Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolimod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation

Yagi, Yuki; Nakamura, Yuji; Kitahara, Koichi; Harada, Tsuyoshi; Kato, Kazuhiko; Ninomiya, Tomohisa; Cao, Xin; Ohara, Hiroshi; Izumi-Nakaseko, Hiroko; Suzuki, Koichi; Ando, Kentaro; Sugiyama, Atsushi

doi:10.1016/j.taap.2014.09.006

Cited by 11 publications

(21 citation statements)

References 30 publications

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“…indicated that the effects on HR and AV conduction are caused via activation of the S1P 1 receptor in guinea pigs as well as in humans . However, such effects in guinea pigs did not completely mimic those in humans; even a high dose of fingolimod (0.1 mg kg –1 per 10 min, intravenously) and ponesimod (30 mg kg –1 , orally) did not lower the atrial rate in guinea pigs . Mazurais et al .…”

Section: Discussionmentioning

confidence: 99%

“…However, recent clinical studies revealed that two selective S1P receptor modulators, siponimod (BAF312) and ceralifimod (ONO-4641), did show a significant HR reduction after the first dose in healthy human subjects, despite their lack of S1P 3 agonist activity [23,24]. Thus, it should be noted that pathogenesis of the cardiac signal transduction system in animal models may not necessarily reflect that in humans owing to species differences in basal HR, inherent ion channel expression, the tissue distribution of S1P receptor subtypes or a combination of these factors [23,[25][26][27]. Indeed, Rey et al indicated that the effects on HR and AV conduction are caused via activation of the S1P 1 receptor in guinea pigs as well as in humans [26].…”

Section: Discussionmentioning

confidence: 99%

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Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Harada¹,

Wilbraham²,

Borderie³

et al. 2017

Brit J Clinical Pharma

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AimAmiselimod (MT‐1303) is a selective sphingosine 1‐phosphate 1 (S1P1) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo.MethodsA total of 81 healthy subjects aged 18–55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography.ResultsUnlike fingolimod, neither amiselimod dose exerted acute (1–6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: −4.40 bpm, 95% confidence interval −7.15, −1.66) and Day 7 in the 0.8 mg group [−3.85 bpm (−6.58, −1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [−6.49 bpm (−8.95, −4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1.ConclusionThe study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Harada¹,

Wilbraham²,

Borderie³

et al. 2017

Brit J Clinical Pharma

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“…Interestingly, Yagi et al . have recently demonstrated that FTY720 may prolong the effective refractory period (ERP) in animal, electrically driven using a cardiac stimulator, suggesting inhibitory effects on the Na + channel and/or K + channel . Na + channel blockers can increase the ERP by slowing the reactivation of fast‐Na + channels, whereas K + channel blockers may delay phase 3 repolarization, leading to the prolongation of the action potential duration and ERP .…”

Section: Discussionmentioning

confidence: 99%

The effect of the sphingosine‐1‐phosphate analogue FTY720 on atrioventricular nodal tissue

Egom¹,

Kružliak

Rotrekl

et al. 2015

J Cellular Molecular Medi

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The sphingosine‐1‐phosphate (S1P) receptor modulator, fingolimod (FTY720), has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular (AV) conduction block have been reported in some patients after the first dose. The underlying mechanism of this AV node conduction blockade is still not well‐understood. In this study, we hypothesize that expression of this particular arrhythmia might be related to a direct effect of FTY720 on AV node rather than a parasympathetic mimetic action. We, therefore, investigated the effect of FTY720 on AV nodal, using in vitro rat model preparation, under both basal as well as ischaemia/reperfusion conditions. We first look at the expression pattern of S1P receptors on the AV node using real‐time PCR. Although all three S1P receptor isoforms were expressed in AVN tissues, S1P1 receptor isoform expression level was higher than S1P2 and S1P3. The effect of 25 nM FTY720 on cycle length (CL) was subsequently studied via extracellular potentials recordings. FTY720 caused a mild to moderate prolongation in CL by an average 9% in AVN (n = 10, P < 0.05) preparations. We also show that FTY720 attenuated both ischaemia and reperfusion induced AVN rhythmic disturbance. To our knowledge, these remarkable findings have not been previously reported in the literature, and stress the importance for extensive monitoring period in certain cases, especially in patients taking concurrently AV node blocker agents.

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“…Five (S1P [1][2][3][4][5] ) subtypes that differ in spatial distribution, coupling, and function can, singly or in combination, play complex roles in the embryonic formation of the arterial media, blood pressure regulation, and cardiac function [reviewed by Mendelson et al (2014)]. For example, FTY720 in humans is associated with significant sinus bradycardia and prolongation of the QTc interval (Schmouder et al, 2006;Kappos et al, 2010;Espinosa and Berger, 2011;Yagi et al, 2014). FTY720 treatment has additionally revealed an increased incidence of atrioventricular (AV) disturbances during the first dose, including AV block and asystole, particularly in subgroups of patients with preexisting cardiac conditions that require other therapeutics, i.e., beta blockers and calcium channel blockers, to maintain adequate cardiovascular dynamics (Vanoli et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction

et al. 2015

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The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P 3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P 3 -knockin and S1P 3 -knockout mice to define the spatial and functional properties of S1P 3 in regulating cardiac conduction. We show that S1P 3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P 3 -knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P 3 -mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P 3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology.

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Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolimod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation

Cited by 11 publications

References 30 publications

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

The effect of the sphingosine‐1‐phosphate analogue FTY720 on atrioventricular nodal tissue

Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction

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