{"title":"在非人灵长类动物中评估作为前心律失常生物标志物的校正JT-峰值(JTpc)和Tpeak-to-Tend(TpTec):HESI 联合会的成果。","authors":"","doi":"10.1016/j.vascn.2024.107543","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG <em>vs.</em> mixed ion channel blocking drugs that prolong QTc.</p></div><div><h3>Methods</h3><p>In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories.</p></div><div><h3>Results</h3><p>In monkeys, dofetilide (0.03–0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2–50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1–15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec.</p></div><div><h3>Discussion</h3><p>Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium\",\"authors\":\"\",\"doi\":\"10.1016/j.vascn.2024.107543\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG <em>vs.</em> mixed ion channel blocking drugs that prolong QTc.</p></div><div><h3>Methods</h3><p>In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories.</p></div><div><h3>Results</h3><p>In monkeys, dofetilide (0.03–0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2–50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1–15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec.</p></div><div><h3>Discussion</h3><p>Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.</p></div>\",\"PeriodicalId\":16767,\"journal\":{\"name\":\"Journal of pharmacological and toxicological methods\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2024-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of pharmacological and toxicological methods\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1056871924000534\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmacological and toxicological methods","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1056871924000534","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium
Introduction
Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG vs. mixed ion channel blocking drugs that prolong QTc.
Methods
In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories.
Results
In monkeys, dofetilide (0.03–0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2–50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1–15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec.
Discussion
Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.
期刊介绍:
Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.