title: A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial.
abstract: Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were -7.0 ± 7.1 and -0.04 ± 0.1, respectively, in the riluzole group and -6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Misawa
authors.affiliation: b Department of Neurology , Tokyo Metropolitan Neurological Hospital , Fuchu , Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: c Department of Molecular Neurology and Gerontology , Kyoto Prefectural University of Me1dicine , Kyoto , Japan.
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Noto
authors.affiliation: d Clinical Research Center, Chiba University Hospital , Chiba , Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Sekiguchi
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Iwai
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mitsuma
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Beppu
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: b Department of Neurology , Tokyo Metropolitan Neurological Hospital , Fuchu , Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fujimaki
authors.affiliation: c Department of Molecular Neurology and Gerontology , Kyoto Prefectural University of Me1dicine , Kyoto , Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: b Department of Neurology , Tokyo Metropolitan Neurological Hospital , Fuchu , Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: c Department of Molecular Neurology and Gerontology , Kyoto Prefectural University of Me1dicine , Kyoto , Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: c Department of Molecular Neurology and Gerontology , Kyoto Prefectural University of Me1dicine , Kyoto , Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: d Clinical Research Center, Chiba University Hospital , Chiba , Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Sawaguchi
authors.affiliation: d Clinical Research Center, Chiba University Hospital , Chiba , Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hanaoka
authors.affiliation: a Department of Neurology , Graduate School of Medicine, Chiba University , Chiba , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D019054:Evoked Potentials, Motor / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008801:Mexiletine / Q000627:therapeutic use*; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D016037:Single-Blind Method; D016896:Treatment Outcome; D061567:Voltage-Gated Sodium Channel Blockers / Q000627:therapeutic use*
chemical_list: D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine
keywords: Mexiletine; amyotrophic lateral sclerosis; clinical trial; nerve excitability; sodium current