Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs.
A total of eight anticholinergic drugs (aprophen, atropine, azaprophen, benactyzine, biperiden, procyclidine, scopolamine, trihexyphenidyl) were tested in parallel with diazepam for the ability to terminate seizure activity induced by the nerve agent soman. Guinea pigs, implanted with electrodes to record cortical electroencephalographic (EEG) activity, were pretreated with pyridostigmine Br (0.026 mg/kg, i.m.) and 30 min later challenged with 2 x LD50 soman (56 microg/kg, s.c.) followed 1 min later by treatment with atropine SO4 (2 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All guinea pigs developed sustained seizure activity following this treatment. Dose-effect curves were determined for the ability of each drug to terminate seizure activity when anticonvulsant treatment was given either 5 or 40 min after seizure onset. Body weight gain and recovery of behavioral performance of a previously trained one-way avoidance task were measured after exposure. With the exception of atropine, all anticholinergic drugs were effective at lower doses than diazepam in terminating seizures when given 5 min after seizure onset; benactyzine, procyclidine and aprophen terminated seizures most rapidly while scopolamine, trihexyphenidyl, biperiden, and diazepam were significantly slower. When given 40 min after seizure onset, diazepam was the most potent compound tested, followed by scopolamine, benactyzine and biperiden; atropine was not effective when tested 40 min after seizure onset. For diazepam, the time to terminate the seizure was the same whether it was given at the 5- or 40-min delay. In contrast, most anticholinergics were significantly slower in terminating seizure activity when
McDonough
J H
JH
Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. john.mcdonough@amedd.army.mil
Zoeffel
L D
LD
McMonagle
J
J
Copeland
T L
TL
Smith
C D
CD
Shih
T M
TM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D003292:Convulsants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D009420:Nervous System / Q000473:pathology; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016019:Survival Analysis; D013997:Time Factors
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D018680:Cholinergic Antagonists; D003292:Convulsants; D012999:Soman; D003975:Diazepam