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Selective inhibitors of mPGES-1, a new class of anti-inflammatory drugs that might lessen chance of COX-2 cardiovascular events

Researchers at the University of Pennsylvania School of Medicine have clarified the mechanism by which drugs like Celebrex and Vioxx cause heart problems, in multiple animal models.

The findings offer the prospect of a new generation of anti-inflammatory drugs that bypass this issue.

Ever since the association of selective inhibitors of COX-2 – Vioxx ( Rofecoxib ), Bextra ( Valdecoxib ), and Celebrex ( Celecoxib ) - with an increased incidence of heart attack and stroke, there has been intense interest in understanding the mechanism involved. Clarification of this issue offers the prospect of conserving the clinical benefit of these drugs for patients with arthritis, while managing the risk.

Almost 10 years ago, FitzGerald noticed that both Celebrex and Vioxx depressed in healthy individuals a protective fat called prostacyclin, while leaving unaltered a harmful one called thromboxane. This led him to predict that drugs in this class might confer a cardiovascular risk before either reached the US market.

In the study, published in the Journal of Clinical Investigation, the researchers used multiple genetically manipulated mice - including mice that mimicked the impact of either COX-2 inhibitors or low-dose aspirin and compared them with treating healthy mice with COX-2 inhibitors.

They found that genetic disruption of COX-2; inhibition of the enzyme by different inhibitors; and disruption of effects of prostacyclin by removing its receptor all had the same effect - a predisposition to clotting and an elevation of blood pressure.

The researchers 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 COX-2 inhibitors.

A surprising finding came when the researchers turned to a drug target that might substitute for COX-2 - an enzyme called microsomal prostaglandin E synthase ( mPGES )-1.
Other studies had shown previously that deletion of this enzyme seemed as effective as treatment with NSAIDs in models of pain and inflammation.

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.

Source: University of Pennsylvania School of Medicine, 2006