Therapeutic Prospects Beyond Vioxx
Penn Study Suggests New Class of Anti-inflammatory Drugs
Might Lessen Chance of COX-2 Cardiovascular Problems
(Philadelphia, PA) - 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, as reported in the April
13 advanced online edition and May print issue of The Journal of Clinical
“Although these results are in mice, not people, they raise an exciting
possibility which can be tested in humans,” says senior author Garret
FitzGerald, MD, Director of Penn’s Institute for Translational
Medicine and Therapeutics.
Ever since the association of selective inhibitors of COX-2 - Vioxx, Bextra,
and Celebrex - 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
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 present studies, the investigators 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, such as Celebrex. They found that genetic disruption
of COX-2; inhibition of the enzyme by different inhibitors; and disruption
of prostacyclin’s effects by removing its receptor all had the same
effect - a predisposition to clotting and an elevation of blood pressure.
“This provides compelling evidence in support of the original hypothesis,”
says co-author Colin Funk, PhD, who has collaborated with FitzGerald 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 may retain much of the benefit
of drugs like Vioxx and Celebrex, while diminishing the risk of heart
attack and stroke by having precisely the opposite effect on prostacyclin,”
Co-authors are Research Associate Yan Cheng and postdoctoral fellows Ying
Yu and Miao Wang, all from Penn. This work was supported by grants from
the National Institutes of Health and, in part, a grant from Merck.
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