title: Interactions of lamotrigine with topiramate and first-generation antiepileptic drugs in the maximal electroshock test in mice: an isobolographic analysis.
abstract: OBJECTIVE
  The study investigated the types of interactions between lamotrigine (LTG) and first-generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis.
  
  
  METHODS
  Anticonvulsant and adverse-effect profiles of combinations of LTG with other AEDs, at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the maximal electroshock (MES)-induced seizures and the chimney test (motor performance) in mice, which allowed the determination of benefit indices (BIs) for individual combinations.
  
  
  RESULTS
  Combinations of LTG with TPM or valproate (VPA), at fixed ratios of 1:1, were significantly supraadditive (synergistic) in the MES test and, simultaneously, subadditive (antagonistic) in the chimney test, showing the best profile for AED combinations. In contrast, combinations between LTG and carbamazepine (CBZ), in terms of antiseizure protection against MES, were subadditive (antagonistic) and additive in the chimney test, resulting in unfavorable AED combinations. Moreover, the combination of LTG with phenobarbital (PB), at a fixed ratio of 1:1, despite synergy in the MES test, also was synergistic in the chimney test, resulting in a modest BI for AED combination. LTG combined with phenytoin was additive in both the MES and chimney tests in mice. The remaining combinations, at fixed ratios not mentioned earlier, also showed an average BI for AED combinations. Furthermore, LTG combined with all studied AEDs did not affect long-term memory in mice. None of the AEDs influenced the free plasma level of LTG, whereas LTG slightly reduced the free plasma concentration of PB.
  
  
  CONCLUSIONS
  Interactions between LTG and TPM or LTG and VPA at a fixed ratio of 1:1 might be profitable from a preclinical point of view, displaying the most optimal BI.
authors.affiliation: Departments of Pathophysiology, Medical University Isotope Laboratory, Institute of Agricultural Medicine, Jaczewskiego, Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
authors.forename: Mirosław
authors.initials: M
authors.lastname: Czuczwar
authors.forename: Jacek
authors.initials: J
authors.lastname: Kis
authors.forename: Jacek
authors.initials: J
authors.lastname: Krysa
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Pasztelan
authors.forename: Mariusz
authors.initials: M
authors.lastname: Swiader
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Czuczwar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock; D004827:Epilepsy / Q000097:blood / Q000503:physiopathology*; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D000077213:Lamotrigine