Evaluation of ADD392124 for the Delayed Treatment of Nerve Agent-Induced Status Epilepticus Seizures
Technical rept. 15 Nov 2009-30 Jan 2010
ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
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ADD392124 was identified by the Anticonvulsant Screening Program as being able to control benzodiazepine-resistant status epilepticus seizures. We evaluated the ability of ADD392124 to control seizures induced by the nerve agent soman. Rats were exposed to a convulsant dose of soman. Seizures were allowed to develop, and the standard treatment for nerve agent intoxication--atropine, 2-PAM an oxime cholinesterase reactivator, and diazepam a benzodiazepine--was administered at either 5 or 20 min after seizures started along with ADD392124 at varying doses. ADD392124 was capable of stopping soman-induced seizures at both treatment delay times anticonvulsant ED50 at the 5-min treatment delay 256.1 mgkg 226.3 336.9 mgkg, 95 confidence limits anticonvulsant ED50 for the 20-min treatment delay was 325.7 mgkg 291.3 937.5 mgkg, 95 confidence limits. The time for seizure termination following administration of ADD392124 at the 5-min treatment delay time was 533.9 sec 8.9 min, while the latency for seizure termination at the 20-min delay was 2258.3 sec 37.6 min. ADD392124 was less potent as an anticonvulsant when compared to anticholinergics, N-methyl-d-aspartate NMDA antagonists or benzodiazepines. Nevertheless, ADD392124 was successful in terminating soman-induced seizures at delay times e.g., 20 min where few other classes of anticonvulsant drugs have proven effective.
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