Journal
CRITICAL CARE MEDICINE
Volume 43, Issue 6, Pages E199-E202Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000000949
Keywords
sirtuin 1; blood coagulation; clinical trial; endotoxemia; inflammation; pharmaceutical preparations
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Funding
- Sirtris, a GlaxoSmithKline company [NCT01014117]
- GSK
- Sirtris
- Center of Translational and Molecular Medicine (CTMM)
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Objectives: Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans. Design: A randomized, double-blind, placebo-controlled study. Setting: An academic hospital. Subjects: Twenty-four healthy humans. Interventions: All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n = 8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo. Measurements and Main Results: SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p < 0.05] and 80.9% [p = 0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p < 0.05 vs placebo] and 77.1% [p < 0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-a and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1 + 2 (mean peak levels 57.9% [p < 0.05] and 64.2% [p < 0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104. Conclusions: This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.
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