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

Abstract

Summary Objectives 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. Methods 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. Results SPD‐ED50 values in the VX model were the following: PND21, 53 mg/kg (male) and 48 mg/kg (female); PND28, 108 mg/kg (male) and 43 mg/kg (female); and PND70, 101 mg/kg (male) and 40 mg/kg (female). SPD‐ED50 values in the sarin model were the following: PND21, 44 mg/kg (male) and 28 mg/kg (female); PND28, 79 mg/kg (male) and 34 mg/kg (female); and PND70, 53 mg/kg (male) and 53 mg/kg (female). VCD‐ED50 values in the VX model were the following: PND21, 34 mg/kg (male) and 43 mg/kg (female); PND28, 165 mg/kg (male) and 59 mg/kg (female); and PND70, 87 mg/kg (male) and 91 mg/kg (female). VCD‐ED50 values in the sarin model were the following: PND21, 45 mg/kg (male), 48 mg/kg (female); PND28, 152 mg/kg (male) 79 mg/kg (female); and PND70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital‐ED50 values in the VX model were the following: PND21, 43 mg/kg (male) and 18 mg/kg (female); PND28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital‐ED50 values in the sarin model were the following: PND21, 32 mg/kg (male) and 32 mg/kg (female); PND28, 58 mg/kg (male) and 97 mg/kg (female); and PND70, 65 mg/kg (female). Significance 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.

Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury

“…Phenobarbital is used as second‐line drug for refractory SE, irrespective of the seizure etiology. Phenobarbital has been tested in a few animal models of OP intoxication 30‐32 . Based on overall survival rate, functional seizure suppression, and histological neurodegeneration outcomes, phenobarbital at 60 mg/kg may be a better option of the other two phenobarbital doses in DFP‐induced epilepsy, especially for ambulatory treatment.…”

“…Patients administered therapeutic or high dosages of phenobarbital for OP‐induced SE must often remain under clinical observation for airway and cardio‐respiratory vital functions, including continuous monitoring of blood pressure and respiratory rate. Because of the strong anticonvulsant property of phenobarbital, it could be used as an alternative to diazepam or midazolam to control SE after nerve agent exposure 4,30‐32 . However, the risk vs benefit of phenobarbital therapy, especially neurological morbidity of varying phenobarbital dosage, for OP‐induced SE remains unclear.…”

Pharmacokinetic and pharmacodynamic analysis of (2S,3S)‐sec‐butylpropylacetamide (SPD) in rats and pigs—A CNS‐active stereoisomer of SPD

“…Previous PK and PD studies show that SPD (and its individual stereoisomers) is significantly more potent than valproic acid in various animal models, indicating the potential of SPD as a new anticonvulsant drug that is superior to valproic acid . It is important to note that the SPD median neurotoxic dose (TD 50 ) values were assessed in previous studies by gross behavioral observations that included ataxia, gait, stance, muscle tone, and placing response, and not respiratory or cardiac depression.…”

“…To date, the PK and PD profiles of SPD have been investigated solely in mice and rats (with one study in guinea pigs) . Consequently, a large nonrodent mammalian animal model is required as a key to translational discovery in order to proceed toward clinical trials in humans.…”

“…sec ‐Butylpropylacetamide (SPD) has proven to be active in five different rat‐SE models induced by pilocarpine, tetramethylenedisulfotetramine (TETS) and the nerve agents: soman, paraoxon,VX and sarin. In the benzodiazepine‐resistant pilocarpine‐ and soman‐induced SE models, SPD and its individual stereoisomers terminated seizures in rats even when given 30 and 60 minutes after seizure onset . Thus, the potential of the CNS‐active SPD individual stereoisomer (2S,3S)‐SPD was investigated by studying for the first time its pharmacokinetics (PK) in pigs as well as its PK‐pharmacodynamic (PK‐PD) correlation utilizing the maximal‐electroshock seizure threshold (MEST) test in rats …”