Oral mexiletine for lidocaine-responsive neonatal epilepsy

Nakazawa, Mika; Okumura, Akihisa; Niijima, Shinichi; Yamashita, Shintaro; Shimono, Kuriko; Hirose, Shinichi; Shimizu, Toshiaki

doi:10.1016/j.braindev.2012.10.011

Cited by 11 publications

(6 citation statements)

References 6 publications

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“…In particular, mexiletine controls hyperexcitability in both dystrophic and non-dystrophic myotonias (Logigian et al, 2010 ; Hoffman and Kaminski, 2012 ) and relieves neuropathic pain (Tremont-Lukats et al, 2005 ). Mex has also been proposed as a novel therapeutic approach in Timothy syndrome (Gao et al, 2013 ) and to successfully treat lidocaine-responsive neonatal epilepsy (Nakazawa et al, 2013 ). In addition, a very recent study has reported, for the first time, that Mex is able to reduce the occurrence of arrhythmic events in LQT3 patients, including infants (Mazzanti et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…A case of two infants with innate refractory seizures, related to mutations in the SCN2A subunit of voltage-gated sodium channels, has also been reported. Although various combinations of antiepileptics remained ineffective, seizures were well controlled by intravenous lidocaine and enteral mexiletine [ 25 – 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Experimental data have demonstrated that mexiletine showed anticonvulsant effects in mice against seizures induced by electroshock, pentetrazole and a sound signal in audiosusceptible DBA/2 mice [ 10 ]. In patients, mexiletine has been shown to be efficacious in symptomatic partial epilepsy, Lennox–Gastaut syndrome and medically refractory early infantile epileptic encephalopathy related to SCN2A mutation [ 25 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

et al. 2018

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The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

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“…23 Lidocaine (also an anesthetic agent) demonstrated anti-epileptic activity in patients with chronically unstable generalized epilepsy. 24 Mexiletine was found to be effective in the treatment of symptomatic partial epilepsy and Lennox-Gastaut syndrome [25][26][27] and decreased pentylenetetrazole-induced convulsions, and sound induced convulsions in DBA/2 mice. 28 In class II AADs, Propranolol decreased seizures in patients with chronically unstable generalized epilepsy 29 and it demonstrated anticonvulsant action in models for generalized tonic-clonic and complex partial seizures, but not for myoclonic convulsions, 30 Timolol reversed the epileptiform activity of pentylenetetrazol (PTZ) in the mouse brain.…”

Section: Drug Repositioning In Epilepsymentioning

confidence: 99%

Drug repositioning

Mehndiratta

Wadhai

Tyagi

et al. 2016

International Journal of Epilepsy

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Rapid advances in pharmacotherapy and bioinformatics has led to the discovery and growing popularity of drug repositioning which includes re-investigating or recycling of existing drugs for new indications. There are innumerable advantages as well as challenges of drug repositioning. Since de-novo drug discovery takes plenty of time, effort and money, it has proved to a preferred alternative strategy for accelerated drug discovery. Moreover it is relatively inexpensive and carries minimal risk due to availability of previous pharmacological, safety and toxicology data. The strategies used are Known drug – new target/Drug focus/Drug-centric, Known target- new indication/Target focus/Target-centric and Disease focus/Disease-centric. Drug repositioning is a new breakthrough strategy to benefit patients by offering safer and effective treatment using shelved drugs.

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Oral mexiletine for lidocaine-responsive neonatal epilepsy

Cited by 11 publications

References 6 publications

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

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

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

Drug repositioning

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