Molecular and cellular actions of galantamine: clinical implications for treatment of organophosphorus poisoning.
There have been continued efforts to develop effective antidotal therapies against poisoning with organophosphorus (OP) compounds, including nerve agents and pesticides. We reported recently that galantamine, a drug used to treat Alzheimer's disease, administered before (up to 3 h) or soon after (up to 5 min) an exposure of guinea pigs to 1.5-2 x LD50 soman or sarin effectively counteracted the acute toxicity and lethality of the nerve agents provided that the animals were also post-treated with atropine. Here, we demonstrate that administered to guinea pigs at 30 min before or up to 15 min after an acute challenge with 1 x LD50 soman, galantamine (8 mg/kg, intramuscular) alone is sufficient to counteract the lethality and acute toxicity of the nerve agent. Evidence is also provided that 100% survival can be attained when the association of appropriate doses of galantamine and atropine is administered 30-45 min after the challenge of the guinea pigs with 1 x LD50 soman. Galantamine counteracts the neurodegeneration and the changes in the nicotinic cholinergic system that result from an acute exposure of guinea pigs to 1 x LD50 soman. The results presented herein corroborate that galantamine is an effective antidote against OP poisoning.
Pereira
Edna F R
EF
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Aracava
Yasco
Y
Alkondon
Manickavasagom
M
Akkerman
Miriam
M
Merchenthaler
Istvan
I
Albuquerque
Edson X
EX
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002801:Cholinesterase Reactivators / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005702:Galantamine / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D009924:Organ Culture Techniques; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors*; D012524:Sarin / Q000037:antagonists & inhibitors / Q000633:toxicity; D012999:Soman / Q000037:antagonists & inhibitors / Q000633:toxicity; D016896:Treatment Outcome
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018727:Muscarinic Antagonists; D009943:Organophosphorus Compounds; D005702:Galantamine; D001285:Atropine; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase
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