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Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey

  • Original Article—Alimentary Tract
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Abstract

Background

Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose–effect on AEs.

Methods

A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception.

Results

Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose–effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported.

Conclusions

IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

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Abbreviations

AE:

Adverse event

ALP:

Alkaline phosphatase

ALT:

Alanine transaminase

AST:

Aspartate transaminase

γ-GTP:

γ-Glutamyl transpeptidase

IN:

Indigo naturalis

PAH:

Pulmonary arterial hypertension

UC:

Ulcerative colitis

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Acknowledgements

We thank all the collaborators who cooperated in this first nationwide survey of IN-induced adverse events in Japan. INDIGO survey Group are Makoto Naganuma, Shinya Sugimoto, Tomohiro Fukuda, Yusuke Yoshimatsu, Po-sung Chu, Nobuhiro Nakamoto, Masaharu Kataoka, Takanori Kanai (Keio University School of Medicine), Toshifumi Hibi (Kitasato Institute Hospital), Hideki Iijima (Osaka University Graduate School of Medicine), Motoi Uchino, Kenji Watanabe, Shiro Nakamura (Hyogo College of Medicine), Yasuo Suzuki (Toho University Sakura Medical Center), Yuichi Matsuno, Atsushi Hirano, Motohiro Esaki (Kyushu University), Ryohei Hayashi, Yoshitaka Ueno (Hiroshima University), Takayuki Yamamoto (Yokkaichi Hazu Medical Center), Koji Sawada (Dojima General and Gastroenterology Clinic), Kosaku Kawashima, Shunji Ishihara (Shimane University), Toshimitsu Araki (Mie University), Shinichi Hashimoto (Yamaguchi University), Junji Yokoyama (Niigata University), Shinya Ashizuka (University of Miyazaki), Hideo Suzuki (Tsukuba University), Tatsuya Toyokawa (Fukuyama Medical Center), Hirotake Sakuraba (Hirosaki University), Kazuhiro Matsueda (Kurashiki Central Hospital), Naoki Yoshimura (Yamate Medical Center), Naoki Ohmiya (Fujita Health University School of Medicine), Yoshiyuki Kayashima (Matsuyama Red Cross Hospital), Shunichi Yanai, Takayuki Matsumoto (Iwate Medical University), Hiroyuki Kobayashi (Fukuoka Sanno Hospital), Sachiko Nakajima, Tsutomu Nishida (Toyonaka Municipal Hospital), Yoshiaki Takeuchi (Showa University), Hirotaka Shimizu (National Center for Child Health and Development), Kenji Ina (Nagoya Memorial Hospital), Takuji Kawamura (Japanese Red Cross Kyoto Daini Hospital).

Funding

This study was supported in part by Research Grants for special research on intractable diseases from the Ministry of Health, Labor and Welfare of Japan.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Makoto Naganuma, Shinya Sugimoto, Tomohiro Fukuda, Nobuhiro Nakamoto & Takanori Kanai

  2. Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School, Ibaraki, Japan

    Hideo Suzuki

  3. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yuichi Matsuno

  4. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan

    Toshimitsu Araki

  5. Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan

    Hirotaka Shimizu

  6. Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan

    Ryohei Hayashi

  7. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan

    Hideki Iijima

  8. Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan

    Shiro Nakamura

  9. Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Masaharu Kataoka

  10. Pulmonary Hypertension Center, International University of Health and Welfare Mita Hospital, Tokyo, Japan

    Yuichi Tamura

  11. Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Koichiro Tatsumi

  12. Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

    Toshifumi Hibi

  13. IBD Center, Toho University Sakura Medical Center, Sakura, Japan

    Yasuo Suzuki

Authors
  1. Makoto Naganuma
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  2. Shinya Sugimoto
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  3. Hideo Suzuki
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  4. Yuichi Matsuno
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  5. Toshimitsu Araki
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  6. Hirotaka Shimizu
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  7. Ryohei Hayashi
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  8. Tomohiro Fukuda
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  9. Nobuhiro Nakamoto
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  10. Hideki Iijima
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  11. Shiro Nakamura
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  12. Masaharu Kataoka
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  13. Yuichi Tamura
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  14. Koichiro Tatsumi
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  15. Toshifumi Hibi
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  16. Yasuo Suzuki
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  17. Takanori Kanai
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Consortia

INDIGO survey Group

  • Makoto Naganuma
  • , Shinya Sugimoto
  • , Tomohiro Fukuda
  • , Yusuke Yoshimatsu
  • , Po-sung Chu
  • , Nobuhiro Nakamoto
  • , Masaharu Kataoka
  • , Takanori Kanai
  • , Toshifumi Hibi
  • , Hideki Iijima
  • , Motoi Uchino
  • , Kenji Watanabe
  • , Shiro Nakamura
  • , Yasuo Suzuki
  • , Yuichi Matsuno
  • , Atsushi Hirano
  • , Motohiro Esaki
  • , Ryohei Hayashi
  • , Yoshitaka Ueno
  • , Takayuki Yamamoto
  • , Koji Sawada
  • , Kosaku Kawashima
  • , Shunji Ishihara
  • , Toshimitsu Araki
  • , Shinichi Hashimoto
  • , Junji Yokoyama
  • , Shinya Ashizuka
  • , Hideo Suzuki
  • , Tatsuya Toyokawa
  • , Hirotake Sakuraba
  • , Kazuhiro Matsueda
  • , Naoki Yoshimura
  • , Naoki Ohmiya
  • , Yoshiyuki Kayashima
  • , Shunichi Yanai
  • , Takayuki Matsumoto
  • , Hiroyuki Kobayashi
  • , Sachiko Nakajima
  • , Tsutomu Nishida
  • , Yoshiaki Takeuchi
  • , Hirotaka Shimizu
  • , Kenji Ina
  •  & Takuji Kawamura

Contributions

TK conceived the study. MN designed the main concept of this study and drafted the main protocol. SS and NN helped to draft the main protocol. MN and SS participated in analysis and interpretation of data. All the authors participated in patient enrolment and clinical data acquisition. MN, SS and TK drafted and wrote the manuscript. All the authors contributed to critical review and approved the final draft.

Corresponding authors

Correspondence to Makoto Naganuma or Takanori Kanai.

Ethics declarations

Conflict of interest

MN received commercial research funds from EA pharma Co., Ltd. and Mochida Pharmaceutical Co., Ltd., outside the submitted work. SN received lecture fees from Mitsubishi Tanabe Pharma Corp., AbbVie GK, Zeria Pharmaceutical co., Ltd., EA pharma Co., Ltd., and commercial research funds from Mitsubishi Tanabe Pharma Corp., AbbVie GK, EA pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd, JIMRO Co., Ltd., Otsuka Pharmaceutical Factory Inc., Takeda Pharmaceutical Co., Ltd, outside the submitted work. YS received lecture fees from Mitsubishi Tanabe Pharma Corp., AbbVie GK, Zeria Pharmaceutical co., Ltd., EA pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd. Janssen Japan Co., Ltd and commercial research funds from Mitsubishi Tanabe Pharma Corp., EA pharma Co., Ltd., AbbVie GK, EA pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd, AbbVie GK, JIMRO Co., Ltd., outside the submitted work. TK received lecture fees from Mitsubishi Tanabe Pharma Corp, Astellas Pharma Inc, Miyarisan Pharmaceutical Co., Ltd. AstraZeneca Plc, EA Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd. and commercial research funds from AbbVie GK, Mochida Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corp, Takeda Pharmaceutical Co., Ltd., Nihon Kayaku, Yakult Honsha Co., Ltd., Zeria Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Ezaki Glico Co., Ltd. JIMRO Co., Ltd., EN Otsuka Pharmaceutical Co., Ltd, outside the submitted work.

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INDIGO survey Group members are listed in the Acknowledgements section.

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Naganuma, M., Sugimoto, S., Suzuki, H. et al. Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey. J Gastroenterol 54, 891–896 (2019). https://doi.org/10.1007/s00535-019-01591-9

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  • DOI: https://doi.org/10.1007/s00535-019-01591-9

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