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Investigation of novel safety biomarker for arteritis using in vivo MRI

藤井, 雄太 大阪大学 DOI:10.18910/93000

2023.09.25

概要

Title

Investigation of novel safety biomarker for
arteritis using in vivo MRI

Author(s)

藤井, 雄太

Citation

大阪大学, 2023, 博士論文

Version Type VoR
URL

https://doi.org/10.18910/93000

rights
Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

様式3




論文題名









藤井







雄太



Investigation of novel safety biomarker for arteritis using in vivo MRI
(in vivo MRIを用いた動脈炎の新規安全性バイオマーカーの探索)

Since drug-induced arteritis is difficult to monitor in clinical trials, the occurrence of arteritis in
nonclinical toxicological studies of a candidate drug makes development of the drug very difficult. Although
arteritis is a severe toxicity, the lesion is completely recovered if the offending drug is discontinued or
treatment is initiated at an early phase. If arteritis can be detected in an early phase with a biomarker,
clinical trials can be conducted safely. Therefore, biomarker for identifying drug-induced arteritis is highly
desirable. Since evaluation in humans is difficult, firstly I conducted the research with rats. On magnetic
resonance imaging (MRI) in rodents, evaluation of the organs requires higher resolution due to their small
size, and research had not progressed as same as in human. However, in vivo imaging techniques, including
MRI in rodents, have made remarkable advances in recent years.
I made hypothesis that MRI could be used to find a biomarker candidate for drug-induced arteritis. However,
there are no reports on the evaluation of drug-induced arteritis by MRI. Therefore, I conducted this study
to clarify whether the finding by MRI can be a biomarker as follows.
First study was conducted to clarify which dosing regimen was appropriate for MRI assessment. Based on the
obtained results, subcutaneously administered once daily 100 mg/kg/day in FM and 40 mg/kg/day in MH for 2
days is considered an optimal dosing regimen for MRI assessment.
The second study was conducted to clarify whether fenoldopam mesylate (FM)-induced arteritis in rats can
be detected by MRI. FM causes arteritis due to its vasodilatory effect. Mesenteric arteries were examined
with ex vivo high-resolution MRI, postmortem MRI and in vivo MRI on the day after final dosing or 3 days after
administration of the final dose. The ex vivo MRI showed low-intensity areas and a high signal intensity region
around the artery, and these findings were considered to be erythrocytes infiltrating the arterial wall and
perivascular edema, respectively. In the in vivo study, the MRI of the FM-administered group showed a high
signal intensity region around the artery.
The third study was conducted to clarify whether arteritis induced by vasoconstrictor effect could be detected
by MRI. The mesenteric arteries of midodrine hydrochloride (MH)-administered animals were examined using in
vivo MRI at 1 day or 7 days after administration of the final dose. High signal intensity region around the
artery was observed in animals with minimal perivascular lesions and not observed in an animal without
histological changes on the day after the final dose. On the 7th day after the final dose, no abnormality
was observed in histopathological examinations and no high signal intensity regions were observed by MRI in
any animal.
In conclusion, our results indicated that regardless of pathogenic mechanism and degree of changes, high
signal intensity region in MRI could be a versatile biomarker for detecting the arteritis with high specificity
and high sensitivity. In addition, it is suggested it could be possible to judge the discontinuation of
administration of a drug in the phase of minimal lesion, which can be completely resolved. This is extremely
useful for conducting clinical trials of drugs that may cause arteritis.

様式7

論文審査の結果の要旨及び担当者






藤 井

雄 太

(職)

論文審査担当者















教授

八木 健

教授

髙島 成二

教授

上田 昌宏

教授

井上 豪



論文審査の結果の要旨
薬剤性血管炎は、バイオマーカーがないため、医薬品開発での大きな問題となっている。課題への
取り組みの第一歩として、ラットにおける動脈炎に対する新規バイオマーカーの探索を行った。異
なるメカニズムにより生じる2つの薬剤性血管炎モデルを用いた検討を行い、MRIによる動脈周囲の
高信号化がバイオマーカーになりうることを見出した。本手法は、軽微な変化であっても検出可能
であり、汎用性のある手法であることを明らかにし、特異的で鋭敏なバイオマーカーになりうるこ
とを見出した。本論文における薬剤性動脈炎の検出はヒトや動物を含め、これまでに報告がなく、
また、ラットにおいて小型の動脈炎をMRIにて評価・検出した研究成果は世界初のものであり、博
士の学位を授与するに値するものと認める。なお、チェックツール“iThenticate”を使用し、剽
窃、引用漏れ、二重投稿等のチェックを終えていることを申し添えます。

この論文で使われている画像

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Record of research achievements

Publications

Fujii Y, Yoshino Y, Chihara K, Nakae A, Enmi JI, Yoshioka Y, Miyawaki I. Detection of fenoldopaminduced arteritis in rats using ex vivo / in vivo MRI. Toxicol Rep. 2022 Jul 28;9:1595-1602.

Fujii Y, Yoshino Y, Chihara K, Nakae A, Enmi JI, Yoshioka Y, Miyawaki I. Evaluation of in vivo MRI

for detecting midodrine-induced arteritis in rats. Toxicol Rep. 2023 Jan 5;10:97-103.

Conference presentations

Title: Detection of drug-induced vasculitis using in vivo MRI

Conference: The 47th Annual Meeting of the Japanese Society of Toxicology

Presentation form: Poster

Title: Evaluation of rodent toxicity using MRI: fatty liver and vasculitis

Conference: The 47th Annual Meeting of the Japanese Society of Toxicology

Presentation form: Oral (Work shop)

Title: in vivo イメージング技術の毒性評価への応用

Conference: 第 4 回 医薬品毒性機序研究会

Presentation form: Oral (Symposium)

Title: Detection of Fenoldopam-induced arteritis in rats using ex vivo/in vivo MRI

Conference: The 3rd Annual Scientific Meeting of Asian Society of Magnetic Resonance in

Medicine and the 49th Annual Meeting of the Japanese Society for Magnetic Resonance in Medicine

Presentation form: Poster

Title: Detection of drug-induced arteritis in rats using ex vivo/in vivo MRI

Conference: The 38th Annual Meeting of the Japanese Society of Toxicologic Pathology

Presentation form: Oral (Work shop)

70

Acknowledgements

I would like to express my deep gratitude to my supervisor, Professor Takeshi Yagi of Osaka

University and Yoshichika Yoshioka (former Professor of Osaka University), for their support and

kind guidance throughout the process of carrying out this research and completing my dissertation.

At the same time, I would like to express my deep gratitude to Dr. Jun-ichiro Enmi for his guidance

on experimental techniques and many valuable advices in carrying out this research.

Furthermore, we would like to express my sincere gratitude to everyone in the Preclinical Research

Unit of Sumitomo Pharma Co., Ltd. for their support in this research.

Finally, I would like to thank my family for their continuous support for my research activities.

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