title: Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice.
abstract: OBJECTIVE
  Lacosamide (LCM, Vimpat) is an anticonvulsant with a unique mode of action. This provides lacosamide with the potential to act additively or even synergistically with other antiepileptic drugs (AEDs). The objective of this study was to determine the presence of such interactions by isobolographic analysis.
  
  
  METHODS
  The anticonvulsant effect of LCM in combination with other AEDs including carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), and levetiracetam (LEV) at fixed dose ratios of 1:3, 1:1, and 3:1, was evaluated in the 6-Hz-induced seizure model in mice. In addition, the impact of the combinations of LCM with the other AEDs on motor coordination was assessed in the rotarod test. Finally, AED concentrations were measured in blood and brain to evaluate potential pharmacokinetic drug interactions.
  
  
  RESULTS
  All studied AEDs produced dose-dependent anticonvulsant effects against 6-Hz-induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP, or LEV were synergistic. All other LCM/AED combinations displayed additive effects with a tendency toward synergism. Furthermore, no enhanced adverse effects were observed in the rotarod test by combining LCM with other AEDs. No pharmacokinetic interactions were seen on brain AED concentrations. Coadministration of LCM and TPM led to an increase in plasma levels of LCM, whereas the plasma concentration of PHT was increased by coadministration of LCM.
  
  
  CONCLUSIONS
  The synergistic anticonvulsant interaction of LCM with various AEDs, without exacerbation of adverse motor effects, highlights promising properties of LCM as add-on therapy for drug refractory epilepsy.
authors.affiliation: Odessa State Medical University, Odessa, Ukraine.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shandra
authors.forename: Pavel
authors.initials: P
authors.lastname: Shandra
authors.forename: Olga
authors.initials: O
authors.lastname: Kaschenko
authors.forename: Alain
authors.initials: A
authors.lastname: Matagne
authors.forename: Thomas
authors.initials: T
authors.lastname: Stöhr
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000009:adverse effects; D000078334:Lacosamide; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009043:Motor Activity / Q000187:drug effects; D045442:Rotarod Performance Test; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide
keywords: Motor impairment; Pharmacodynamic drug interactions; Pharmacokinetic drug interactions