Comparative efficacy of valnoctamide and sec‐butylpropylacetamide (SPD) in terminating nerve agent–induced seizures in pediatric rats

Abstract

Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic-VCD), sec-butylpropylacetamide (racemic-SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats. Female and male postnatal day (PND) 21, 28, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED50 ) of the drugs. SPD-ED50 values in the VX model were the following: PND21, 53mg/kg (male) and 48mg/kg (female); PND28, 108mg/kg (male) and 43mg/kg (female); and PND70, 101mg/kg (male) and 40mg/kg (female). SPD-ED50 values in the sarin model were the following: PND21, 44mg/kg (male) and 28mg/kg (female); PND28, 79mg/kg (male) and 34mg/kg (female); and PND70, 53mg/kg (male) and 53mg/kg (female). VCD-ED50 values in the VX model were the following: PND21, 34mg/kg (male) and 43mg/kg (female); PND28, 165mg/kg (male) and 59mg/kg (female); and PND70, 87mg/kg (male) and 91mg/kg (female). VCD-ED50 values in the sarin model were the following: PND21, 45mg/kg (male), 48mg/kg (female); PND28, 152mg/kg (male) 79mg/kg (female); and PND70, 97mg/kg (male) 79mg/kg (female). Phenobarbital-ED50 values in the VX model were the following: PND21, 43mg/kg (male) and 18mg/kg (female); PND28, 48mg/kg (male) and 97mg/kg (female). Phenobarbital-ED50 values in the sarin model were the following: PND21, 32mg/kg (male) and 32mg/kg (female); PND28, 58mg/kg (male) and 97mg/kg (female); and PND70, 65mg/kg (female). SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.