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A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects
INTRODUCTION: We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. METHODS: We used stable isotope labeli...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644280/ https://www.ncbi.nlm.nih.gov/pubmed/29067298 http://dx.doi.org/10.1016/j.trci.2016.06.001 |
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author | Ghosal, Kaushik Haag, Michael Verghese, Philip B. West, Tim Veenstra, Tim Braunstein, Joel B. Bateman, Randall J. Holtzman, David M. Landreth, Gary E. |
author_facet | Ghosal, Kaushik Haag, Michael Verghese, Philip B. West, Tim Veenstra, Tim Braunstein, Joel B. Bateman, Randall J. Holtzman, David M. Landreth, Gary E. |
author_sort | Ghosal, Kaushik |
collection | PubMed |
description | INTRODUCTION: We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. METHODS: We used stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C(13)-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. RESULTS: Oral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides. DISCUSSION: Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (NCT02061878). |
format | Online Article Text |
id | pubmed-5644280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-56442802017-10-24 A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects Ghosal, Kaushik Haag, Michael Verghese, Philip B. West, Tim Veenstra, Tim Braunstein, Joel B. Bateman, Randall J. Holtzman, David M. Landreth, Gary E. Alzheimers Dement (N Y) Featured Article INTRODUCTION: We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. METHODS: We used stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C(13)-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. RESULTS: Oral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides. DISCUSSION: Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (NCT02061878). Elsevier 2016-06-17 /pmc/articles/PMC5644280/ /pubmed/29067298 http://dx.doi.org/10.1016/j.trci.2016.06.001 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Featured Article Ghosal, Kaushik Haag, Michael Verghese, Philip B. West, Tim Veenstra, Tim Braunstein, Joel B. Bateman, Randall J. Holtzman, David M. Landreth, Gary E. A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title | A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title_full | A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title_fullStr | A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title_full_unstemmed | A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title_short | A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects |
title_sort | randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein e metabolism in healthy subjects |
topic | Featured Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644280/ https://www.ncbi.nlm.nih.gov/pubmed/29067298 http://dx.doi.org/10.1016/j.trci.2016.06.001 |
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