title: Physiological and neurobehavioral effects of cholinesterase inhibition in healthy adults.
abstract: BACKGROUND
  Based on common pharmacodynamic mechanisms, recent efforts to develop second generation alternatives for organophosphate (OP) prophylaxis have expanded to include cholinesterase (ChE) inhibiting compounds traditionally approved for use in the treatment of Alzheimer's disease (AD). The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance.
  
  
  METHODS
  In addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5mg), or placebo (n=12 subjects per drug/dose).
  
  
  RESULTS
  Compared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 μg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects.
  
  
  CONCLUSIONS
  Although huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function.
authors.affiliation: Walter Reed Army Institute of Research, United States. Electronic address: kmorasch@gmail.com.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Morasch
authors.affiliation: Fort Belvoir Community Hospital, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Aaron
authors.affiliation: Walter Reed Army Institute of Research, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Moon
authors.affiliation: United States Army Medical Research and Materiel Command, United States.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gordon
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000293:Adolescent; D000328:Adult; D000470:Alkaloids / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000097:blood; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood*; D000077265:Donepezil; D005260:Female; D005702:Galantamine / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012717:Sesquiterpenes / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D012717:Sesquiterpenes; C050426:huperzine A; D005702:Galantamine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases
keywords: Acetylcholinesterase inhibition; Donepezil; Galantamine; Huperzine A; Neurobehavioral performance; Organophosphate prophylaxis