Résumé :
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The aim of this project is to determine whether 3,4 diaminopyridine (3,4DAP) is a viable treatment candidate for spinal muscular atrophy (SMA). Aminopyridines are voltage dependent potassium channel inhibitors that increase the duration and the amplitude of the presynaptic action potential and increase the release of acetylcholine at central and peripheral synapses. 3,4DAP has been used for more than 30 years in presynaptic neuromuscular disorders, including Lambert-Eaton syndrome. Recent studies on SMA animal models have demonstrated that motoneuron death is a relatively late event, preceded by distal axonopathy and functional defects of the presynaptic part of the neuromuscular synapse, as well as a loss of synaptic input on motoneurons from spinal interneurons. Electrophysiological parameters were improved by an aminopyridine and a neuroprotective effect of these compounds is hypothesized. We propose a 6-month phase Ib pilot study of 3,4DAP in ambulatory children with SMA to evaluate dosing, safety, tolerability, pharmacokinetics and effects on selected outcome measures. Primary Objectives: 1. To assess safety, dosing and tolerability of oral administration of 3,4DAP in 20 ambulatory SMA patients 5 to 17 years of age. Dose escalation will be performed to achieve a target dosage of 1mg/kg/day. Safety and tolerability will be monitored by questionnaire via telephone, EKG and biology at months M0, M1, M2 and M3 of the trial. 2. To assess pharmacokinetic parameters of 3,4DAP in the study population. A subgroup of 5 SMA patients in the same range of age and weight will be selected for the pharmacokinetic study. Parameters will be evaluated after oral intake of single and repeated doses of 3,4DAP. Secondary Objectives: 1. To assess potential efficacy of an oral dosing regimen of 3,4DAP on selected measures of fatigue, motor function, and strength. Fatigue will be measured using the 6-minute walk test administered twice at baseline, and repeated at M3 and M6. Motor function and limb strength will be assessed at M0, M3, M6 using the Hammersmith Functional Motor Scale Extend, timed tests of motor function, and a hand-held dynamometer. 2. To assess potential efficacy of an oral dosing regimen of 3,4DAP on neurotransmission using electrophysiological assays. Maximum ulnar compound muscle action potential (CMAP) amplitude and area, and repetitive electrostimulation at distal and proximal sites will evaluate the integrity of neuromuscular transmission at M0, M3, and M6.
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