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ID 119327
Title Alternative
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
Author
Tsujinaka, Kaito Tokushima University
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
Chuma, Masayuki Asahikawa Medical University
Keywords
Angiogenesis inhibitors
Aortic dissection
Real-world database
Hypertension
FDA Adverse Event Reporting System
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Biomedicine & Pharmacotherapy
ISSN
07533322
19506007
NCID
AA10506249
AA11523196
Publisher
Elsevier
Volume
167
Start Page
115504
Published Date
2023-09-16
Rights
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3798号
Diploma Number
甲医第1606号
Granted Date
2024-03-22
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital