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Therapeutic prospects beyond Vioxx

zGerald at Penn over the last decade on this line of research. Funk is now the Canada Research Chair of Physiology at Queen's University, Ontario. "One does not need additional explanations to understand what we have seen in clinical trials. COX-2 inhibitors confer a small, but absolute cardiovascular risk using the same mechanism by which they relieve pain and inflammation".

The investigators also addressed the likely benefit of adding aspirin to diminish this effect of the inhibitors. Surprisingly, this appeared to reduce not only the clotting response, but also the rise in blood pressure caused by drugs like Celebrex.

"Despite some chatter to the contrary, this issue of an aspirin effect has not been addressed directly in any of the clinical trials of COX-2 inhibitors," says FitzGerald. "However, although these studies indicate that it would limit the cardiovascular risk, it would also be expected to add to the risk of stomach problems, undermining the reason for choosing COX-2 inhibitors in the first place."

A surprising finding came when the investigators turned to a drug target that might substitute for COX-2 ?an enzyme called microsomal prostaglandin E synthase (mPGES)-1. Other investigators had shown previously that deletion of this enzyme seemed as effective as treatment with NSAIDs in models of pain and inflammation. This has prompted several large pharmaceutical companies to develop drugs targeting this enzyme. Such inhibitors will soon enter human trials.

FitzGerald and his colleagues showed that deletion of mPGES-1, in contrast to deletion or inhibition of COX-2, did not predispose the animals to thrombosis or elevate blood pressure. A clue to this surprising finding was that while mPGES-1 deletion suppressed profoundly another product of the COX-2 pathway called PGE2, the deletion of mPGES-1 actually elevated prostacyclin, the complete reverse of what was observed with COX-2 inhibitors. "Selective inhibitors of mPGES-1
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Source:University of Pennsylvania School of Medicine


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