title: Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis.
abstract: OBJECTIVE
  This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging.
  
  
  BACKGROUND
  The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis.
  
  
  METHODS
  Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured.
  
  
  RESULTS
  The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo: ΔTBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat.
  
  
  CONCLUSIONS
  Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022).
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maysoon
authors.initials: M
authors.lastname: Elkhawad
authors.forename: James H F
authors.initials: JH
authors.lastname: Rudd
authors.forename: Lea
authors.initials: L
authors.lastname: Sarov-Blat
authors.forename: Gengqian
authors.initials: G
authors.lastname: Cai
authors.forename: Richard
authors.initials: R
authors.lastname: Wells
authors.forename: L Ceri
authors.initials: LC
authors.lastname: Davies
authors.forename: David J
authors.initials: DJ
authors.lastname: Collier
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marber
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.forename: Ahmed
authors.initials: A
authors.lastname: Tawakol
authors.forename: Fergus V
authors.initials: FV
authors.lastname: Gleeson
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Bill
authors.initials: B
authors.lastname: Davis
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Ian B
authors.initials: IB
authors.lastname: Wilkinson
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Sprecher
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001025:Aortitis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D050197:Atherosclerosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D002340:Carotid Artery Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D003521:Cyclopropanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000097:blood; D050152:Intra-Abdominal Fat / Q000000981:diagnostic imaging / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D016017:Odds Ratio; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D050151:Subcutaneous Fat / Q000000981:diagnostic imaging / Q000187:drug effects; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D006113:United Kingdom; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D048051:p38 Mitogen-Activated Protein Kinases