| ジャーナル名 | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie |
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| 投稿日 | 2023/9/19 |
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| 投稿者 | Tsujinaka, Kaito; Izawa-Ishizawa, Yuki; Miyata, Koji; Yoshioka, Toshihiko; Oomine, Kohei; Nishi, Honoka; Kondo, Masateru; Itokazu, Syuto; Miyata, Tatsumi; Niimura, Takahiro; Sato, Maki; Aizawa, Fuka; Yagi, Kenta; Chuma, Masayuki; Zamami, Yoshito; Goda, Mitsuhiro; Ishizawa, Keisuke |
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| 組織名 | Department of Clinical Pharmacology and Therapeutics, Tokushima University;Graduate School of Biomedical Sciences, Tokushima, Japan; Department of Pharmacy,;Tokushima University Hospital, Tokushima, Japan.;Graduate School of Biomedical Sciences, Tokushima, Japan; Department of General;Medicine, Taoka Hospital, Tokushima, Japan. Electronic address:;yuki.ishizawa@gmail.com.;Graduate School of Biomedical Sciences, Tokushima, Japan.;Graduate School of Biomedical Sciences, Tokushima, Japan; Clinical Research;Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima,;Japan.;Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical University &;University Hospital, Asahikawa, Japan.;Department of Pharmacy, Okayama University Hospital, Okayama, Japan.;Tokushima University Hospital, Tokushima, Japan; Clinical Research Center for;Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/37722188/ |
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| アブストラクト | 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. |
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