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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...

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Autores principales: Ghosal, Kaushik, Haag, Michael, Verghese, Philip B., West, Tim, Veenstra, Tim, Braunstein, Joel B., Bateman, Randall J., Holtzman, David M., Landreth, Gary E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
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).
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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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