ABSTRACT
OBJECTIVE: To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimer's disease. METHODS: Plasma physostigmine concentration and butyrylcholinesterase inhibition were measured in blood samples collected during and after a single high-dose (1 to 1.5 mg for 45 to 60 minutes) and a sustained low-dose steady-state intravenous infusion in nine subjects with Alzheimer's disease. Escalating doses (0.5 to 25 mg/day) were administered during a 2-week period. A dose (2 to 12 mg/day) that optimized cognition in each subject was identified and then administered in a randomized, double-blind, placebo-controlled crossover design for 1 week. RESULTS: The elimination half-life of physostigmine was 16.4 +/- 3.2 (SE) minutes. Clearance and volume of distribution were 7.7 +/- 0.9 (SE) L/min and 2.4 +/- 0.6 (SE) L/kg, respectively. Butyrylcholinesterase inhibition half-life was 83.7 +/- 5.2 (SE) minutes. During sustained steady-state infusion, plasma physostigmine concentration (r = 0.95) and butyrylcholinesterase inhibition (r = 0.99) were linearly correlated with the dose. In five cognitive responders, the memory enhancement was significantly correlated (r = 0.86; p < 0.05) with butyrylcholinesterase inhibition. CONCLUSIONS: These results showed that, in cognitive responders, memory enhancement by physostigmine in Alzheimer's disease is correlated directly to the magnitude of plasma cholinesterase inhibition. Furthermore, during single-dose conditions, the dynamic half-life is five-fold longer than the kinetic half-life.
Subject(s)
Alzheimer Disease/metabolism , Cholinesterase Inhibitors/pharmacokinetics , Physostigmine/pharmacokinetics , Aged , Aged, 80 and over , Alzheimer Disease/blood , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/blood , Cholinesterase Inhibitors/pharmacology , Cognition/drug effects , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Humans , Individuality , Infusions, Intravenous , Male , Middle Aged , Physostigmine/blood , Physostigmine/pharmacologyABSTRACT
Treatment with the muscarinic agonist arecoline improves memory retention in patients with Alzheimer's disease (AD). In animal models, arecoline selectively increases local cerebral glucose utilization (LCGU). We examined (1) whether these focal increases in metabolism were coupled to local cerebral blood flow (LCBF) and (2) whether the effect of arecoline on LCGU and LCBF was dependent upon duration of drug administration. In groups of young Fischer-344 rats, LCGU and LCBF were determined in 59 brain regions by the [14C]2-deoxyglucose and the [14C]iodoantipyrine autoradiographic methods following either the acute administration of arecoline (2 mg/kg and 15 mg/kg) or the chronic three week administration of arecoline (50 mg/kg/day). In general, LCBF correlated closely with LCGU following arecoline 2 mg/kg administration, but heterogeneous regions were present. Following treatment with arecoline 15 mg/kg, the two parameters became uncoupled with LCBF increasing disproportionately in relation to LCGU. Coupling between LCBF and LCGU was preserved during chronic arecoline treatment (50 mg/kg/day) but some regions, such as the hippocampus, were uncoupled with LCGU increasing to a greater extent than LCBF. Thus, we demonstrate that acute and chronic administration of arecoline can differentially modulate LCBF and LCGU. Since clinical administration of arecoline can improve cognitive function in patients with AD, understanding the ability of arecoline to selectively alter LCBF and LCGU in regions such as the hippocampus may offer insight into the pathophysiology of AD and provide direction for the development of definitive therapy for neurodegenerative disorders.
