{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T02:59:41Z","timestamp":1740106781190,"version":"3.37.3"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K16136"],"award-info":[{"award-number":["20K16136"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP18mk0104117"],"award-info":[{"award-number":["JP18mk0104117"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5\u2009mg\/kg, n\u2009=\u20095 for each dose), dl-sotalol (0, 1, 3, and 10\u2009mg\/kg, n\u2009=\u20095 for each dose), bepridil (0, 10, and 100\u2009mg\/kg, n\u2009=\u20094 for each dose), verapamil (0, 1.5, 15, and 75\u2009mg\/kg, n\u2009=\u20094 for each dose) were orally administered to the monkeys in conscious state. Five mg\/kg of cisapride, 1, 3, and 10\u2009mg\/kg of dl-sotalol and 100\u2009mg\/kg of bepridil prolonged \u0394\u0394QTcF, which was not observed by verapamil. Torsade de pointes was induced by 5\u2009mg\/kg of cisapride in 2 out of 5 animals, by 10\u2009mg\/kg of dl-sotalol in 5 out of 5 and by 100\u2009mg\/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol &amp;gt;bepridil \u2265cisapride &amp;gt;verapamil in our study. Since the order was bepridil \u2265dl-sotalol &amp;gt;cisapride &amp;gt;verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab015","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T18:03:04Z","timestamp":1612375384000},"page":"125-133","source":"Crossref","is-referenced-by-count":2,"title":["Torsadogenic Action of Cisapride, <i>dl<\/i>-Sotalol, Bepridil, and Verapamil Analyzed by the Chronic Atrioventricular Block Cynomolgus Monkeys: Comparison With That Reported in the CiPA <i>In Silico<\/i> Mechanistic Model"],"prefix":"10.1093","volume":"181","author":[{"given":"Ai","family":"Goto","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Safety Research Center Ina Research Inc., Ina-shi, Nagano 399-4501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Kambayashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshio","family":"Nunoi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Izumi-Nakaseko","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Inflammation & Pain Control Research, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Takei","sequence":"additional","affiliation":[{"name":"Department of Translational Research & Cellular Therapeutics, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akio","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Aging Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunari","family":"Kanda","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Inflammation & Pain Control Research, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Translational Research & Cellular Therapeutics, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Aging Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"2021092714022070000_kfab015-B1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1254\/jphs.QT-A4","article-title":"QT PRODACT: In vivo QT assay with a conscious monkey for assessment of the potential for drug-induced QT interval prolongation","volume":"99","author":"Ando","year":"2005","journal-title":"J. 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