The ability of the
nerve agents tabun,
sarin,
soman, GF, VR, and
VX to produce brain
seizures and the effectiveness of the
anticholinergics biperiden HCl or
atropine SO4 as an
anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical
electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with
pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of
soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg
atropine SO4 admixed with 25 mg/kg
2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of
nerve agent-induced EEG
seizures, animals were treated i.m. with different doses of
biperiden HCl or
atropine SO4 and observed for seizure termination. The
anticonvulsant ED50 of
biperiden HCl and
atropine SO4 for termination of
seizures induced by each
nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG
seizures (
status epilepticus) developed in all animals challenged with
soman,
tabun, or VR, and in more than 90% of the animals challenged with GF or
sarin. In contrast, only 50% of the animals developed
seizures when challenged with
VX. The times to onset of
seizures for
soman,
tabun, GF, and
sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of
VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the
anticonvulsant ED50s of
biperiden HCl for
soman, GF, VR,
tabun,
sarin, and
VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of
atropine SO4 for
soman, VR,
tabun, GF,
sarin, and
VX were 12.2, 11.9, 10.4, 10.3, 5.1, and 4.1 mg/kg, respectively. In separate experiments, the
anticonvulsant ED50 doses of
biperiden for animals challenged with 2 or 5 x LD50 of
soman were 0.48 (95% confidence limits 0.25-0.73) or 0.57 (95% CI 0.38-0.84) mg/kg, respectively, while the
anticonvulsant ED50s for
atropine (12.2 mg/kg, i.m.) were identical under these same two challenge conditions. The present study demonstrates that all
nerve agents can produce
status epilepticus and that the therapeutic effectiveness of
atropine and
biperiden roughly paralleled the seizurogenic potential of these agents.