토끼 심장에서 단상활동전위의 TRIaD 분석을 이용한 약물에 대한 심장 안전성 평가
Cardiac safety evaluation on drugs using the TRIaD assay in the rabbit cardiac monophasic action potential
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Drug-induced torsades de pointes (TdP) have been linked to a sudden cardiac death. Prolongation of the action potential duration (APD) and the QT interval (PQT), in nonclinical assays, have been investigated before drug development. However, TdP can often occur without any appreciable QT prolongation, and drug development companies and researchers may ask better accurate models or methods. We wish to verify whether it is effective to determine the cardiac toxicity as a result of the measurement using the TRIaD assay in the rabbit cardiac monophasic action potential. ‘TRIaD’ means Trianguation, Reverse use dependence, Instability and Dispersion. In this study, to confirm this assay, control, negative control and positive control were classified based on the degree of cardiotoxicity. Control group was perfused by only normal Tyrode’s solution. Diltiazem and Amoxicillin were used as negative controls. Terfenadine, Quinidine, Amiodarone, and Nifedipine were used as positive controls. Based on these, proarrhythmic scores were calculated as follow: instability 20 points, triangulation 10 points, and RUD 5 points. Both in control and negative groups, proarrhythmic score did not exceed the 25 points, but exceeded in all positive groups. These data propose that this is robust and reliable assay that can add value to drug-induced prolongation/TdP risk assessment. Additionally, this assay provides detailed information on the overall profile of drug-induced electrophysiological effects. Therefore, TRIaD assay can be a valuable to establish for the cardiovascular risk assessment of drugs.
Abstract
Drug-induced torsades de pointes (TdP) have been linked to a sudden cardiac death. Prolongation of the action potential duration (APD) and the QT interval (PQT), in nonclinical assays, have been investigated before drug development. However, TdP can often occur without any appreciable QT prolongation, and drug development companies and researchers may ask better accurate models or methods. We wish to verify whether it is effective to determine the cardiac toxicity as a result of the measurement using the TRIaD assay in the rabbit cardiac monophasic action potential. ‘TRIaD’ means Trianguation, Reverse use dependence, Instability and Dispersion. In this study, to confirm this assay, control, negative control and positive control were classified based on the degree of cardiotoxicity. Control group was perfused by only normal Tyrode’s solution. Diltiazem and Amoxicillin were used as negative controls. Terfenadine, Quinidine, Amiodarone, and Nifedipine were used as positive controls. Based on these, proarrhythmic scores were calculated as follow: instability 20 points, triangulation 10 points, and RUD 5 points. Both in control and negative groups, proarrhythmic score did not exceed the 25 points, but exceeded in all positive groups. These data propose that this is robust and reliable assay that can add value to drug-induced prolongation/TdP risk assessment. Additionally, this assay provides detailed information on the overall profile of drug-induced electrophysiological effects. Therefore, TRIaD assay can be a valuable to establish for the cardiovascular risk assessment of drugs.
참고문헌 (28)
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