Abstracts

RWJ 333369, S-2-O-carbamoyl-1[italic]-O-[/italic]chlorophenyl-ethanol, is in clinical development for the treatment of focal epilepsy. The present investigation describes the results obtained from the extensive preclinical anticonvulsant studies that have been conducted to date., RWJ 333369 was tested in several mouse [MES, pentylenetetrazol (PTZ), bicuculline, and picrotoxin] and rat (MES and PTZ) acute seizure models following oral (p.o.) and intraperitoneal (i.p.) administration. It was also tested for its ability to: block audiogenic seizures in the Frings mouse, block behavioral and electrographic seizures in the corneal and hippocampal kindled rat, the lamotrigine (LTG)-resistant amygdala kindled rat; and refractory seizures in the 6 Hz seizure model. Lastly, RWJ 333369 was tested for its ability to prevent and interrupt Li-pilocarpine (Li-Pilo)-induced status epilepticus in rats., In mice, i.p. RWJ 333369 was found to be active in the MES, PTZ, bicuculline, picrotoxin and audiogenic seizure tests. In rats, it was active in the acute MES test following p.o. administration. RWJ 333369 reduced seizure severity in the corneal kindled rat and seizure severity and afterdischarge duration (ADD) in the hippocampal kindled rat models of partial epilepsy. RWJ 333369 was also active in two models of refractory epilepsy at doses devoid of motor impairment. In the LTG-resistant amygdala kindled rat, RWJ 333369 produced a dose-dependent reduction in the behavioral seizure score and ADD. In the 6 Hz seizure model, the antiseizure activity of RWJ 333369 was maintained as the stimulus intensity was increased from 22 to 44 mAmp. When administered prior to Li-Pilo, RWJ 333369 (i.p.) prevented the onset of status epilepticus. Following i.v. administration, it was able to interrupt fully established Li-Pilo-induced status epilepticus., In animal models, RWJ 333369 was active at non-toxic doses and found to possess a broad-spectrum anticonvulsant profile in rodent models of generalized and partial epilepsy. When administered prior to, or after, the onset of Li-Pilo-induced status epilepticus, it was able to either prevent, or halt, Li-Pilo-induced status epilepticus, respectively. In contrast to CBZ, PHT, LTG, and TPM, RWJ 333369 possesses activity in the LTG-resistant amygdala kindled rat and the 6 Hz seizure models. These latter findings suggest that RWJ 333369 possesses a unique profile relative to these well-established AEDs and support the continued development of this investigational AED., (Supported by NINDS Contract 1-NO1-NS-4-2311 and a contract from Johnson and Johnson Pharmaceutical Research and Development, L.L.C.)