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 (ED50 close to 5mg/kg);
flecainide and
orphenadrine showed greater potency (ED50 near 1mg/kg);
lubeluzole and
riluzole were the more potent (ED50 near 0.1mg/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.