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Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease
Author(s) -
Asthana Sanjay,
Greig Nigel H.,
Holloway Harold W.,
Raffaele Kathleen C.,
Berardi Annamaria,
Schapiro Mark B.,
Rapoport Stanley I.,
Soncrant Timothy T.
Publication year - 1996
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(96)90054-5
Subject(s) - arecoline , pharmacokinetics , medicine , crossover study , plasma clearance , volume of distribution , placebo , pharmacodynamics , alzheimer's disease , pharmacology , anesthesia , disease , pathology , receptor , muscarinic acetylcholine receptor , alternative medicine
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. Clinical Pharmacology & Therapeutics (1996) 60 , 276–282; doi: