This report describes studies of
anticonvulsants for the organophosphorus (OP)
nerve agent soman: a basic research effort to understand how different pharmacological classes of compounds influence the expression of seizure produced by
soman in rats, and a
drug screening effort to determine whether clinically useful
antiepileptics can modulate
soman-induced
seizures in rats. Electroencephalographic (EEG) recordings were used in these studies. Basic studies were conducted in rats pretreated with
HI-6 and challenged with 1.6 x LD50
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 for more than 10 min, and some
antimuscarinic compounds lost
anticonvulsant efficacy when treatment was delayed for more than 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
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 alpha2-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
benzodiazepines (
diazepam,
midazolam and
lorazepam) were quite effective when given 5 min after seizure onset, but lost their efficacy when given 40 min after onset. The
barbiturate,
pentobarbital, was modestly effective in terminating
seizures when given 5 or 40 min after seizure onset, while other clinically effective
antiepileptic drugs,
trimethadione and
valproic acid, were only slightly effective when given 5 min after onset. In contrast,
phenytoin,
carbamazepine,
ethosuximide,
magnesium sulfate,
lamotrigine,
primidone,
felbamate,
acetazolamide, and
ketamine were ineffective.