Anticonvulsants for nerve agent-induced seizures: The influence of the therapeutic dose of atropine.

Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl)methylphosphonothioate (VX), and O-isobutyl S-(2-diethylamino)ethyl)-methyl phosphonothioate (VR). Animals instrumented for electroencephalogram recording were pretreated with pyridostigmine bromide (0.026 mg/kg i.m.) 30 min before challenge with 2 x LD50 (s.c.) of a nerve agent. In model A, atropine sulfate (2.0 mg/kg i.m.) and pyridine-2-aldoxime methylchloride (2-PAM; 25.0 mg/kg i.m.) were given 1 min after nerve agent challenge, and the tested anticonvulsant was given (i.m.) 5 min after seizure onset. In model B, a lower dose of atropine sulfate (0.1 mg/kg i.m.) was given along with 2-PAM 1 min after nerve agent challenge, and the anticonvulsant was given at seizure onset. With the lower dose of atropine, seizure occurrence increased to virtually 100% for all agents; the time to seizure onset decreased for sarin, cyclosarin, and VX; the signs of nerve agent intoxication were more severe; and coma resulted frequently with cyclosarin. The anticonvulsant ED50 doses for scopolamine or diazepam were, in general, not different between the two models, whereas the anticonvulsant ED50 values of midazolam increased 3- to 17-fold with the lower atropine dose. Seizure termination times were not systematically effected by the different doses of atropine. The order of anticonvulsant effectiveness within each model was scopolamine > or = midazolam > diazepam. The findings indicate that the dose of atropine given as antidotal therapy can significantly influence measures of nerve agent toxicity and responsiveness to anticonvulsant therapy.

Effects of fosphenytoin on nerve agent-induced status epilepticus.

This study evaluated the effectiveness of fosphenytoin as a single or adjunctive anticonvulsant treatment for nerve agent-induced status epilepticus. Guinea pigs, implanted with cortical electroencephalographic (EEG) recording electrodes, were pretreated with pyridostigmine bromide (0.026 mg/kg, intramuscular (i.m.)) 30 min before challenge with 56 micrograms/kg, subcutaneous (s.c.), (2 x LD50) of the nerve agent soman. One min after soman, the animals were treated (i.m.) with 2 mg/kg atropine sulfate admixed with 25 mg/kg of the oxime 2-pralidoxime chloride, and the EEG was observed for seizure onset. When administered (intraperitoneal, i.p.) therapeutically 5 min after seizure onset, only the highest fosphenytoin dose (180 mg/kg) was capable of terminating seizure activity in 50% of the animals tested (3 of 6). When fosphenytoin (18-180 mg/kg) was administered as a pretreatment, i.p., 30 min before soman challenge, seizures were blocked or terminated in a dose-dependent fashion (ED50 = 61.8 mg/kg; 40.5-94.7 mg/kg = 95% confidence limits). Combinations of diazepam and fosphenytoin were also tested for effectiveness. No dose of fosphenytoin (18-56 mg/kg), given in conjunction with a fixed dose of diazepam (4.8 mg/kg, i.m.) 5 min after seizure onset, enhanced the anticonvulsant effect of diazepam. When fosphenytoin (18 or 32 mg/kg, i.p.) was given as a pretreatment and diazepam was given 5 min after seizure onset, the 32 mg/kg dose of fosphenytoin significantly reduced the time for seizure control. These studies show that fosphenytoin, either alone or in combination with diazepam, has little or no therapeutic anticonvulsant effectiveness for nerve agent-induced status epilepticus.