Galantamine is a novel post-exposure therapeutic against lethal VX challenge.
The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 microg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).
Hilmas
Corey J
CJ
Neurobehavioral Toxicology Branch, Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, USA. corey.john.hilmas@us.army.mil
Poole
Melissa J
MJ
Finneran
Kathryn
K
Clark
Matthew G
MG
Williams
Patrick T
PT
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005702:Galantamine / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D018763:Muscle Fatigue / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009946:Organothiophosphorus Compounds; D010243:Paralysis / Q000139:chemically induced / Q000517:prevention & control; D010791:Phrenic Nerve / Q000187:drug effects / Q000503:physiopathology; D011220:Pralidoxime Compounds / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013997:Time Factors
D000110:Acetylcholinesterase; D000931:Antidotes; D001285:Atropine; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D005702:Galantamine; D009946:Organothiophosphorus Compounds; D011220:Pralidoxime Compounds; C009680:VX-agent; C028797:pralidoxime