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

2018 ◽  
Vol 8 ◽  
Author(s):  
Michela De Bellis ◽  
Francesca Sanarica ◽  
Alessia Carocci ◽  
Giovanni Lentini ◽  
Sabata Pierno ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channel ◽  
Therapeutic Potential ◽  
Channel Blockers ◽  
Sodium Channel Blockers ◽  
Dual Action ◽  
Anti Oxidant ◽  
Novel Therapeutic

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

2020 ◽  
pp. 1-25
Author(s):  
Jean-François Desaphy ◽  
Concetta Altamura ◽  
Savine Vicart ◽  
Bertrand Fontaine
Keyword(s):  
Systematic Review ◽  
Skeletal Muscle ◽  
Sodium Channel ◽  
Precision Medicine ◽  
Human Studies ◽  
Channel Blockers ◽  
Preclinical Studies ◽  
Sodium Channel Blockers ◽  
Congenital Myopathies ◽  
Therapeutic Benefits

Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP. Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background. Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process. Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from DCP compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies. Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

scholarly journals Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

2021 ◽  
Vol 12 ◽  
Author(s):  
Stephan Lauxmann ◽  
Lukas Sonnenberg ◽  
Nils A. Koch ◽  
Christian Bosselmann ◽  
Natalie Winter ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Channel Coding ◽  
Therapeutic Potential ◽  
Drug Repurposing ◽  
Episodic Ataxia ◽  
Channel Blockers ◽  
Loss Of Function ◽  
Review Of The Literature ◽  
Sodium Channel Blockers ◽  
Comprehensive Review

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents

2008 ◽  
Vol 43 (11) ◽  
pp. 2535-2540 ◽  
Author(s):  
Alessia Catalano ◽  
Alessia Carocci ◽  
Filomena Corbo ◽  
Carlo Franchini ◽  
Marilena Muraglia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channel ◽  
Channel Blockers ◽  
Sodium Channel Blockers

Reconsidering the role of selective sodium channel blockers in genetic generalized epilepsy

2021 ◽  
Author(s):  
Emanuele Cerulli Irelli ◽  
Alessandra Morano ◽  
Martina Fanella ◽  
Biagio Orlando ◽  
Enrico M Salamone ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Channel Blockers ◽  
Sodium Channel Blockers ◽  
Generalized Epilepsy
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