The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
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.
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Plasma and Cerebrospinal Fluid Levels of Amyloid β Proteins 1-40 and 1-42 in Alzheimer Disease
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Cited by
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134
A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
Doody, R. S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1210951 · Cited by 1,224
Self-citationCurrent and future treatments for Alzheimer's disease
Yiannopoulou, K. G., & Papageorgiou, S. G. (2013) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756285612461679 · Cited by 677
Alzheimer's Disease: From Pathology to Therapeutic Approaches
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Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo
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Metadata
- Authors
- Siemers, E., Skinner, M., Dean, R. A., Gonzales, C., Satterwhite, J., Farlow, M., Ness, D., & May, P. C.
- Venue
- Clinical Neuropharmacology
- Published
- 2005-05
- Volume
- 28
- Issue
- 3
- Pages
- 126-132
- ISSN
- 0362-5664 (ISSN-L)
- OpenAlex
- W2068660068
- Cited by
- 216
- References
- 11
- FWCI
- 12.23
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers. https://app.cochat.ai/papers/10.1097/01.wnf.0000167360.27670.29
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- Siemers, E., Skinner, M., Dean, R. A., Gonzales, C., Satterwhite, J., Farlow, M., Ness, D., & May, P. C. (2005). Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers. Clinical Neuropharmacology. https://doi.org/10.1097/01.wnf.0000167360.27670.29
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
