New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

A, De Luca; Pierno, Sabata; Liantonio, Antonella; Desaphy, Jean-François; Natuzzi, F.; Didonna, Maria Paola; Ferrannini, E.; Jockusch, Harald; Franchini, Carlo; Lentini, Giovanni; Corbo, Filomena; Tortorella, Vincenzo; Camerino, Diana Conte

doi:10.1016/j.nmd.2004.04.006

Cited by 27 publications

(26 citation statements)

References 35 publications

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“…We used previous studies 22–24 as well as our in vitro data to guide initial choices of drug doses and performed a dose escalation study as described in Methods. All three drugs improved motor function as measured by the decrease in time of the righting reflex (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

“…22 Neither ranolazine nor lacosamide have been studied as treatment for myotonia congenita. However, ranolazine has been given daily to mice at a dose of 50mg/kg via intraperitoneal injection, 23 and lacosamide has been given to mice at doses up to 100mg/kg via intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

“…All mice were tested for baseline motor function before each treatment. Motor function was analyzed by timing the righting reflex 3 times 22, 28 and by scoring 2 performance trials on a modified Rotarod test. In a traditional Rotarod test, mice are placed on a stationary rod and the speed of the rod is gradually increased until the mice can no longer stay on the rod.…”

Section: Methodsmentioning

confidence: 99%

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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Objective Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm up and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warm-up, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warm-up in a mouse model of myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warm-up. These data suggested enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are FDA-approved for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine’s hypoexcitability side effects. Interpretation We conclude ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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“…Then the phenyl analog 5 was designed in order to evaluate the steric requirements for potent and use-dependent block of skeletal muscle sodium channels. Given that studies on adult skeletal muscle fibers evidenced the stereoselective behavior of Mex and its analogs toward the binding sites 18,19 we prepared compounds 2, 3, and 5 in their homochiral forms. The effects of the newly synthesized compounds were evaluated on single fibers of frog skeletal muscle, under both tonic and phasic conditions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

et al. 2009

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New chiral mexiletine analogs were synthesized in their optically active forms and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. Tests carried out on sodium currents of single muscle fibers of Rana esculenta demonstrated that all of them exerted a higher use-dependent block than mexiletine. The most potent analog, (S)-3-(2,6-dimethylphenoxy)-1-phenylpropan-1-amine (S)-(5), was six-fold more potent than (R)-Mex in producing a tonic block. As observed with mexiletine, the newly synthesized compounds exhibit modest enantioselective behavior, that is more evident in 3-(2,6-dimethylphenoxy)butan-1-amine (3).

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“…(Table 1) Non-dystrophic myotonic disorders are a group of rare congenital disease with either autosomal dominant or recessive transmission characterised by myotonia, that is, by the inability of the skeletal muscles to relax after contractions. These disorders belong to the larger group of neurologic channelopathies and have, as the major pathogenic feature, the alteration in membrane excitability due to abnormal sodium and chloride transmembrane conductance [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Fresh from the designation pipeline: orphan drugs recently designated in the European Union (September – November 2013)

Antoniu

2014

Expert Opinion on Orphan Drugs

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New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

Cited by 27 publications

References 35 publications

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

Fresh from the designation pipeline: orphan drugs recently designated in the European Union (September – November 2013)

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