Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia

Sato, Shiho; Zamami, Yoshito; Imai, Toru; Tanaka, Satoshi; Koyama, Toshihiro; Niimura, Takahiro; Chuma, Masayuki; Koga, Tadashi; Takechi, Kenshi; Kurata, Yasuko; Kondo, Yutaka; Izawa‐Ishizawa, Yuki; Sendo, Toshiaki; Nakura, Hironori; Ishizawa, Keisuke

doi:10.1038/s41598-017-13073-0

Cited by 9 publications

(13 citation statements)

References 32 publications

(44 reference statements)

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“…The maximal therapeutic dose of class III antiarrhythmics is generally limited by proarrhythmic risk of I Kr block. At low doses with minimal proarrhythmic risk, nifekalant suppresses malignant ventricular tachyarrhythmia (Takenaka et al, 2001) and improves short-term and long-term survival of adult patients with ventricular fibrillation/pulseless ventricular tachycardia (Sato et al, 2017). In animal models, a torsades de pointes response was not detected with the therapeutic dose of nifekalant (Satoh et al, 2004), and nifekalant has a broader safety window than I Kr blockers without facilitation (Sugiyama, 2008; Yamakawa et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Stringently testing this hypothesis requires a system in which facilitation can be selectively removed from an hERG blocker’s mechanism. In the present study, we test the aforementioned facilitation hypothesis by developing a mathematical model of the actions of nifekalant, a hERG channel blocker that induces facilitation and has been used safely in the treatment of life-threatening ventricular tachyarrhythmias (Nakaya et al, 1993; Takenaka et al, 2001; Igawa et al, 2002; Sato et al, 2017), and calculating the impact of facilitation on the APs of human ventricular myocytes.…”

Section: Introductionmentioning

confidence: 99%

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Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Furutani

Tsumoto

Chen

et al. 2019

Journal of General Physiology

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Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Furutani

Tsumoto

Chen

et al. 2019

Journal of General Physiology

View full text Add to dashboard Cite

show abstract

“…The maximal therapeutic dose of Class III antiarrhythmics is generally limited by proarrhythmic risk of IKr block. At low doses with minimal proarrhythmic risk, nifekalant suppresses malignant ventricular tachyarrhythmia (Takenaka et al 2001) and improves short-term and longterm survival of adult patients with ventricular fibrillation/pulseless ventricular tachycardia (Sato et al 2017). In animal models, a torsades de pointes response was not detected with the therapeutic dose of nifekalant (Satoh et al 2004), and nifekalant has a broader safety window than IKr blockers without facilitation (Sugiyama 2008, Yamakawa et al 2012.…”

Section: Modeling Suggests Ikr Facilitation Could Improve Patient Safetymentioning

confidence: 99%

“…Stringently testing this hypothesis requires a system where facilitation can be selectively removed from a hERG blocker's mechanism. In the present study, we test the aforementioned facilitation hypothesis with a mathematical model of the actions of nifekalant, a hERG channel blocker that induces facilitation and has been used safely in the treatment of lifethreatening ventricular tachyarrhythmias (Nakaya et al 1993, Takenaka et al 2001, Igawa et al 2002, Sato et al 2017, on the APs of human ventricular myocytes.…”

Section: Introductionmentioning

confidence: 99%

Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias

Furutani

Tsumoto

Chen

et al. 2018

Preprint

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Abstract:Fatal cardiac arrhythmias are caused by some, but not all, drugs that inhibit the cardiac rapid delayed-rectifier current (IKr) by blocking hERG channels. Here, we propose a novel mechanism that could make certain hERG blockers less proarrhythmic. Several drugs that block hERG channels, yet have favorable cardiac safety profiles, also evoke another effect; they increase the current amplitude upon low-voltage depolarization (facilitation). Voltage-clamp recordings of hERG block and facilitation by nifekalant, a Class III antiarrhythmic agent, constrained a model of human cardiac IKr. In human ventricular action potential simulations, nifekalant showed its therapeutic ability to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evoked early afterdepolarizations, which cause lethal arrhythmias. Facilitation prevented early afterdepolarizations at the same degree of block by increasing IKr during repolarization phase of action potentials. Thus, facilitation is proposed to reduce the arrhythmogenic risk of hERG blockers.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…Therefore, AADs or external electric cardioversion were needed to convert AF during the procedure. Nifekalant, a novel class III AAD, is mainly used to treat ventricular arrhythmias and its therapeutic dose ranges from 0.3 to 0.5 mg/kg, as recommended by the European Resuscitation Council Guidelines and International Consensus on Cardiopulmonary Resuscitation 6‐9 . More recently, nifekalant has been used in the treatment of atrial arrhythmia and cardioversion of AF and atrial flutter 10‐13 .…”

Section: Introductionmentioning

confidence: 99%

Comparison of the efficacy and safety of different doses of nifekalant in the instant cardioversion of persistent atrial fibrillation during radiofrequency ablation

Zhai

Xia

et al. 2020

Basic Clin Pharma Tox

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Nifekalant has been used in the treatment of atrial arrhythmia recently. However, there is no consensus on the preferable nifekalant dose to treat atrial fibrillation (AF). The purpose of this study was to explore efficacy and safety of different doses of nifekalant in the cardioversion of persistent AF. The study was a single‐centre, randomized controlled trial. All subjects received nifekalant or placebo intravenously, and the nifekalant was given at the dosage of 0.3, 0.4 or 0.5 mg/kg. Primary efficacy end‐point: compared with 0.3 mg group, the rate of cardioversion to sinus rhythm from AF in 0.4 and 0.5 mg group was higher. The 0.4 and 0.5 mg/kg doses were associated with a similar magnitude of efficacy (P > .05). Secondary efficacy end‐point: termination rates of AF in the group of 0.4 mg and 0.5 mg were higher than 0.3 mg. Primary safety end‐point: the rate of Torsades de Pointes or ventricular fibrillation was numerically lower in the 0.4 mg group than 0.5 mg group (P = .02). Secondary safety end‐point: The rates of the majority of other common drug‐related adverse events in the group of 0.5 and 0.4 mg were higher than the 0.3 mg group. A 0.4 mg/kg dose of intravenous nifekalant may be recommended during the radiofrequency ablation for persistent AF considering the benefit‐risk profile.

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Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia

Cited by 9 publications

References 32 publications

Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias

Comparison of the efficacy and safety of different doses of nifekalant in the instant cardioversion of persistent atrial fibrillation during radiofrequency ablation

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