Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication.
The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO4 as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO4 admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO4 and observed for seizure termination. The anticonvulsant ED50 of biperiden HCl and atropine SO4 for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED50s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO4 for soman, VR, tabun, GF, sarin, and VX were 12.2, 11.9, 10.4, 10.3, 5.1, and 4.1 mg/kg, respectively. In separate experiments, the anticonvulsant ED50 doses of biperiden for animals challenged with 2 or 5 x LD50 of soman were 0.48 (95% confidence limits 0.25-0.73) or 0.57 (95% CI 0.38-0.84) mg/kg, respectively, while the anticonvulsant ED50s for atropine (12.2 mg/kg, i.m.) were identical under these same two challenge conditions. The present study demonstrates that all nerve agents can produce status epilepticus and that the therapeutic effectiveness of atropine and biperiden roughly paralleled the seizurogenic potential of these agents.
Shih
T M
TM
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. dr.tony.shih@amedd.army.mil
McDonough
J H
JH
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use*; D001712:Biperiden / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D012524:Sarin / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D012999:Soman / Q000633:toxicity
D000927:Anticonvulsants; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D009943:Organophosphorus Compounds; D011220:Pralidoxime Compounds; D001712:Biperiden; D001285:Atropine; D012999:Soman; D012524:Sarin; D011729:Pyridostigmine Bromide; C028797:pralidoxime; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate