hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia

Nogawa, Hisashi; Kawai, Tadao

doi:10.1016/j.ejphar.2014.06.044

Cited by 44 publications

(31 citation statements)

References 46 publications

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“…Some potential causes for hysteresis include distribution delay between the plasma and effect site, response delay, sensitization of receptors or slow receptor kinetics, regulation of receptors after ongoing exposure, and the formation and subsequent accumulation of active metabolites through drug metabolism, as well as delayed or modified activity . Patch‐clamp studies have shown that the binding of moxifloxacin to hERG is reversible and use dependent; thus, the long‐term effect on repolarization may be exerted through another long‐term mechanism, such as the production of the pharmacologically active moxifloxacin glucuronide metabolite or the inhibition of expression or trafficking of hERG to the cardiomyocyte plasma membrane . Moxifloxacin is mainly metabolized to glucuronide and sulfate conjugates.…”

Section: Discussionmentioning

confidence: 99%

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Täubel

Ferber

Fernandes

et al. 2018

The Journal of Clinical Pharma

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Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.

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Section: Discussionmentioning

confidence: 99%

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Täubel

Ferber

Fernandes

et al. 2018

The Journal of Clinical Pharma

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“…37 There are, however, also examples of drugs that reduce I Kr by inhibiting, directly or indirectly, the trafficking of K v 11.1 to the plasma membrane. 38 Given their specific mode of action, it is unlikely that the I Kr -inhibiting effects of these drugs can be abolished by LUF7244 or a related compound.…”

Section: Luf7244's Mode Of Actionmentioning

confidence: 99%

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Liu

Veldhoven

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background— Ventricular arrhythmias as a result of unintentional blockade of the K v 11.1 (hERG [human ether-à-go-go–related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by K v 11.1 allosteric modulators. Methods and Results— Using [ 3 H]dofetilide-binding assays with membranes of human K v 11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the K v 11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The K v 11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays. Conclusions— Allosteric modulation of the K v 11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended K v 11.1 blockers via pharmacological combination therapy.

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“…Multiple receptors sites for hERG blockers have been determined and are all located on the S6: a pair of polar residues (Thr 623 and Ser 624) sit just below the selectivity filter and a pair of aromatic residues (Tyr 652 and Phe 656) in the lower part of the S6 helix [121–123]. Apart from direct channel block, some drugs may also cause inhibition of membrane trafficking of hERG subunits [124, 125]. Arsenic trioxide [126], geldanamycin [127], pentamidine [128, 129] and probucol [130, 131] have been shown to inhibit trafficking without causing channel block.…”

Section: Delayed Rectifiers and Cardiac Rhythm Disordersmentioning

confidence: 99%

“…Arsenic trioxide [126], geldanamycin [127], pentamidine [128, 129] and probucol [130, 131] have been shown to inhibit trafficking without causing channel block. Other reports have also suggested that some previously described hERG blockers may also cause additional inhibition of trafficking and are thus termed dual inhibitors [124]. …”

Section: Delayed Rectifiers and Cardiac Rhythm Disordersmentioning

confidence: 99%

Cardiac Delayed Rectifier Potassium Channels in Health and Disease

Chen

Sampson

Kass

2016

Cardiac Electrophysiology Clinics

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Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this chapter, we will review the molecular identities and biophysical properties of these channels. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the possibility and prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia.

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hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia

Cited by 44 publications

References 46 publications

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Cardiac Delayed Rectifier Potassium Channels in Health and Disease

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hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia

Cited by 44 publications

References 46 publications

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Allosteric Modulation of K v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Cardiac Delayed Rectifier Potassium Channels in Health and Disease

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Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias