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A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers

Title: A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers
Authors: Libri, V
Brown, AP
Gambarota, G
Haddad, G
Shields, GS
Dawes, H
Pinato, DJ
Hoffman, E
Elliot, PJ
Vlasuk, GP
Jacobson, E
Wilkins, MR
Matthews, PM
Item Type: Journal Article
Abstract: Background: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD + -dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age- related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. Methods: Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. Results: SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2–4 hours with elimination half-life of 15–20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. Conclusions: SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.
Issue Date: 20-Dec-2012
Date of Acceptance: 31-Oct-2012
URI: http://hdl.handle.net/10044/1/57628
DOI: https://dx.doi.org/10.1371/journal.pone.0051395
ISSN: 1932-6203
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS ONE
Volume: 7
Issue: 12
Copyright Statement: © 2012 Libri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MAGNETIC-RESONANCE-SPECTROSCOPY
SKELETAL-MUSCLE
MITOCHONDRIAL DISEASE
LIPID-METABOLISM
OXYGEN-UPTAKE
LIFE-SPAN
P-31 MRS
INSULIN
EXERCISE
FAT
Aged
Double-Blind Method
Endpoint Determination
Enzyme Activation
Exercise
Female
Glucose Tolerance Test
Humans
Imidazoles
Lipids
Male
Middle Aged
Pilot Projects
Placebo Effect
Safety
Sirtuin 1
Thiazoles
Time Factors
MD Multidisciplinary
General Science & Technology
Article Number: e51395
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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