Referenced in: none

Automatically associated channels: Kv11.1

Title: Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Authors: Lars Johannesen, Jose Vicente, Jay W Mason, Cassandra Erato, Carlos Sanabria, Kristin Waite-Labott, Mira Hong, John Lin, Ping Guo, Abdul Mutlib, Jianyao Wang, William J Crumb, Ksenia Blinova, Dulciana Chan, Jayna Stohlman, Jeffry Florian, Martin Ugander, Norman Stockbridge, David G Strauss

Journal, date & volume: Clin. Pharmacol. Ther., 2015 Aug 11 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26259627

Abstract
Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.