P.12.12 Preclinical in vitro and in vivo evaluation of sodium channel blockers as possible alternative to mexiletine in the treatment of myotonia

Abstract

The efficacy of mexiletine in the treatment of non-dystrophic myotonias was recently confirmed in a randomized, double-blind, placebo-controlled crossover trial (Statland et al., JAMA 2012). Nevertheless, not all myotonic patients can obtain benefits from mexiletine, either due to lack of therapeutic effects or occurrence of side effects limiting the compliance. In addition, mexiletine has been withdrawn from a number of European countries, leaving patients with an unmeet medical need. Thus there is a critical need to increase the arsenal of antimyotonic drugs. In this study, we tested the antimyotonic activity of a number of marketed sodium channel blockers in vivo, by using a rat model in which myotonia is pharmacologically induced by i.p. injection of 9-anthracene carboxylic acid (Desaphy et al., Neuropharmacology 2013). The myotonic state was assessed by measuring the time of righting reflex of rats after 9-AC injection and oral administration of drugs. The dose–response curves indicate an ED50 of 7.0 ± 1.4 mg/kg for mexiletine. Propafenone and carbamazepine were twofold, orphenadrine 7-fold, flecainide 10-fold, lubeluzole and riluzole 70-fold, more efficient that mexiletine in vivo. The in vivo antimyotonic activity was in accord with the relative activity of sodium channel blockade in vitro, determined on heterologously expressed skeletal muscle hNav1.4 channels with patch-clamp technique. Two exceptions regard carbamazepine, which was more efficient in vivo compared to in vitro, and propafenone, which was less efficient in vivo than in vitro. Such discrepancies are likely related to pharmacokinetic mechanisms. The comparison of antimyotonic doses in the rat with clinical doses used in human indications suggest that all the tested sodium channels might be used safely in myotonic patients, except for lubeluzole that may present some cardiac risk. Supported by Telethon-Italy (grant GGP10101) and Association Francaise contre les Myopathies (grant 1502).