title: Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.
abstract: The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, 21201, USA. ealbuque@umaryland.edu
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
authors.forename: Edna F R
authors.initials: EF
authors.lastname: Pereira
authors.forename: Yasco
authors.initials: Y
authors.lastname: Aracava
authors.forename: William P
authors.initials: WP
authors.lastname: Fawcett
authors.forename: Maristela
authors.initials: M
authors.lastname: Oliveira
authors.forename: William R
authors.initials: WR
authors.lastname: Randall
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Hamilton
authors.forename: Robert K
authors.initials: RK
authors.lastname: Kan
authors.forename: James A
authors.initials: JA
authors.lastname: Romano
authors.forename: Michael
authors.initials: M
authors.lastname: Adler
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000470:Alkaloids; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000506:poisoning / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005702:Galantamine / Q000494:pharmacology*; D006168:Guinea Pigs; D007306:Insecticides / Q000506:poisoning / Q000633:toxicity*; D007928:Lethal Dose 50; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010261:Paraoxon / Q000633:toxicity; D011041:Poisoning / Q000517:prevention & control*; D011729:Pyridostigmine Bromide / Q000633:toxicity; D012524:Sarin / Q000633:toxicity; D012717:Sesquiterpenes / Q000633:toxicity; D012999:Soman / Q000633:toxicity; D013997:Time Factors
chemical_list: D000470:Alkaloids; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D012717:Sesquiterpenes; C050426:huperzine A; D005702:Galantamine; D001285:Atropine; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide; D010261:Paraoxon