Combination anticonvulsant treatment of soman-induced seizures.
These studies investigated the effectiveness of combination treatment with a benzodiazepine and an anticholinergic drug against soman-induced seizures. The anticholinergic drugs considered were biperiden, scopolamine, trihexaphenidyl, and procyclidine; the benzodiazepines were diazepam and midazolam. Male guinea pigs were implanted surgically with cortical screw electrodes. Electrocorticograms were displayed continually and recorded on a computerized electroencephalographic system. Pyridostigmine (0.026 mg x kg(-1), i.m.) was injected as a pretreatment to inhibit red blood cell acetylcholinesterase by 30-40%. Thirty minutes after pyridostigmine, 2 x LD50 (56 microg x kg(-1)) of soman was injected s.c., followed 1 min later by i.m. treatment with atropine (2 mg x kg(-1)) + 2-PAM (25 mg x kg(-1)). Electrographic seizures occurred in all animals. Anticonvulsant treatment combinations were administered i.m. at 5 or 40 min after seizure onset. Treatment consisted of diazepam or midazolam plus one of the above-mentioned anticholinergic drugs. All doses of the treatment compounds exhibited little or no antiseizure efficacy when given individually. The combination of a benzodiazepine and an anticholinergic drug was effective in terminating soman-induced seizure, whether given 5 or 40 min after seizure onset. The results suggest a strong synergistic effect of combining benzodiazepines with centrally active anticholinergic drugs and support the concept of using an adjunct to supplement diazepam for the treatment of nerve-agent-induced seizures.
Koplovitz
I
I
Drug Assessment Division, US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground, MD 21010, USA. Koplovitz@asia.apgea.army.mil
Schulz
S
S
Shutz
M
M
Railer
R
R
Macalalag
R
R
Schons
M
M
McDonough
J
J
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000009:adverse effects*; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D006168:Guinea Pigs; D008297:Male; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy*; D012999:Soman / Q000009:adverse effects*
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D012999:Soman; D003975:Diazepam