TdP 고⋅중⋅저 위험군 3종에 대한 in vitro 심혈관계 안전성약리 평가

안진렬; 정인교; 박성혜; 김관수; 권찬혁; 최선옥

추천

검색

자료유형: 학술저널

저자정보: 안진렬 (식품의약품안전평가원 독성평가연구부 약리연구과) 정인교 (식품의약품안전평가원 독성평가연구부 약리연구과) 박성혜 (식품의약품안전평가원 독성평가연구부 약리연구과) 김관수 (식품의약품안전평가원 독성평가연구부 약리연구과) 권찬혁 (식품의약품안전평가원 독성평가연구부 약리연구과) 최선옥 (식품의약품안전평가원 독성평가연구부 약리연구과)

저널정보: 한국동물실험대체법학회 한국동물실험대체법학회 한국동물실험대체법학회지 제16권 제1호

발행연도: 2022.12

수록면: 15 - 24 (10page)

이용수

📌

연구주제

📖

연구배경

🔬

연구방법

🏆

연구결과

초록· 키워드

오류제보하기

The Comprehensive in vitro Proarrhythmia Assay (CiPA) project has been recently proposed to assess the proarrhythmic risk on multiple cardiac ion channels in the development of new drugs. Due to be based solely on in vitro hERG channel block and in vivo QT prolongation, the current ICH S7B nonclinical testing strategy is imperfect and used to be mis-identified for an evaluation of drug-associated torsade de pointes (TdP) risk. The inhibition of hERG channels induces QT prolongation and even generate TdP, while the balanced block of other cardiac ion channels such as Nav1.5 sodium channels and Cav1.2 calcium channels reduces QT prolongation or TdP occurrence. From this reasons, we investigated the drug effects on Nav1.5 channels and Cav1.2 channels as well as hERG channels. First, we examined the effect of the 3 CiPA training set drugs categorized as proarrhythmic low risk (mexiletine), intermediate risk (chloropromazine) and high risk (sotalol) on three cardiac ion channels. Using the manual whole-cell patch clamp technique, each cardiac ion currents were measured in cell lines expressing hERG, Nav1.5, and Cav1.2 channels, respectively. In addition, field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded by performing microelectrode array (MEA) to confirm the integrative channel effect of those drugs. As a result, all of sotalol, chloropromazine and mexiletine blocked hERG channels, whereas chloropromazine and mexiletine inhibited Cav1.2 calcium currents more than sotalol, expecting the reduction of QT prolongation and TdP occurrence via balanced ion channel block by chloropromazine and mexiletine. Corresponding to these results, furthermore, sotalol induced more prolonged FPD in hiPSC-CMs as compared to chloropromazine and mexiletine. Thus, we suggest that the optimization and development of new in vitro cardiac safety and pharmacology test strategy on multiple cardiac ion channels to comprehensively predict proarrhythmic risk.

#CiPA initiative #TdP #in vitro multiple ion channel assay #MEA #hiPSC-CMs

참고문헌 (0)

참고문헌 신청

참고문헌이 DBpia에서 서비스 중이라면, [참고문헌 신청]을 통해 등록해보세요

함께 읽어보면 좋을 논문

논문 유사도에 따라 DBpia 가 추천하는 논문입니다. 함께 보면 좋을 연관 논문을 확인해보세요!