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

药物引起的QT间期延长综合征的分子机制及临床试验中心

• 批准号: 16390222
• 负责人: KAMIYA Kaichiro
• 金额: $ 9.22万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390222/
• 关键词: Long QT syndrome; ICH guideline; Arrhythmia; Drug induced

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.

众所周知，服用普通药物会意外地导致心电图QT延长和致死性心律失常。由于常见药物引起的死亡，这种药物引起的心室复极延迟(QT延长)引起了全球的关注。迫切需要阐明这种药物所致QT延长的机制，以防止医源性事故的发生。本研究试图阐明药物引起QT延长的机制。此外，还建立了临床试验中心，建设药物安全数据库。在两年的项目中，我们获得了新的发现，并成功地启动了临床试验中心。(1)药物引起的长QT综合征的分子分析：确定了结构不同的药物如苯丙地尔、硝苯卡兰、胺碘酮、屈诺酮等的结合部位。药物与通道结合的亲和力与通道腔内的药物捕获无关。这些数据发表在2006年的Mol Phrmacol杂志上。临床试验中心：与我所生物信息学教研室合作开发了符合ICH指南E14的QT间期精确分析系统。为2006年成立的临床试验中心提供技术支持。

项目成果

Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von willebrand factor binding by clustered charged-to-alanine scanning mutagenesis.

通过聚集电荷丙氨酸扫描诱变鉴定对于冯维勒布兰德因子结合所必需的血小板糖蛋白 Ib (GPIb) 的氨基酸残基。

• 发表时间: 2004
• 期刊: Journal of Biological Chemistry 279
• 作者: Niwa N;et al.;SHIMIZU Atsuya et al.
• 通讯作者: SHIMIZU Atsuya et al.

Sinoatrial node dysfunction and eary unexpected death of mice with a defect of klotho gene expression.

klotho 基因表达缺陷小鼠的窦房结功能障碍和早期意外死亡。

• 发表时间: 2004
• 期刊: Circulation 109
• 作者: TAKESHITA Kyosuke;FUJIMORI Toshihiko;KUROTAKI Yoko;HONJO Haruo et al.
• 通讯作者: HONJO Haruo et al.

Pathophysiological significance of T-type Ca2+ channels: expression of T-type Ca2+ channels in fetal and diseased heart.

• DOI: 10.1254/jphs.fmj05002x3
• 发表时间: 2005
• 期刊: Journal of pharmacological sciences
• 影响因子: 3.5
• 作者: K. Yasui;Noriko Niwa;Haruki Takemura;T. Opthof;Takao Muto;M. Horiba;A. Shimizu;Jong‐Kook Lee;H. Honjo;K. Kamiya;I. Kodama

不整脈の病態生理(小室一成(編))

心律失常的病理生理学（Kamushige Komuro（编））

• 发表时间: 2004
• 作者: NIWA Noriko;YASUI Kenji;OPTH OF Tobias;TAKEMURA Haruki;SHIMIZU Atsuya;HORIBA Mitsuru;LEE Jong-Kook;HONJO Haruo;KAMIYA Kaichiro;KODAMA Itsuo;神谷 香一郎;神谷 香一郎;神谷 香一郎;Nukiwa M;神谷香一郎;Fujiwara T;Kamiya K.;Inoue A;神谷 香一郎
• 通讯作者: 神谷 香一郎

Heart View

心观

• 发表时间: 2019
• 作者: Takafumi Sakamoto;Keita Saku;Kenji Sunagawa;Hiroyuki Tsutsui;Takafumi Sakamoto;坂本 隆史;坂本 隆史;坂本 隆史
• 通讯作者: 坂本 隆史