Valnoctamide and sec‐butyl‐propylacetamide (SPD) for acute seizures and status epilepticus

Abstract

sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20-60min after seizure onset. When administered 20 and 40min after SE onset, SPD (100-174mg/kg) produced long-lasting efficacy (e.g., 4-8h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20-60min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .