title: Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial.
abstract: BACKGROUND
  Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine's clinical profile.
  
  
  METHODS
  To investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT).
  
  
  METHODS
  Threshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm.
  
  
  RESULTS
  Flupirtine (3-30 μM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.).
  
  
  CONCLUSIONS
  Clinical doses of flupirtine reduce the excitability of peripheral myelinated axons.
  
  
  BACKGROUND
  ClinicalTrials registration is NCT01450865.
authors: Department of Anaesthesiology, University of Munich, Munich, Germany. johannes.fleckenstein@med.uni-muenchen.de
authors: Johannes
authors: J
authors: Fleckenstein
authors: Ruth
authors: R
authors: Sittl
authors: Beate
authors: B
authors: Averbeck
authors: Philip M
authors: PM
authors: Lang
authors: Dominik
authors: D
authors: Irnich
authors: Richard W
authors: RW
authors: Carr
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000627:therapeutic use*; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004311:Double-Blind Method; D004576:Electromyography; D005260:Female; D006801:Humans; D007511:Ischemia; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000627:therapeutic use; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism*; D013497:Sural Nerve / Q000187:drug effects* / Q000502:physiology
chemical_list: D000631:Aminopyridines; D051657:KCNQ1 Potassium Channel; D009125:Muscle Relaxants, Central; C034161:flupirtine
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