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      Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs

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          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 (ED 50 close to 5 mg/kg); flecainide and orphenadrine showed greater potency (ED 50 near 1 mg/kg); lubeluzole and riluzole were the more potent (ED 50 near 0.1 mg/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.

          Highlights

          • •

            Seven sodium channel blockers show antimyotonic activity in a rat model of myotonia.

          • •

            The ED 50 value ranges from 0.1 (riluzole, lubeluzole) to 5 mg/kg (mexiletine, carbamazepine).

          • •

            The drugs use-dependently block hNav1.4 channels in cells in myotonic-like conditions.

          • •

            The IC 50 values in vitro were well linearly correlated with the ED 50 values in vivo.

          • •

            The study discloses promising new therapeutic options for myotonic patients.

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          The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment.

          Thomas R. Griggs, L Venance, Fiona Matthews … (2009)
          The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
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            Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.

            Jeffrey M Statland (2012)
            Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. clinicaltrials.gov Identifier: NCT00832000.
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              Ion channel pharmacology.

              Diana Conte Camerino, Domenico Tricarico, Jean-François Desaphy (2007)
              Because ion channels are involved in many cellular processes, drugs acting on ion channels have long been used for the treatment of many diseases, especially those affecting electrically excitable tissues. The present review discusses the pharmacology of voltage-gated and neurotransmitter-gated ion channels involved in neurologic diseases, with emphasis on neurologic channelopathies. With the discovery of ion channelopathies, the therapeutic value of many basic drugs targeting ion channels has been confirmed. The understanding of the genotype-phenotype relationship has highlighted possible action mechanisms of other empirically used drugs. Moreover, other ion channels have been pinpointed as potential new drug targets. With regards to therapy of channelopathies, experimental investigations of the intimate drug-channel interactions have demonstrated that channel mutations can either increase or decrease affinity for the drug, modifying its potential therapeutic effect. Together with the discovery of channel gene polymorphisms that may affect drug pharmacodynamics, these findings highlight the need for pharmacogenetic research to allow identification of drugs with more specific effects on channel isoforms or mutants, to increase efficacy and reduce side effects. With a greater understanding of channel genetics, structure, and function, together with the identification of novel primary and secondary channelopathies, the number of ion channel drugs for neurologic channelopathies will increase substantially.
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                Author and article information

                Contributors
                Jean-François Desaphy
                Journal
                Journal ID (nlm-ta): Exp Neurol
                Journal ID (iso-abbrev): Exp. Neurol
                Title: Experimental Neurology
                Publisher: Academic Press
                ISSN (Print): 0014-4886
                ISSN (Electronic): 1090-2430
                Publication date PMC-release: 1 May 2014
                Publication date (Print): May 2014
                Volume: 255
                Issue: 100
                Pages: 96-102
                Affiliations
                Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari-Aldo Moro, Bari I-70125, Italy
                Author notes
                [* ]Corresponding author at: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari-Aldo Moro, Via Orabona 4, campus, 70125 Bari, Italy. Fax: + 39 080 544 22 17. jeanfrancois.desaphy@ 123456uniba.it
                Article
                Publisher ID: S0014-4886(14)00075-2
                DOI: 10.1016/j.expneurol.2014.02.023
                PMC ID: 4004800
                PubMed ID: 24613829
                SO-VID: 59c5ac20-8cda-4221-b34b-14578b8e04c8
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 4 January 2014
                Date revision received : 17 February 2014
                Date accepted : 26 February 2014
                Categories
                Subject: Regular Article

                ScienceOpen disciplines: Neurology
                Keywords: non-dystrophic myotonia,sodium channel blockers,mexiletine,rat model,patch-clamp,over-excitability
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: non-dystrophic myotonia, sodium channel blockers, mexiletine, rat model, patch-clamp, over-excitability

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