{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:32:03Z","timestamp":1777717923424,"version":"3.51.4"},"reference-count":36,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T00:00:00Z","timestamp":1545177600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction:<\/jats:title>\n                    <jats:p>\n                      Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-\u00e0-go-go-Related Gene [hERG] I\n                      <jats:sub>Kr<\/jats:sub>\n                      or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Telemetry data from Beagle dogs given dofetilide (0.3 mg\/kg), sotalol (32 mg\/kg), and verapamil (30 mg\/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg\/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Dofetilide and cisapride (I\n                      <jats:sub>Kr<\/jats:sub>\n                      or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion:<\/jats:title>\n                    <jats:p>\n                      Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective I\n                      <jats:sub>Kr<\/jats:sub>\n                      blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1091581818813601","type":"journal-article","created":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T23:13:50Z","timestamp":1545261230000},"page":"23-32","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium"],"prefix":"10.1177","volume":"38","author":[{"given":"Emmanuel","family":"Boulay","sequence":"first","affiliation":[{"name":"GREPAQ (Groupe de recherche en pharmacologie animale du Qu\u00e9bec), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, Quebec, Canada"},{"name":"CiToxLAB North America, Laval, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew M.","family":"Abernathy","sequence":"additional","affiliation":[{"name":"Eli Lily, Indianapolis, IN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ray","family":"Chui","sequence":"additional","affiliation":[{"name":"Amgen, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory S.","family":"Friedrichs","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariane","family":"Menard","sequence":"additional","affiliation":[{"name":"CiToxLAB North America, Laval, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill","family":"Steidl-Nichols","sequence":"additional","affiliation":[{"name":"Covance, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Pierson","sequence":"additional","affiliation":[{"name":"HESI, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael K.","family":"Pugsley","sequence":"additional","affiliation":[{"name":"CiToxLAB North America, Laval, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric I.","family":"Rossman","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, King of Prussia, PA, United 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