title: Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat.
abstract: OBJECTIVE
  Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.
  
  
  METHODS
  Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.
  
  
  RESULTS
  The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.
  
  
  CONCLUSIONS
  These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.
authors.affiliation: New Frontiers Science Park, GlaxoSmithKline plc, Harlow, Essex, UK.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Andrea
authors.initials: A
authors.lastname: Bradford
authors.forename: Silvia
authors.initials: S
authors.lastname: Bison
authors.forename: Adam
authors.initials: A
authors.lastname: Lucas
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sartori
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Garbati
authors.forename: Filippo
authors.initials: F
authors.lastname: Andreetta
authors.forename: Simon
authors.initials: S
authors.lastname: Bate
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Austin
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004597:Electroshock / Q000009:adverse effects; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D015222:Sodium Channels / Q000378:metabolism*; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D015222:Sodium Channels; D013777:Tetrazoles; C103207:vofopitant