Neuroendocrine responses to intravenous infusion of physostigmine in patients
with Alzheimer disease.
Author(s): Asthana S, Raffaele KC, Greig NH, Schapiro MB, Blackman MR, Soncrant TT.
Affiliation(s): Laboratory of Neurosciences, National Institute on Aging, National Institutes of
Health, Bethesda, Maryland, USA.
Publication date & source: 1999, Alzheimer Dis Assoc Disord. , 13(2):102-8
We have reported that physostigmine, a reversible cholinesterase inhibitor,
enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the
mechanism of cognition enhancement, plasma hormones were measured during
high-dose acute and low-dose chronic steady-state intravenous infusions of
physostigmine in nine subjects with AD. High-dose hormone responses were measured
during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min.
Chronic responses were measured during continuous intravenous infusions of
physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then
during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or
placebo administered in a randomized, double-blind, cross-over design. A
replicable improvement in verbal memory was found in five subjects. High-dose
physostigmine infusion that produced noxious side effects resulted in significant
elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH)
(p = 0.0001), cortisol (p = 0.0001), and beta-endorphin (p = 0.0001). Chronic
physostigmine administration, in the absence of adverse effects, produced no
significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or beta-endorphin
(p = 0.82). These results indicate that high-dose physostigmine activates the
hypothalamic-pituitary-adrenal (HPA) axis, likely representing a "stress
response." In contrast, cognition-enhancing doses do not produce a peripheral
corticosteroid response. Thus, physostigmine-induced memory improvement is
independent of the activation of the HPA axis.
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