A comparative electrographic analysis of the effect of sec-butyl-propylacetamide on pharmacoresistant status epilepticus

Abstract

Better treatment of status epilepticus (SE), which typically becomes refractory after about 30min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15min after the first motor seizure, but not after 30min (100mg/kg). VPA (300mg/kg) also lacked efficacy at 30min. SPD (130mg/kg) strongly suppressed ESE at 30min, less after 45min, and not at 60min. At a higher dose (180mg/kg), SPD profoundly suppressed ESE at 60min, similar to propofol (100mg/kg) and pentobarbital (30mg/kg). After 4–6h of SPD-induced suppression, EEG activity often overshot control levels at 7–12h. Valnoctamide (VCD, 180mg/kg), an SPD homolog, was also efficacious at 30min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.