Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans.
In imaging studies of brain functions using pharmacological probes, identification of the time point at which central effects of intravenously infused drugs become stable is crucial to separate the effects of experimental variables from the concomitant changes in drug effects over time. We evaluated the time courses of the pharmacokinetics and pharmacodynamics, including butyrylcholinesterase inhibition and central neural responses, of physostigmine in healthy young subjects. Ten positron emission tomography (PET) scans that alternated between a rest condition (eyes open, ears unplugged) and a working memory for faces (WM) task were acquired in healthy subjects. Subjects in the drug group received a saline infusion for the first two scans, providing a baseline measure, then received an infusion of physostigmine for all subsequent scans. Subjects in the control group received a placebo infusion of saline for all scans. Physostigmine plasma levels and percent butyrylcholinesterase inhibition increased over time (p < 0. 0001), and both became stable by 40 min. Physostigmine decreased reaction time (RT) (p = 0.0005), and this effect was detected after 20 min of infusion and stable thereafter. Physostigmine also decreased regional cerebral blood flow (rCBF) in right prefrontal cortex during task (p = 0.0002), and this effect was detected after 40 min of infusion and stable thereafter. No change in RT or rCBF was observed in the control group. These results indicate that a 40-min infusion of physostigmine was necessary to obtain stable central effects. More generally, we have demonstrated that experimental effects can vary with time, especially during the initial phases of a drug infusion, indicating that it is critical that these changes are controlled.
Furey
M L
ML
Laboratory of Neurosciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA. furey@nih.gov
Pietrini
P
P
Alexander
G E
GE
Mentis
M J
MJ
Szczepanik
J
J
Shetty
U
U
Greig
N H
NH
Holloway
H W
HW
Schapiro
M B
MB
Freo
U
U
D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010830:Physostigmine / Q000493:pharmacokinetics* / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors; D014055:Tomography, Emission-Computed
D002800:Cholinesterase Inhibitors; D010830:Physostigmine