Showing papers by "Eric Siemers published in 2005"

Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

Abstract: Amyloid beta (Abeta) may play a central role in the pathogenesis of Alzheimer disease. A functional gamma-secretase inhibitor, LY450139, was developed that inhibits Abeta formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Abeta in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Abeta(1-40) and Abeta(1-X) ("Abeta(total)") were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 +/- 19.2 ng/mL after a 50-mg dose. Plasma Abeta concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Abeta concentrations were transiently increased. CSF Abeta concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Abeta was demonstrated, and changes in plasma Abeta concentrations were temporally related to the pharmacokinetic characteristics of LY450139.

Neuropsychological test performance in healthy elderly volunteers before and after donepezil administration: a randomized, controlled study.

Abstract: Neuropsychological performance was examined in healthy elderly participants administered the cholinesterase inhibitor donepezil. Of principal interest was examination of the sensitivity of a series of neuropsychological measures to detect cognitive changes after drug administration using typical phase I research parameters (eg, a small sample over a short treatment period). In this double-blind parallel study over a period of 6 weeks, 26 healthy elderly participants (aged 55 to 75 years) were randomized into 1 of 2 arms (14 donepezil and 12 placebo) and completed 14 days of donepezil (5 mg, twice a day) or placebo (twice a day). A battery of neuropsychological tests was administered on days 0, 14 (prerandomization), 28 (end of treatment), and 42 (washout). After 2 weeks of donepezil treatment (day 28), subjects in the donepezil group performed slightly but significantly worse on 2 tests of speed, attention, and short-term memory (P < 0.05) compared with the placebo group. No significant improvement in performance was present on any test during treatment with donepezil. These results are consistent with a previous study in healthy young participants in which transient mild worsening on some cognitive tests during donepezil administration was observed, possibly caused by perturbation of an already optimized cholinergic system in healthy participants. These results are important to consider when designing clinical development plans for putative cognitive-enhancing drugs; in addition, these results raise questions about when the optimal point to begin treatment is for patients who have not yet met criteria for dementia.

Role of biomarkers in studies of presymptomatic Alzheimer's disease.

Abstract: Background Biomarkers that have been developed largely for the study of patients with clinically diagnosed Alzheimer’s disease (AD) can also be used in the study of cognitively normal individuals who may harbor underlying AD pathology. Methods A meeting of invited experts on AD biomarkers was held on November 11 and 12, 2004 to review currently available data and to discuss unmet needs for biomarker research in presymptomatic AD. Results Neuroimaging biomarkers have been studied to some extent in subjects at risk for AD. These imaging techniques include volumetric magnetic resonance imaging and positron emission tomography using either fluorodeoxyglucose or newer ligands that bind directly to amyloid plaque. Similarly, biochemical measures from cerebrospinal fluid or other physiologic fluids are emerging as potentially useful tools. Such biomarkers may be used either as diagnostic tools or as indicators of disease severity when followed longitudinally. A clinical diagnosis of asymptomatic individuals using biomarkers and studies involving asymptomatic subjects may raise logistical and ethical concerns. Conclusions The technical development of biomarkers that are used for presymptomatic AD diagnosis and for longitudinally measuring disease severity is evolving rapidly. Ethical and privacy considerations must be made before such biomarkers can be applied routinely to asymptomatic populations.