Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans.
OBJECTIVE
To evaluate whether a p38α/β mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI).


RESULTS
Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (n=46), or placebo (n=46) daily for 28 days, starting 3 days before PCI. On day 3, before PCI, hsCRP was decreased in the SB-681323 group relative to the placebo group (29% lower; P=0.02). After PCI, there was a statistically significant attenuation in the increase in hsCRP in the SB-681323 group relative to the placebo group (37% lower on day 5 [P=0.04]; and 40% lower on day 28 [P=0.003]). There were no adverse safety signals after 28 days of treatment with SB-681323.


CONCLUSIONS
In the setting of statin therapy, SB-681323 significantly attenuated the post-PCI inflammatory response, as measured by hsCRP. This inflammatory dampening implicates p38 mitogen-activated protein kinase in the poststent response, potentially defining an avenue to limit poststent restenosis.
Sarov-Blat
Lea
L
Heart Failure Discovery Performance Unit, Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, 709 Swedeland Rd, UW2301, King of Prussia, PA 19406, USA.
Morgan
John M
JM
Fernandez
Pedro
P
James
Rachel
R
Fang
Zixing
Z
Hurle
Mark R
MR
Baidoo
Charlotte
C
Willette
Robert N
RN
Lepore
John J
JJ
Jensen
Svend E
SE
Sprecher
Dennis L
DL
D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000032:analysis; D003324:Coronary Artery Disease / Q000628:therapy; D003331:Coronary Vessels / Q000293:injuries*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood; D008297:Male; D008875:Middle Aged; D019919:Prosthesis Implantation / Q000009:adverse effects; D015607:Stents / Q000009:adverse effects*; D057772:Vascular System Injuries / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases