Safinamide effects on skeletal muscle sodium channels and models of non-dystrophic myotonia (NDM) compared to mexiletine: Exploring potential for clinical utility

Abstract

The antiarrhythmic sodium channel blocker mexiletine is used clinically to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or poor therapeutic response. Safinamide (Xadago®) is licensed for Parkinson’s disease treatment. Besides MAO-B inhibition, safinamide modulates glutamate release through blockade of neuronal sodium channels. The in-vitro and in-vivo effects of safinamide compared to mexiletine were investigated in skeletal muscle hNav1.4 sodium channels and in rat models of myotonia. Using patch-clamp, safinamide reversibly inhibited wild-type hNav1.4 sodium currents (INa) with an IC50 of 160 and 33 μM at stimulation frequencies of 0.1 and 10 Hz respectively, compared to 256 and 46 μM for mexiletine (holding potential (hp) −120 mV). In a condition mimicking myotonia, i.e. hp of -90 mV and 50-Hz stimulation, both drugs exerted similar INa inhibition with IC50 of 5-6 μM. When applied in vitro to isolated rat skeletal muscle fibers in a myotonia-like condition induced by 9-anthracene carboxylic acid (9-AC), safinamide inhibited action potential firing with an IC50 of 13 μM, compared to 55 μM for mexiletine. In vivo in rats, oral safinamide (ED50 1.2 mg/kg) was more potent than mexiletine (ED50 7.0 mg/kg) in counteracting 9-AC induced myotonia. Safinamide inhibited myotonic skeletal muscle sodium channels in vitro and had more potent antimyotonic properties than mexiletine in vivo. Further work is warranted to evaluate if safinamide may be clinically effective for NDM.