Control of nerve agent-induced seizures is critical for neuroprotection and survival.
This study evaluated the potency and rapidity of some anticholinergics (atropine, biperiden, and trihexyphenidyl) and benzodiazepines (diazepam and midazolam) as an anticonvulsant treatment against seizures induced by six nerve agents (tabun, sarin, soman, cyclosarin, VR, and VX) and summarized the relationship between anticonvulsant activity and nerve agent-induced lethality and neuropathology. Guinea pigs, previously implanted with cortical electrodes for EEG recording, were pretreated with pyridostigmine bromide (0.026 mg/kg im) 30 min prior to challenge with 2x LD50 dose (sc) of a given nerve agent; in a separate experiment, animals were challenged with 5x LD50 sc of soman. One minute after agent challenge the animals were treated im with 2 mg/kg atropine SO(4) admixed with 25 mg/kg 2-PAM Cl. Five minutes after the start of EEG seizures, animals were treated im with different doses of anticholinergics or benzodiazepines and observed for seizure termination. The time to seizure onset, the time to seizure termination, and 24-h lethality were recorded. The anticonvulsant ED50 of each drug for termination of seizures induced by each agent was calculated and compared. Brain tissue from animals that survived 24 h was examined for pathology. All drugs were capable of terminating seizure activity, with midazolam and trihexyphenidyl being significantly more potent than the other drugs, and midazolam being more rapid in controlling seizure than atropine, trihexyphenidyl, or diazepam against each agent. Seizures induced by sarin or VX required lower doses of all the test anticonvulsants. The dose of a given drug that was an effective anticonvulsant against a 2x LD50 challenge of soman was equally effective against seizures induced by a 5x LD50 challenge. All nerve agents were capable of producing neuropathology. Seizure control was strongly associated with protection against acute lethality and brain pathology.
Shih
Tsung-Ming
TM
Pharmacology and Comparative Medicine Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. dr.tony.sshih@amedd.army.mil
Duniho
Steven M
SM
McDonough
John H
JH
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D001285:Atropine / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use; D001921:Brain / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D018680:Cholinergic Antagonists / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D011729:Pyridostigmine Bromide / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced* / Q000401:mortality / Q000628:therapy*; D013534:Survival
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D001569:Benzodiazepines; D001285:Atropine; D011729:Pyridostigmine Bromide