title: Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial.
abstract: BACKGROUND
  The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.
  
  
  METHODS
  Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.
  
  
  RESULTS
  Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.
  
  
  CONCLUSIONS
  Short-term treatment (14 ± 4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Joel L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Rose
authors.initials: R
authors.lastname: Snipes
authors.affiliation: GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
authors.forename: Salim
authors.initials: S
authors.lastname: Janmohamed
authors.affiliation: GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Rolfe
authors.affiliation: GlaxoSmithKline, Addenbrook, Cambridge, United Kingdom.
authors.forename: Bill
authors.initials: B
authors.lastname: Davis
authors.affiliation: University of Southampton, Southampton, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Postle
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors.forename: Colin H
authors.initials: CH
authors.lastname: Macphee
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood / Q000378:metabolism*; D000368:Aged; D001547:Benzaldehydes / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000201:enzymology* / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016894:Endarterectomy, Carotid; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D013997:Time Factors; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D015415:Biomarkers; D053148:Caspase 3; D053181:Caspase 8; D008244:Lysophosphatidylcholines; D010091:Oximes; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides