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.
McDonough
John H
JH
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, 3100 Ricketts Point Road, APG-EA, MD 21010-5400, USA. john.mcdonough@apg.amedd.army.mil
Benjamin
Alex
A
McMonagle
Joseph D
JD
Rowland
Tami
T
Shih
Tsung-Ming
TM
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D008297:Male; D010672:Phenytoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D011220:Pralidoxime Compounds; D010672:Phenytoin; D001285:Atropine; D012999:Soman; C043114:fosphenytoin; D011729:Pyridostigmine Bromide; C028797:pralidoxime; D003975:Diazepam