Harold Holloway

Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease

To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimers disease.

Effect of acute and chronic arecoline treatment on cerebral metabolism and blood flow in the conscious rat

Treatment with the muscarinic agonist arecoline improves memory retention in patients with Alzheimers 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.