Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.
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.
Asthana
S
S
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, USA.
Greig
N H
NH
Holloway
H W
HW
Raffaele
K C
KC
Berardi
A
A
Schapiro
M B
MB
Rapoport
S I
SI
Soncrant
T T
TT
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*
D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D001115:Arecoline