Abstracts

Rufinamide (CGP-33101) is an investigational anticonvulsant compound with demonstrated efficacy in the treatment of electrically and chemically induced seizures in animals. Several anticonvulsant drugs, including phenytoin, carbamazepine, lamotrigine, and oxcarbazepine have similar efficacy in animal models and are used to treat partial and generalized tonic-clonic seizures. Blockade of sodium channels, and limitation of high-frequency action potential firing as a consequence, is believed to contribute to the efficacy of these drugs. Here, we describe effects of rufinamide on electrophysiological properties of neurons in vitro. Sodium currents were recorded from freshly dispersed rat cortical neurons with and without rufinamide in the extracellular buffer using whole-cell patch-clamp recording techniques. Sodium-dependent action potential firing of cultured mouse central neurons was recorded with intracellular microelectrode recording techniques. Cells were exposed to rufinamide in the superfusate for greater than 30 minutes and/or in the culture medium for up to 48 hours to ensure equilibration. The recording chamber was perfused with phosphate-buffered saline containing 7 mmol/L magnesium to suppress spontaneous firing at 35^oC to 37^oC. Exposure to rufinamide produced rest- and use-dependent block of sodium currents, and slowed recovery from inactivation. Exposure to 1-500 [mu]mol/L of rufinamide reduced the rate and duration of action potential firing in response to depolarizing current pulses of up to 40 seconds in duration. Response to 1-100 [mu]moles/L rufinamide was variable; firing was severely inhibited in some cells, while others displayed only mild or moderate decreases in firing rate. Firing was severely limited in all cells exposed to rufinamide concentrations [underline][gt][/underline]200 [mu]mol/L. The concentration of rufinamide required to limit firing in 50% of neurons (IC[sub]50[/sub]) was 3.8 [mu]mol /L (range 2-10 [mu]moles/L). Over a broad range of concentrations, rufinamide reduced sodium currents and limited high-frequency action potential firing of neurons in vitro. These findings suggest that rufinamide achieves its anticonvulsant effects, at least in part, by blocking sodium channels. (Supported by Eisai Inc.)