(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 Investigation.
“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 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 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
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
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