Long-Term Safety and Usefulness of Mexiletine in a Large Cohort of Patients Affected by Non-dystrophic Myotonias

Abstract

The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The study was performed at the Neurophysiologic Division of Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome and the Children's Hospital Bambino Gesù, Rome. Methods: The treatment was accepted by 59 patients according to clinical severity, individual needs, and concerns about a chronic medication. Forty-three patients were affected by recessive congenita myotonia, 11 by sodium channel myotonia, and five by dominant congenital myotonia. They underwent clinical examination before and after starting therapy, and Electromyography (EMG). A number of recessive myotonia patients underwent a protocol of repetitive nerve stimulations, for detecting and quantifying the transitory weakness, and a modified version of the Timed Up and Go test, to document and quantify the gait impairment. Results: Treatment duration ranged from 1 month to 20 years and the daily dosages in adults ranged between 200 and 600 mg. No patient developed cardiac arrhythmias causing drug discontinuation. Mexiletine was suspended in 13 cases (22%); in three patients, affected by Sodium Channel myotonia, because flecainide showed better efficacy; in one patient because of a gastric cancer antecedent treatment; in four patients because of untreatable dyspepsia; and five patients considered the treatment not necessary. Conclusions: In our experience, mexiletine is very useful and not expensive. We did not observe any hazarding cardiac arrhythmias. Dyspepsia was the most frequent dose-limiting side effect.

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use‐Dependent Inhibitors of Voltage‐Gated Sodium Channels

“…Both drugs display a mild ability to block sodium channels in a use‐dependent manner, with greater affinity for the channel under conditions of high‐frequency discharge of action potentials, thus mainly acting in pathological rather than physiological excitability conditions [10,11] . Although mexiletine is generally well tolerated, lack of tolerability, lack of response, as well as side effects, may occur in a significant number of myotonic patients limiting its usefulness [12,13] . As a result of over 20 years of studies that our research group dedicated to the identification of structural determinants of skeletal muscle VCSG block and structure‐activity relationships (SAR), [14–24] a new promising candidate drug for myotonia has been identified (To042, Figure 1) which was 120 times more potent than mexiletine in blocking hNav1.4 channels in myotonia‐like cellular conditions, and 100 times more potent in improving muscle stiffness in vivo in the rat model of myotonia [14] .…”

“…[ 10 , 11 ] Although mexiletine is generally well tolerated, lack of tolerability, lack of response, as well as side effects, may occur in a significant number of myotonic patients limiting its usefulness. [ 12 , 13 ] As a result of over 20 years of studies that our research group dedicated to the identification of structural determinants of skeletal muscle VCSG block and structure‐activity relationships (SAR),[ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] a new promising candidate drug for myotonia has been identified (To042, Figure 1 ) which was 120 times more potent than mexiletine in blocking hNav1.4 channels in myotonia‐like cellular conditions, and 100 times more potent in improving muscle stiffness in vivo in the rat model of myotonia. [14] Despite its excellent pharmacodynamic profile, the clinical use of this compound, which represents the N ‐[(1‐naphthyl)methyl]‐derivative of the tocainide homologue, could be threatened by the presence in its structure of an anilide moiety, a well‐known chemical structural alert.…”

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

“…Another observational study was performed in two Italian centers [ 42 ]. Of the 112 NDM patients followed, 59 began mexiletine therapy, according to severity and individual needs and concerns (11 with SCN4A mutations and 48 with CLCN1 mutations).…”

The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia

“…Sodium channel blockers (mexiletine, carbamazepine) are recommended to treat myotonia in NDM patients, which can slow down the depolarization speed of AP, thereby preventing repetitive Aps ( 37 , 38 ). In this study, patients were treated with mexiletine or/and carbamazepine, and myotonia symptoms were partially improved.…”