title: Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers.
abstract: BACKGROUND
  We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers.
  
  
  RESULTS
  Twenty-four otherwise healthy cigarette smokers participated in a randomized double-blind, placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328 ± 748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (-11.6 ± 20 versus 6 ± 21 mg/dL), low-density lipoprotein cholesterol (-10 ± 17 versus 3 ± 21 mg/dL), and triglyceride (-39.8 ± 77 versus 13.3 ± 57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose-dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014.
  
  
  CONCLUSIONS
  SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT01031108.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, UK. s.venkat@ed.ac.uk
authors.forename: Sowmya
authors.initials: S
authors.lastname: Venkatasubramanian
authors.forename: Radzi Mohd
authors.initials: RM
authors.lastname: Noh
authors.forename: Shruti
authors.initials: S
authors.lastname: Daga
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Langrish
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Joshi
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Mills
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffmann
authors.forename: Eric W
authors.initials: EW
authors.lastname: Jacobson
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Brian R
authors.initials: BR
authors.lastname: Waterhouse
authors.forename: Ninian N
authors.initials: NN
authors.lastname: Lang
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D056564:Sirtuin 1 / Q000187:drug effects*; D012907:Smoking; D055815:Young Adult
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; C584666:SRT2104; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: SIRT1; cigarette smokers; endothelium; forearm plethysmography; platelet activation; sirtuins; vascular