title: Pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock seizure models.
abstract: There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.
authors.affiliation: Epilepsy Unit, Clinical Pharmacology Section, University Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT, Scotland, UK. g.j.sills@clinmed.gla.ac.uk
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Sills
authors.forename: Elaine
authors.initials: E
authors.lastname: Butler
authors.forename: George G
authors.initials: GG
authors.lastname: Thompson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Brodie
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004597:Electroshock / Q000009:adverse effects; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D010433:Pentylenetetrazole