title: Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs.
abstract: Although the sodium channel blocker mexiletine is considered the first-line drug in myotonia, some patients experiment adverse effects, while others do not gain any benefit. Other antimyotonic drugs are thus needed to offer mexiletine alternatives. In the present study, we used a previously-validated rat model of myotonia congenita to compare six marketed sodium channel blockers to mexiletine. Myotonia was induced in the rat by injection of anthracen-9-carboxylic acid, a muscle chloride channel blocker. The drugs were given orally and myotonia was evaluated by measuring the time of righting reflex. The drugs were also tested on sodium currents recorded in a cell line transfected with the human skeletal muscle sodium channel hNav1.4 using patch-clamp technique. In vivo, carbamazepine and propafenone showed antimyotonic activity at doses similar to mexiletine (ED50 close to 5mg/kg); flecainide and orphenadrine showed greater potency (ED50 near 1mg/kg); lubeluzole and riluzole were the more potent (ED50 near 0.1mg/kg). The antimyotonic activity of drugs in vivo was linearly correlated with their potency in blocking hNav1.4 channels in vitro. Deviation was observed for propafenone and carbamazepine, likely due to pharmacokinetics and multiple targets. The comparison of the antimyotonic dose calculated in rats with the current clinical dose in humans strongly suggests that all the tested drugs may be used safely for the treatment of human myotonia. Considering the limits of mexiletine tolerability and the occurrence of non-responders, this study proposes an arsenal of alternative drugs, which may prove useful to increase the quality of life of individuals suffering from non-dystrophic myotonia. Further clinical trials are warranted to confirm these results.
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari I-70125, Italy. Electronic address: jeanfrancois.desaphy@uniba.it.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari I-70125, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Carbonara
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari I-70125, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Costanza
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari I-70125, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D008801:Mexiletine / Q000494:pharmacology / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects*; D009224:Myotonia Congenita / Q000188:drug therapy*; D009966:Orphenadrine / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011405:Propafenone / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019782:Riluzole / Q000494:pharmacology / Q000627:therapeutic use; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010880:Piperidines; D026941:Sodium Channel Blockers; D013844:Thiazoles; D008801:Mexiletine; D002220:Carbamazepine; D011405:Propafenone; D019782:Riluzole; D009966:Orphenadrine; D005424:Flecainide; C097722:lubeluzole
keywords: Mexiletine; Non-dystrophic myotonia; Over-excitability; Patch-clamp; Rat model; Sodium channel blockers