Abstracts

Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a structurally unique antiepileptic drug (AED) that interacts with inactivated sodium channels to limit high-frequency firing of neuron action potentials. This investigation compares the preclinical anticonvulsant profile and tolerability of rufinamide to those of established AEDs, including phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and sodium valproate (VPA). Doses of each AED were administered via both oral (CF1 mice and Sprague-Dawley rats) and intraperitoneal (IP) (CF1 mice) routes; a minimum of 8 animals received each dose and at least 5 doses were administered per test. For both species and administration routes, the maximal electroshock (MES) test evaluated the efficacy of rufinamide against seizure spread and predicted its effectiveness against tonic-clonic (and also partial) seizures in man; subcutaneous pentylenetetrazol (PTZ) tested for raised seizure threshold and protection against clonic seizures. Mice receiving the IP dose were also administered subcutaneous strychnine (STR) to evaluate protection against tonic seizures, and subcutaneous bicuculline (BIC) and picrotoxin (PIC) to further characterize elevations in seizure threshold and clonic-seizure protection. Tolerance was assessed over 5 days with the MES test in orally administered rats. The effective dose (ED[sub]50[/sub]) for each AED was defined as the amount of drug necessary to achieve a 50% decrease of induced seizure frequency. Minimal neurotoxic dose (TD[sub]50[/sub]) was determined with the chimney test (rats) or the rotorod test (6 rpm) at time of peak neurotoxic effect (mice). Oral rufinamide was protective against MES-induced tonic-clonic seizures in both mice and rats (ED[sub]50[/sub], 23.9 and 6.1 mg/kg, respectively) and suppressed PTZ-induced seizures in mice (ED[sub]50[/sub], 45.8 mg/kg); tolerance was not observed. Intraperitoneal rufinamide suppressed PTZ-, BIC-, and PIC-induced clonus (ED[sub]50[/sub], 54.5, 50.5, and 76.3 mg/kg, respectively) in IP-administered mice and was partially effective in the mouse STR test. For both species and delivery routes, rufinamide tolerability exceeded or was similar to that of any established AED except PHT administered orally to rats. For all tests, the protective index (ratio of TD[sub]50[/sub] to anticonvulsant ED[sub]50[/sub]) of rufinamide was greater than that of any established AED. Rufinamide displayed a broad-spectrum anticonvulsant profile in mice and rats at doses where no side effects were observed. Rufinamide was well-tolerated by animals of both species, and the protective indices determined for rufinamide were superior to those of established AEDs. (Supported by Eisai Inc.)