Galantamine (Reminyl庐) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current

详细信息	查看全文 | 推荐本文 |

• 作者：Patrick Vigneault^a ; ^b ; ^{patrick.vigneault@criucpq.ulaval.ca} ; Sarah Bourgault^a ; ^b ; ^{sarah.bourgault@umontreal.ca} ; Nisrin Kaddar^a ; ^b ; ^{nisrin.kaddar@criucpq.ulaval.ca} ; Bertrand Caillier^a ; ^b ; ^{bertrand.caillier.1@ulaval.ca} ; Sylvie Pilote^b ; ^{sylvie.pilote@criucpq.ulaval.ca} ; Dany Patoine^b ; ^{dany.patoine@criucpq.ulaval.ca} ; Chantale Simard^a ; ^b ; ^{chantale.simard@pha.ulaval.ca} ; Benoit Drolet^a ; ^b ; ^{benoit.drolet@pha.ulaval.ca}
• 关键词：Galantamine ; Ventricular repolarization ; QT interval prolongation ; Action potential ; HERG blocker
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 April, 2012
• 卷：681
• 期：1-3
• 页码：68-74
• 文件大小：699 K

摘要

Galantamine is a reversible inhibitor of acetylcholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. It is used for treating mild-to-moderate Alzheimer's disease. Interestingly, QT interval prolongation on the electrocardiogram (ECG), malignant ventricular arrhythmias and syncope have been reported with galantamine. Our objective was to evaluate the effects of galantamine on cardiac ventricular repolarization. Three sets of experiments were undertaken: 1) Whole cell patch-clamp experiments: HERG- or KCNQ1 + KCNE1-transfected cells were exposed to galantamine 0.1-1000 渭mol/l (n = 25 cells, total) to assess drug effect on HERG and KCNQ1 + KCNE1 currents. 2) Langendorff perfusion experiments: Isolated hearts from male Hartley guinea pigs (n = 9) were exposed to galantamine 1 渭mol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90%repolarization (MAPD₉₀). 3) Cardiac telemetry experiments: Guinea pigs (n = 7) implanted with wireless transmitters were injected a single intraperitoneal (i.p.) dose of galantamine 3 mg/kg and 24 h ECG recordings were made. 1) The estimated IC₅₀ for galantamine on HERG current was 760.2 渭mol/l. Moreover, galantamine 10 渭mol/l had a small inhibiting effect on KCNQ1 + KCNE1 current (12.17 卤 2.19%inhibition, n = 10 cells). 2) While pacing at cycle lengths of 150, 200 or 250 ms, galantamine 1 渭mol/l prolonged MAPD₉₀ by respectively 5.1 卤 1.6 ms, 9.4 卤 1.9 ms and 12.1 卤 2.1 ms. 3) Galantamine 3 mg/kg i.p. caused a maximal 11.9 卤 2.7 ms prolongation of the corrected QT (QTc). Galantamine is a weak HERG blocker. This contributes to its mild QT-prolonging effect. Patients could be at risk of cardiac proarrhythmia during drug overdosage or interactions involving cytochrome 2D6 drug-metabolizing enzyme.