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Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.

AbstractOBJECTIVE:
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.
AuthorsS Asthana, N H Greig, H W Holloway, K C Raffaele, A Berardi, M B Schapiro, S I Rapoport, T T Soncrant
JournalClinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 60 Issue 3 Pg. 276-82 (Sep 1996) ISSN: 0009-9236 [Print] UNITED STATES
PMID8841150 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)
Chemical References
  • Muscarinic Agonists
  • Nicotinic Agonists
  • Arecoline
Topics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease (blood, drug therapy, psychology)
  • Arecoline (administration & dosage, blood, pharmacokinetics)
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Memory (drug effects)
  • Middle Aged
  • Muscarinic Agonists (administration & dosage, blood, pharmacokinetics)
  • Nicotinic Agonists (administration & dosage, blood, pharmacokinetics)

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