title: Fingolimod (Gilenya®) in multiple sclerosis: bradycardia, atrioventricular blocks, and mild effect on the QTc interval. Something to do with the L-type calcium channel?
abstract: Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav1.2-transfected tsA201 cells exposed to fingolimod-phosphate 100 or 500 nmol/L (n = 27 cells, total) to measure drug effect on L-type calcium current (ICaL). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea-pigs isolated hearts (n = 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug-induced effects on monophasic action potential duration measured at 90% repolarization (MAPD90). (iii) Implanted cardiac telemeters were used to record ECGs in guinea-pigs (n = 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod-phosphate causes a concentration-dependent reduction in ICaL. (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD90. (iii) Fingolimod caused significant prolongations of the RR, PR, QT, and QTcFintervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses ICaL-blocking properties, further contributing to its AV conduction-slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG-blocking effect.
authors.affiliation: Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.affiliation: Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5.|Faculté de Pharmacie, Université Laval, 1050 Avenue de la médecine, Québec, QC, Canada, G1V 0A6.
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.affiliation: Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5.|Faculté de Pharmacie, Université Laval, 1050 Avenue de la médecine, Québec, QC, Canada, G1V 0A6.
authors.forename: Benoit
authors.identifier: http://orcid.org/0000-0003-4871-4742
authors.initials: B
authors.lastname: Drolet
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000139:chemically induced / Q000503:physiopathology*; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D020746:Calcium Channels, L-Type / Q000502:physiology*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
keywords: 
  ECG
  ; action potentials; calcium currents; cardiac arrhythmias; fingolimod