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

Journal Article · 06 January 2019 · Epilepsia

DOI: https://doi.org/10.1111/epi.14630 · OSTI ID:1490105

Haines, Kari M. ^[1]; Matson, Liana M. ^[1]; Dunn, Emily N. ^[1]; Ardinger, Cherish E. ^[1]; Lee‐Stubbs, Robyn ^[2]; Bibi, David ^[3]; McDonough, John H. ^[1]; Bialer, Meir ^[4]

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1. Nerve Agent Countermeasures, Medical Toxicology Division US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground Maryland
2. Research Support Division US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground Maryland
3. Institute for Drug Research School of Pharmacy Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel
4. Institute for Drug Research School of Pharmacy Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel, David R. Bloom Center for Pharmacy School of Pharmacy Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel

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 (ED ₅₀ ) of the drugs. Results SPD‐ED ₅₀ values in the VX model were the following: PND 21, 53 mg/kg (male) and 48 mg/kg (female); PND 28, 108 mg/kg (male) and 43 mg/kg (female); and PND 70, 101 mg/kg (male) and 40 mg/kg (female). SPD ‐ ED ₅₀ values in the sarin model were the following: PND 21, 44 mg/kg (male) and 28 mg/kg (female); PND 28, 79 mg/kg (male) and 34 mg/kg (female); and PND 70, 53 mg/kg (male) and 53 mg/kg (female). VCD ‐ ED ₅₀ values in the VX model were the following: PND 21, 34 mg/kg (male) and 43 mg/kg (female); PND 28, 165 mg/kg (male) and 59 mg/kg (female); and PND 70, 87 mg/kg (male) and 91 mg/kg (female). VCD ‐ ED ₅₀ values in the sarin model were the following: PND 21, 45 mg/kg (male), 48 mg/kg (female); PND 28, 152 mg/kg (male) 79 mg/kg (female); and PND 70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital‐ ED ₅₀ values in the VX model were the following: PND 21, 43 mg/kg (male) and 18 mg/kg (female); PND 28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital‐ ED ₅₀ values in the sarin model were the following: PND 21, 32 mg/kg (male) and 32 mg/kg (female); PND 28, 58 mg/kg (male) and 97 mg/kg (female); and PND 70, 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 PND 21 animals than in the older animals, and overall, males required higher amounts of drug than females.

• Sponsoring Organization: USDOE
• OSTI ID: 1490105
• Journal Information: Epilepsia, Journal Name: Epilepsia Journal Issue: 2 Vol. 60; ISSN 0013-9580
• Publisher: Wiley-BlackwellCopyright Statement
• Country of Publication: Netherlands
• Language: English