Evaluation of ADD392124 for the Delayed Treatment of Nerve Agent-Induced Status Epilepticus Seizures

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 mg/kg (226.3 336.9 mg/kg, 95% confidence limits); anticonvulsant ED50 for the 20-min treatment delay was 325.7 mg/kg (291.3 937.5 mg/kg, 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. The original document contains color images.