| March 7, 2001
Aspirin and Other Non-Specific
COX Inhibitors May Slow Atherosclerosis, Penn Study
Finds
Making sure cardiac patients
take an aspirin a day to prevent a second heart attack
is part of established treatment for most physicians,
and many recommend the same regimen for patients at
risk of suffering a first attack. But there has never
been scientific evidence to demonstrate that this common,
over-the-counter medication really provides any benefit
in staving off the underlying condition of atherosclerosis.
Now, mouse-model research by scientists at the University
of Pennsylvania School of Medicine has demonstrated
that aspirin, ibuprofen and other drugs in the class
of pharmaceuticals known as non-specific COX inhibitors
may aid substantially in preventing heart disease, slowing
the build-up of plaque in blood vessels by more than
50 percent.
"This study suggests that a product of the cyclooxegenase
enzyme known as COX-1 -- which is the form targeted
by aspirin in the prevention of heart attacks -- may
also have a part to play in the gradual hardening of
the arteries that precedes acute events like heart attack
or stroke," said Garret A. FitzGerald, MD, chairman
of Penn's Department of Pharmacology. The research will
be published March 13 in the Proceedings of the National
Academy of Science.
The study also demonstrates that a separate class of
drugs that specifically target the COX-2 enzyme -- so-called
"super aspirins" such as Celebrex and Vioxx -- do not
speed up the development of atherosclerosis, a concern
based on some biochemical effects of those drugs.
In their work, the Penn scientists scrutinized both
known forms of the enzyme cyclooxygenase: COX-1, which
is present throughout the body, and COX-2, which is
present in some tissues, including the lining of the
blood vessels.
COX-1 is the only form of the enzyme in platelets --
blood cells that stick together in the first stages
of clotting. Suppression of the platelet COX-1 product,
thromboxane, is how aspirin protects against heart attack
and stroke.
The COX-2 enzyme produces prostacyclin, a hormone-like
substance that might work against atherosclerosis by
keeping blood vessels elastic, slowing the division
of cells in the blood vessel wall, and preventing blood
clots. On the other hand, prostacyclin is also pro-inflammatory
-- a property that may speed up atherosclerosis. Before
the experiment, it was impossible to know how these
conflicting effects would play out when COX-2 inhibitors
were given.
When they were introduced a few years ago as anti-inflammatories,
the COX-2 inhibitors quickly became popular for treating
illnesses such as arthritis. But because of the properties
of prostacyclin, FitzGerald and his colleagues wondered
whether blocking this COX-2 product might lead to hardening
of the arteries, particularly in young patients with
juvenile arthritis who might take the drug for long
periods.
Using mice that had been engineered to produce high
levels of cholesterol, the scientists injected one group
with the non-specific inhibitor indomethacin, a second
group with the COX-2 blocker nimesulide, and a third
control group with a placebo. Analyzing the mice's aortas
at the conclusion of the 16-weeks study, the researchers
found that atherosclerotic lesions were reduced by 55
percent in mice exposed to the non-specific COX inhibitor,
compared to lesions in the untreated mice. Mice exposed
to the COX-2 inhibitor showed the same progression of
atherosclerosis as the control group.
"Because prostacyclin is potentially pro-inflammatory,
inhibiting it might have proved beneficial, and there
was a hint of that in our data. But it did not attain
significance - in fact the effects of inhibiting prostacyclin
paled in comparison with the use of a mixed inhibitor,"
FitzGerald said.
"The real story is that atherosclerosis is not only
inflammation. There is something else at work here,
and that is the production of thromboxane by COX-1,"
added Domenico Pratico, MD, a research assistant professor
of Pharmacology at Penn who collaborated with FitzGerald
in the study.
The research was funded by grants from the American
Heart Association and the National Institutes of Health.
Others assisting in the study were Cyrus Tillman, Zhi-Bing
Zhang and Hongwei Li, all of Penn.
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