Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Maria O Kovalchuk, Jules A A C Heuberger, Boudewijn T H M Sleutjes, Dimitrios Ziagkos, Leonard H van den Berg, Toby A Ferguson, Hessel Franssen, Geert Jan Groeneveld

Journal: Clinical pharmacology and therapeutics 2019;104(6):1136-1145

PMID: 29672831

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Abstract

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.

Address: University Medical Center Utrecht, Department of Neurology, Utrecht, the Netherlands.; Centre for Human Drug Research, Leiden, the Netherlands.; Biogen, Department of Neurology Research and Early Clinical Development, Cambridge, Massachusetts, USA.

DOI: 10.1002/cpt.1096

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MeSH Terms: Adult, Aged, Amyotrophic Lateral Sclerosis, Axons, Carbamates, Cross-Over Studies, Double-Blind Method, Electromyography, Evoked Potentials, Motor, Excitatory Amino Acid Antagonists, Female, Humans, Male, Middle Aged, Motor Neurons, Netherlands, Neuroprotective Agents, Phenylenediamines, Refractory Period, Electrophysiological, Riluzole, Time Factors, Treatment Outcome