Evaluation of Anticonvulsant Drugs for Soman-Induced Seizure Activity

Abstract

This report describes three lines of organophosphorus (OP) nerve-agent anticonvulsant studies: (a) a basic research effort to understand how different pharmacological classes of compounds influence the expression of seizure produced by soman in rats, (b) a drug-screening effort to determine whether clinically useful antiepileptic drugs can modulate soman-induced seizures in rats, and (c) an advanced testing effort in which anticholinergic compounds are evaluated in comparison to the current anticonvulsant treatment (i.e., diazepam) in guinea pigs. Electroencephalographic (EEG) recordings were used in all studies. Basic studies were conducted in rats pretreated with HI-6 and challenged with 1.6 x the median lethal dose (LD 50 ) soman. Antimuscarinic compounds were extremely effective in blocking (pretreatment) or terminating soman seizures when given 5 min after seizure onset; however, significantly higher doses were required when treatment was delayed >10 min, and some antimuscarinic compounds lost anticonvulsant efficacy when treatment was delayed 40 min. Diazepam blocked seizure onset, yet seizures could recur after an initial period of anticonvulsant effect at doses ≤2.5 mg/kg. Diazepam could terminate ongoing seizures when given 5 min after seizure onset, but doses up to 20 mg/kg were ineffective when treatment was delayed for 40 min. The γ-aminobutyric acid (GABA) uptake inhibitor tiagabine was ineffective in blocking or terminating soman motor convulsions or seizures. The glutamate receptor antagonists NBQX, GYKI 52466, and memantine had weak or minimal antiseizure activity, even at doses that virtually eliminated signs of motor convulsions. The antinicotinic mecamylamine was ineffective in blocking or stopping seizure activity. Pretreatment with a narrow range of doses of the alpha-2-adrenergic agonist clonidine produced variable protection (40-60%) against seizure onset; treatment after seizure onset with clonidine was not effective. Screening studies in rats, using HI-6 pretreatment, showed that the clinically effective antiepileptic drugs pentobarbital and valproic acid were modestly effective in terminating seizures when given shortly (5 min) after seizure onset. In contrast, phenytoin, carbamazepine, felbamate, magnesium sulfate, ketamine, primidone, and lamotrigine were ineffective. Advanced studies of eight anticholinergic drugs compared with diazepam anticonvulsant therapy were performed in guinea pigs pretreated with pyridostigmine, challenged with soman (2 x LS 50 ), and immediately treated with 2-PAM Cl and atropine. The rank of potency for diazepam and eight antimuscarinic compounds, when administered 5 min after seizure onzet (scopolamine, , biperiden, benactyzine, trihexyphenidyl, azaprophen, procyclidine, aprophen, diazempam, atropine), closely resembles that obtained from the rat model.