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タイトル別表記
血管新生阻害剤特異的な高血圧は大動脈解離発症のリスクを高める
著者
辻󠄀中, 海斗 徳島大学大学院医学研究科(医学専攻)
Miyata, Koji Tokushima University
Yoshioka, Toshihiko Tokushima University
Oomine, Kohei Tokushima University
Nishi, Honoka Tokushima University
Kondo, Masateru Tokushima University
Itokazu, Syuto Tokushima University
Miyata, Tatsumi Tokushima University
Sato, Maki Tokushima University
中馬, 真幸 Asahikawa Medical University
キーワード
Angiogenesis inhibitors
Aortic dissection
Real-world database
Hypertension
FDA Adverse Event Reporting System
資料タイプ
学位論文
抄録
Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p<0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.
掲載誌名
Biomedicine & Pharmacotherapy
ISSN
07533322
19506007
cat書誌ID
AA10506249
AA11523196
出版者
Elsevier
167
開始ページ
115504
発行日
2023-09-16
権利情報
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3798号
学位記番号
甲医第1606号
学位授与年月日
2024-03-22
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院