Toward precision medicine in myotonic syndromes

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

“…Surprisingly, the new analog CI16 is the most use-dependent mexiletine-like sodium channel blocker described so far, with a ratio IC 50 TB/IC 50 10-Hz UDB of 21 (Table 2 ). The use-dependent behavior is a complex dynamic process involving the kinetics of drug binding to and unbinding from the channel in relation to both state-dependent drug affinity and physicochemical properties (De Bellis et al, 2017a , b ). The recovery from inactivation of drug-bound channels was determined.…”

“…The present study was the first attempt to characterize Mex derivatives for their ability to combine the block of voltage-gated sodium channels with an anti-oxidant activity in skeletal muscle, considering the potential need to reduce the stress of unbalanced excitation-contraction in degenerating myopathies in which both alteration of voltage-gated sodium channels and oxidative stress can occur. The large number of physiological processes regulated by sodium channels and their role in many diseases make the voltage-gated sodium channels highly interesting as targets for new drugs (Chahine and Desaphy, 2016 ; De Bellis et al, 2017b ). Mexiletine has been used for two decades as off-label drug in nondystrophic myotonias, and recently has appointed an orphan drug designation in myotonic syndromes.…”

“…Hence, it has now been discontinued in many countries including the US and the UK (Suetterlin et al, 2015 ; Roselli et al, 2016 ). Consequently, numerous attempts have been made in recent years to develop an alternative to mexiletine, including the design of new analogs that offer the same pharmacological effect but without the unwanted side effects (Roselli et al, 2016 ; De Bellis et al, 2017b ). In fact, in a series of our previous structure-activity relationship studies (SAR), we have tested a number of rationally-designed mexiletine derivatives in the attempt to increase potency and use-dependent behavior.…”

“…In particular, CI16 was up to 40-fold more potent to block Na V 1.4 channels in a use-dependent manner with respect to Mex and it is the strongest use-dependent Mex-like compound described so far. The key structural features of CI16 with respect to the parent compound, i.e., the introduction of a tetramethyl-pyrroline moiety on the amino group of the isopropyl derivative, is a modification that may further enhance the interaction with amino acid residues and/or better positioning of the drug in the channel pore during voltage-dependent conformational changes of Na V 1.4 (Sheets et al, 2010 ; De Bellis et al, 2017b ), as also supported by the molecular modeling. In fact, the new pyrroline-derivatives maintain the main mode of action of parent compounds in terms of acting with a modest stereo-selective behavior (De Luca et al, 2000 ; Talon et al, 2001 ; Muraglia et al, 2007 ).…”

Guidelines on clinical presentation and management of nondystrophic myotonias

“…One group is currently studying beta adrenergic drugs, which have been found to have an effect similar to mexiletine in a myotonic rat 142 . This same group is also exploring a pharmacogenetics approach to find the best medication option for a particular mutation 143,144 . From a methodological perspective, aggregated N‐of‐1 trials (ie, single patient multiple cross‐over trials) can help to create the desired personalized treatment outcome estimates, with increased power due to the multiple cross‐over design and use of a Bayesian hierarchical model, while also providing results on the (sub)group level(s) 116 …”