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A pilot randomized, placebo controlled, double blind Phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers

Libri, V; Brown, AP; Gambarota, G; Haddad, J; Shields, GS; Dawes, H; Pinato, DJ; ... Matthews, PM; + view all (2012) A pilot randomized, placebo controlled, double blind Phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLoS One , 7 (12) , Article e51395. 10.1371/journal.pone.0051395. Green open access

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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. Trial Registration ClinicalTrials.gov NCT00964340

Type: Article
Title: A pilot randomized, placebo controlled, double blind Phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0051395
Publisher version: http://dx.doi.org/10.1371/journal.pone.0051395
Language: English
Additional information: © 2012 Libri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3527451
Keywords: 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
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > IoN Central Administration
URI: https://discovery.ucl.ac.uk/id/eprint/1403213
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