Effects of Fosphenytoin on Nerve Agent‐InducedStatus epilepticus

Abstract

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.

Evaluating of the Anticonvulsant Gabapentin against Nerve Agent-Induced Seizures in a Guinea Pig Model

“…Thirty min after pyridostigmine the animals were challenged SC with 56 ug/kg soman (2 X LD50) and one min later were treated IM with the admixed 2.0 mg/kg atropine and 25.0 mg/kg 2-PAM. This procedure results in seizures in 100% of animals tested in multiple studies (McDonough et al, 1999(McDonough et al, , 2000(McDonough et al, , 2004Capacio et al, 2003Capacio et al, , 2004. The animals were then monitored for seizure onset by a technician and the investigator, who were well-experienced with the appearance of nerve agent-induced EEG seizure activity in guinea pigs.…”

“…For each animal in which the seizure was terminated, the latency to seizure termination was measured as the time from when the animal received gabapentin treatment to the last observable epileptiform event in the EEG. These evaluation procedures and operational criteria for seizure control are identical to those used in previous studies utilizing this animal model (McDonough et al, 1999(McDonough et al, , 2000(McDonough et al, , 2004Capacio et al, 2003Capacio et al, , 2004Shih et al, 2003Shih et al, , 2007.…”

“…Due to the difficulty in treating nerve agent-induced seizures there has been an ongoing effort to determine if there are better anticonvulsants to control these seizures. Previous work (Shih et al, 1991(Shih et al, , 1999McDonough et al, 2004) has shown that most antiepileptic drugs used to treat seizure disorders are ineffective in controlling nerve agentinduced seizures. This is possibly because most anticonvulsant drugs are taken to prevent the development of seizure activity in epileptic patients rather than to stop ongoing seizure activity such as occurs in nerve agent poisoning.…”

“…Gabapentin is one of the few clinically used antiepileptic drugs that has not been evaluated as a potential anticonvulsant against nerve agent-induced seizures. The current study examined whether gabapentin would be capable of stopping or modulating nerve agent-induced seizures in a validated guinea pig nerve agent seizure-anticonvulsant model (Shih et al, 2003(Shih et al, , 2007McDonough et al, 1999McDonough et al, , 2000McDonough et al, , 2004McDonough et al, , 2008.…”

Nerve Agents

“…Animal experiments have clearly shown that these seizures will not stop without industrial-strength doses of phenytoin, phenobarbital, lamotrigine, carbamazepine, or valproic acid. 28,29 The reason for this may lie in the wide anatomic distribution of the cholinergic system within human brain. Effectively, status in nerve agent poisoning is extremely multicentric, and thus drugs which work, at least in part, by dampening the spread of seizure discharges are ineffective.…”