Molecular mechanism and clinical trial center for the drug-induced QT prolongation syndrome

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It is well known that administration of common drugs unexpectedly induce QT prolongation in ECG and lethal arrhythmias. This drug-induced delay in ventricular repolarization (QT prolongation) attracts global attention because of the death caused by common drugs. It is an urgent need to clarify the mechanism of this drug-induced QT prolongation to prevent iatrogenic accidents. In this study, we try to clarify the mechanisms of drug-induced QT prolongation. In addition, clinical trial center was founded to construct drug data base for safety. During two years of the project, we could get novel findings and start clinical trial center successfully.(1)Molecular analysis of drug-induced long QT syndrome : Binding sites were determined in structurally diverse drugs such as bepridil, nifekalant, amiodarone, dronedarone and so on. Affinity of drug binding to channel was revealed not to correlate with drug trapping within the channel cavity. These data were published in Mol Phrmacol 2006. And also drug action to IKs channel was demonstrated to be modulated by expression of KCNE1, be-ta subunit.(2)Clinical trial center : System of precise analysis of QT interval compatible with ICH guideline E14 was developed with the collaboration of Department of Bioinformatics of our research institute. Technical support was delivered to clinical trial center founded in 2006.