Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.
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 x LD(50) soman (42 microg/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 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) 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 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.
Aracava
Yasco
Y
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Pereira
Edna F R
EF
Akkerman
Miriam
M
Adler
Michael
M
Albuquerque
Edson X
EX
D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000506:poisoning*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000008:administration & dosage / Q000627:therapeutic use*; D006168:Guinea Pigs; D007189:Indans / Q000008:administration & dosage / Q000627:therapeutic use*; D007928:Lethal Dose 50; D008297:Male; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011041:Poisoning / Q000201:enzymology / Q000517:prevention & control; D000068836:Rivastigmine; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D012999:Soman / Q000737:chemistry / Q000506:poisoning*; D013997:Time Factors; D023382:Toxicity Tests, Acute
D000470:Alkaloids; D000931:Antidotes; D002619:Chemical Warfare Agents; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D012717:Sesquiterpenes; C050426:huperzine A; D005702:Galantamine; D000077265:Donepezil; D012999:Soman; D000110:Acetylcholinesterase; D000068836:Rivastigmine