{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T02:58:43Z","timestamp":1740106723474,"version":"3.37.3"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Toho University School of Medicine","award":["21-10"],"award-info":[{"award-number":["21-10"]}]},{"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":["JP21mk0101189"],"award-info":[{"award-number":["JP21mk0101189"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6 pharmacologically distinct drugs. The following drugs were orally administered in conscious state, astemizole: 1, 5, and 10\u2009mg\/kg (n\u2009=\u20096); haloperidol: 1, 10, and 30\u2009mg\/kg (n\u2009=\u20095); amiodarone: 30\u2009mg\/kg (n\u2009=\u20094); famotidine: 10\u2009mg\/kg (n\u2009=\u20094); levofloxacin: 100\u2009mg\/kg (n\u2009=\u20094); and tolterodine: 0.2, 1, and 4.5\u2009mg\/kg (n\u2009=\u20094). Astemizole of 5 and 10\u2009mg\/kg significantly prolonged \u0394\u0394QTcF, whereas no significant change was observed by the others. Torsade de pointes (TdP) was induced by astemizole of 5 and 10\u2009mg\/kg in 3\/6 and 6\/6, and by haloperidol of 10 and 30\u2009mg\/kg in 1\/5 and 1\/5, respectively, which was not observed in the others. Torsadogenic risk of the drugs was quantified using the criteria for the monkey model specified in our previous study. Namely, high-risk drugs induced TdP at \u2264 3 times of their maximum clinical daily dose. Intermediate-risk drugs did not induce TdP at this dose range, but induced it at higher doses. Low\/no-risk drugs never induced TdP at any dose tested. The magnitude of risk was intermediate for astemizole and haloperidol, and low\/no risk for the others. The prespecified, risk-stratification method for the monkey model may solve the issue existing between nonclinical models and patients with labile repolarization, which can reinforce the regulatory decision-making and labeling at time of marketing application of nondouble-negative drug candidate (hERG assay positive and\/or in vivo QT study positive).<\/jats:p>","DOI":"10.1093\/toxsci\/kfac088","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T12:37:58Z","timestamp":1661171878000},"page":"99-109","source":"Crossref","is-referenced-by-count":1,"title":["Validation of Risk-Stratification Method for the Chronic Atrioventricular Block Cynomolgus Monkey Model and Its Mechanistic Interpretation Using 6 Drugs With Pharmacologically Distinct Profile"],"prefix":"10.1093","volume":"190","author":[{"given":"Ai","family":"Goto","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Toho University , Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Ina Research Inc. , 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 , Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Izumi-Nakaseko","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Toho University , 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 , Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Takei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Toho University , 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 , 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, Faculty of Medicine, Toho University , Tokyo 143-8540, Japan"},{"name":"Department of Inflammation & Pain Control Research, Faculty of Medicine, Toho University , Tokyo 143-8540, Japan"},{"name":"Department of Aging Pharmacology, Faculty of Medicine, Toho University , Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"2022102808010884600_kfac088-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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