi
  • Journal Title: Journal of Pediatric Surgery Volume: 53 Issue: 12 Pages: 2444-2448
  • DOI: 10.1016/j.jpedsurg.2018.08.019
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin Stimulates Intestinal Adaptation Following Massive Small Bowel Resection (2018)
  • Author(s): Onishi S, Kaji T, Yamada W, Nakame K, Machigashira S, Yano K, Kawano M, Harumatsu T,Masuya R, Kawano T, Mukai M, Yoshioka T, Souda M, Hamada T, Tanimoto A, Ieiri S
  • Journal Title: Peptide Volume: 106 Pages: 264-267
  • DOI: 10.1016/j.peptides.2018.06.009
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcomes of surgery for choledochal cysts: a single-institution study focusing on follow-up and late complications (2018)
  • Author(s): Mukai Motoi、Kaji Tatsuru、Masuya Ryuta、Yamada Koji、Sugita Koshiro、Moriguchi Tomoe、Onishi Shun、Yamada Waka、Kawano Takafumi、Machigashira Seiro、Nakame Kazuhiko、Takamatsu Hideo、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 48 Issue: 9 Pages: 835-840
  • DOI: 10.1007/s00595-018-1660-9
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of a successful outcome for infants with short bowel syndrome: a 30-year single-institution experience (2017)
  • Author(s): Kaji Tatsuru、Nakame Kazuhiko、Machigashira Seiro、Kawano Takafumi、Masuya Ryuta、Yamada Waka、Yamada Koji、Onishi Shun、Moriguchi Tomoe、Sugita Koshiro、Mukai Motoi、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 47 Issue: 11 Pages: 1391-1396
  • DOI: 10.1007/s00595-017-1534-6
  • Peer Reviewed / Open Access
• [Journal Article] A comparison of the characteristics and precision of needle driving for right-handed pediatric surgeons between right and left driving using a model of infant laparoscopic diaphragmatic hernia repair (2017)
  • Author(s): Ikee Takamasa、Onishi Shun、Mukai Motoi、Kawano Takafumi、Sugita Koshiro、Moriguchi Tomoe、Yamada Koji、Yamada Waka、Masuya Ryuta、Machigashira Seiro、Nakame Kazuhiko、Kaji Tatsuru、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 33 Issue: 10 Pages: 1103-1108
  • DOI: 10.1007/s00383-017-4144-x
  • Peer Reviewed / Open Access
• [Journal Article] The bowel function and quality of life of Hirschsprung disease patients who have reached 18 years of age or older ? the long-term outcomes after undergoing the transabdominal soave procedure (2017)
  • Author(s): Onishi Shun、Nakame Kazuhiko、Kaji Tatsuru、Kawano Masato、Moriguchi Tomoe、Sugita Koshiro、Yano Keisuke、Nomura Mioko、Yamada Koji、Yamada Waka、Masuya Ryuta、Kawano Takafumi、Machigashira Seiro、Mukai Motoi、Ieiri Satoshi
  • Journal Title: Journal of Pediatric Surgery Volume: 52 Issue: 12 Pages: 2001-2005
  • DOI: 10.1016/j.jpedsurg.2017.08.036
  • Peer Reviewed / Open Access
• [Journal Article] The protective effect of fish oil lipid emulsions on intestinal failure-associated liver disease in a rat model of short-bowel syndrome (2017)
  • Author(s): Machigashira Seiro、Kaji Tatsuru、Onishi Shun、Yamada Waka、Yano Keisuke、Yamada Koji、Masuya Ryuta、Kawano Takafumi、Nakame Kazuhiko、Mukai Motoi、Ieiri Satoshi
  • Journal Title: Pediatric Surgery International Volume: 34 Issue: 2 Pages: 203-209
  • DOI: 10.1007/s00383-017-4190-4
  • Peer Reviewed / Open Access
• [Journal Article] GvHD仮説からみた成因と発症時期 (2017)
  • Author(s): 連 利博, 桝屋隆太、向井 基、家入里志
  • Journal Title: 小児外科 Volume: 48 Pages: 16-20
• [Presentation] Morphometrical analyses on the narrowing of portal veins and thickening of media of hepatic arteries in the liver of biliary atresia. (2018)
  • Author(s): Masuya R, Muraji T, Ohtani H, Mukai M, Onishi S, Harumatsu T, Yamada K, Yamada W, Kawano T, Machigashira S, Nakame K, Kaji T, Ieiri S
  • Organizer: The 25th Congress of the Asian Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] The physical growth and social prognosis of esophageal atresia patients who reach 15 years of age or older: The long-term outcomes at a single institution (2018)
  • Author(s): Masuya R, Kaji T, Murakami M, Yano K, Baba T, Harumatsu T, Onishi S, Yamada K, Yamada W, Kawano T, Machigashira S, Mukai M, Nakame K, Mukai M, Ieiri S
  • Organizer: The 25th Congress of the Asian Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] 定量的PCRを用いた母親由来キメラ細胞の定量および母児間混合リンパ球培養との比較検討を行った胆道閉鎖症患児の1例 (2018)
  • Author(s): 桝屋隆太, 連 利博, 矢野圭輔, 大西 峻, 山田耕嗣, 山田和歌, 川野孝文, 中目和彦,向井 基, 加治 建, Sami B Kanaan, J Lee Nelson, 家入里志
  • Organizer: 第45回日本胆道閉鎖症研究会
• [Presentation] 胆道閉鎖症の葛西手術時肝生検検体における門脈枝および肝動脈枝の形態計測学的検討 (2018)
  • Author(s): 桝屋隆太, 連 利博, 大谷明夫, 矢野圭輔, 大西 峻, 山田耕嗣, 山田和歌, 川野孝文,中目和彦, 向井 基, 加治 建, 家入里志
  • Organizer: 第45回日本胆道閉鎖症研究会
• [Presentation] Morphometrical analyses on narrowing of portal veins and thickening of hepatic arteries in liver of biliary atresia. (2018)
  • Author(s): Masuya R, Muraji T, Ohtani H, Mukai M, Yano K, Kawano M, Onishi S, Yamada K, Yamada W, Kawano T, Machigashira S, Nakame K, Kaji T, Ieiri S
  • Organizer: The 51st Annual Scientific Meeting of the Pacific Association of Pediatric Surgeons 2018
  • Int'l Joint Research
• [Presentation] 15歳以上に到達した先天性食道閉鎖症術後患者に対する身体的・社会的長期予後の解析 (2018)
  • Author(s): 桝屋隆太, 加治 建, 矢野圭輔, 大西 峻, 山田耕嗣, 山田和歌, 川野孝文, 町頭成郎, 中目和彦, 向井 基, 家入里志
  • Organizer: 第55回日本小児外科学会学術集会
• [Presentation] Predictive factors affecting the prognosis and late complications of 73 consecutive cases of esophageal atresia in 2 centers of Kagoshima Prefecture over 30 years. (2017)
  • Author(s): 1.Masuya R, Nakame K, Moriguchi T, Sugita K, Onishi S, Yamada K, Yamada W, Kawano T,
  • Organizer: The 50th Annual Scientific Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research