title: Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques.
abstract: Galantamine hydrobromide and (-)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID50) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.
authors.affiliation: Department of Psychology, University of Colorado Denver, Denver, CO, 80217, USA.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Hamilton
authors.affiliation: Departments of Neurology Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Harvard Medical School, Consortia for Improving Medicine with Innovation and Technology, 125 Nashua Street, 3rd Floor, Boston, MA, 02114, USA. sschacht@bidmc.harvard.edu.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Schachter
authors.affiliation: Neurobehavioral Toxicology Branch, Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 2900 Ricketts Point Rd, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Myers
mesh_terms: D000470:Alkaloids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D011729:Pyridostigmine Bromide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012717:Sesquiterpenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012999:Soman / Q000633:toxicity*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000470:Alkaloids; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D003292:Convulsants; D012717:Sesquiterpenes; C050426:huperzine A; D012999:Soman; D011729:Pyridostigmine Bromide
keywords: Acetylcholinesterase; Behavioral toxicity; Galantamine; Huperzine; Nerve agent; Pyridostigmine bromide