Abstracts

Rationale: Perampanel, a structurally novel, potent, orally active AMPA receptor antagonist, is currently under development for the treatment of epilepsy. Perampanel has previously been shown to have anti-seizure effects in animal models (Hanada T, et al. Epilepsia 2011;52:1331-1340). In experimental models of status epilepticus, the ability of agents (including other AMPA receptor antagonists) to terminate seizures typically declines as the duration of status epilepticus increases. Perampanel has been shown to terminate established, diazepam-resistant status epilepticus in the lithium-pilocarpine rat model of status epilepticus. Here, we examined pharmacodynamic interactions between perampanel and diazepam in this same model. Methods: Male Sprague Dawley rats weighing 250-450 g were implanted with an electroencephalography (EEG) electrode on the surface of the primary somatosensory cortex (AP: -2.5 mm; L: 3 mm according to coordinates of Paxinos and Watson [1997]). After at least 1 week recovery, 3 mEq/kg of lithium chloride wasadministered to the rats (intraperitoneal). This was followed 18-26 hours later by 5 mg/kg scopolamine methyl bromide and 30 mg/kg of pilocarpine. Seizure initiation was documented when the first spike train was observed on EEG. Thirty minutes after seizure initiation, perampanel alone, diazepam alone, or the combination, was administered intravenously. Results: Perampanel at 1 mg/kg failed to terminate EEG seizures, and 5 mg/kg perampanel terminated seizures in some rats (Table 1). Diazepam alone at 5 mg/kg and 20 mg/kg failed to terminate EEG seizure. Combination of perampanel (1 mg/kg) and diazepam (5 mg/kg), doses that were individually ineffective, terminated seizures in all treated rats. Conclusions: Our data demonstrate that, after 30 minutes of status epilepticus (at which point it is typically considered to be self-sustaining and resistant), seizures were terminated by combination treatment with perampanel and diazepam at doses that were ineffective alone. Thus, perampanel shows synergistic pharmacodynamic interaction with diazepam in diazepam-resistant and established status epilepticus in the rat. Supported by Eisai Co., Ltd.