Abstract
Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (±)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 × LD50 soman (42 μg/kg s.c.). All animals that were pretreated with galantamine (6–8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 × LD50 soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 × LD50 soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 × LD50 soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.
Footnotes
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This work was supported by the Army Research Office [Contract W911NF-06-1-0098]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant UO1NS059344] (CounterACT Program).
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Disclosures: Opinions or assertions contained herein are the private views of the authors and should not be construed as official or as reflecting the views of the U.S. Army, the Department of Defense or the federal government. The use of galantamine as an antidote against OP poisoning is protected under Albuquerque EX, Adler M, and Pereira EFR (2005) inventors; University of Maryland, Baltimore, Assignee. International Patent Application PCT/US05/33789. 2005 Sept 23.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.160028
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ABBREVIATIONS:
- ACh
- Acetylcholine
- AChE
- acetylcholinesterase
- APL
- allosteric potentiating ligand
- BuChE
- butyrylcholinesterase
- ChE
- cholinesterase
- OP
- organophosphorus
- CNS
- central nervous system
- ANOVA
- analysis of variance
- NMDA
- N-methyl-d-aspartate.
- Received August 11, 2009.
- Accepted September 8, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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