title: Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.
abstract: OBJECTIVE
  To study the pharmacokinetics and pharmacodynamics of intravenously administered arecoline in subjects with Alzheimer's disease.
  
  
  METHODS
  Plasma arecoline concentrations were measured during and after high-dose (i.e., 5 mg intravenously over 30 minutes) and up to 2 weeks of continuous multiple-dose steady-state intravenous infusions of arecoline in 15 subjects with mild to moderate Alzheimer's disease. During multiple-dose infusions, the dose of arecoline was escalated from 0.5 to 40 mg/day. Psychometric tests were administered at baseline and every other dose to determine an "optimal dose" for each subject. This dose then was administered for 1 week using a randomized, placebo-controlled, double blind, crossover design. Plasma drug concentrations were measured by GC-MS.
  
  
  RESULTS
  The optimal dose of arecoline varied fourfold across subjects (4 mg/day, n = 6; 16 mg/day, n = 3) with mean plasma half-lives of 0.95 +/- 0.54 and 9.3 +/- 4.5 (SD) minutes. Clearance and volume of distribution were 13.6 +/- 5.8 L/min and 205 +/- 170 (SD) L, respectively. At the dose that optimized memory, the mean plasma level was 0.31 +/- 0.14 (SD) ng/ml, and it predicted the optimal dose in all subjects.
  
  
  CONCLUSIONS
  Because optimal dose variation is due to differing plasma kinetics, the plasma arecoline level measured at a single infusion rate can be used to choose the optimal dose for memory enhancement in patients with Alzheimer's disease.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, USA.
authors.forename: S
authors.initials: S
authors.lastname: Asthana
authors.forename: N H
authors.initials: NH
authors.lastname: Greig
authors.forename: H W
authors.initials: HW
authors.lastname: Holloway
authors.forename: K C
authors.initials: KC
authors.lastname: Raffaele
authors.forename: A
authors.initials: A
authors.lastname: Berardi
authors.forename: M B
authors.initials: MB
authors.lastname: Schapiro
authors.forename: S I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: T T
authors.initials: TT
authors.lastname: Soncrant
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000188:drug therapy* / Q000523:psychology; D001115:Arecoline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D001115:Arecoline