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Aspirin Might Prevent Vioxx Cardiac Damage

Aspirin Might Prevent Vioxx Cardiac Damage
Aspirin Might Prevent Vioxx Cardiac Damage


Duke Health News Duke Health News

Durham, N.C. -- Low-dose aspirin might prevent the
cardiovascular damage known to arise from use of the painkiller
rofecoxib (Vioxx®), suggest
new findings from mouse studies by Duke University Medical
Center researchers. Their findings that a chemical imbalance
might underlie such damage could also lead to the development
of anti-inflammatory drugs without the adverse side effects,
the researchers said.

The researchers reported their findings in the September 14,
2005, issue of Cell
. The work was supported by the Medical Research
Service of the Veterans Administration and the National
Institutes of Health.

Earlier studies in humans have found that cox-2 inhibitors
such as rofecoxib cause a decline in prostacyclin, a chemical
that normally keeps blood vessels open and prevents blood
clots. That decline occurs without a change in concentration of
thromboxane, a related agent that constricts vessels and
promotes clot formation.

The new study found that, in a strain of mice prone to high
blood pressure, an inability to respond to prostacyclin led to
cardiac complications, including hypertension, enlarged hearts
and severe scarring of the heart. Moreover, they showed,
unrestrained action of thromboxane in the mice accentuated the
intensity of cardiac damage caused by the high blood

"The current results suggest that such a chemical imbalance
in patients taking selective cox-2 inhibitor painkillers may
present a cardiovascular hazard -- particularly for people
already predisposed to high blood pressure," said senior author
of the study Thomas Coffman, M.D., chief of nephrology in the
department of medicine.

Cox-2 inhibitors and other non-steroidal anti-inflammatory
drugs (NSAIDS) -- including aspirin and ibuprofen -- all reduce
inflammation and pain by blocking the function of the so-called
cox enzymes, cox-1 and cox-2. Cox enzymes normally produce
prostanoids-- a family of chemicals, including prostaglandins
and thromboxanes, with many important functions throughout the

Prostaglandins produced by both enzymes promote
inflammation, pain, and fever, while others made by cox-1
protect the stomach from the damaging effects of acid. Two
important prostanoids produced by the cox-1 and cox-2 enzymes,
respectively, are thromboxane and prostacyclin.

Traditional NSAIDs relieve pain and inflammation by
simultaneously blocking the function of both cox enzymes,
Coffman explained. However, the effects of such drugs on cox-1
can leave the stomach unprotected, causing gastrointestinal
bleeding. Drugs such as rofecoxib, celecoxib (Celebrex®) and
valdecoxib (Bextra®) avoid the gastrointestinal side effects by
acting only on cox-2.

A 2004 study, however, found an increased rate of heart
attack and stroke in patients treated with the specific cox-2
inhibitor rofecoxib for more than 18 months. The study also
found that patients taking the drug showed a more immediate
rise in blood pressure. The findings led Merck, the
manufacturer of Vioxx, to
withdraw the drug from the market last year.

While earlier research has implicated the abnormal chemical
profile in the vascular disease associated with cox-2
inhibitors, its role in the development of high blood pressure
remained unclear, Coffman said. Hypertension is the most common
cardiovascular complication associated with cox-2 inhibition,
he added.

To examine the consequences of prostacyclin decline for
blood pressure and cardiac damage, the team manipulated mice
such that they completely lacked the receptors that normally
respond to the vessel dilator. The mice belonged to a strain
particularly vulnerable to developing increased blood pressure
when fed a diet high in salt.

"Hypertension is the most common cardiovascular complication
associated with cox-2 inhibition, yet not everybody who takes
the drugs develops high blood pressure," Coffman said. "The
mice appear to have characteristics similar to the subset of
patients who are prone to experience this side effect."

In the absence of the prostacyclin receptor, mice exhibited
elevated blood pressure, the team reported. The animals also
suffered exaggerated cardiac fibrosis and heart enlargement.
Fibrosis, or scarring of the heart, can lead to arrhythmias and
organ failure as the heart loses its ability to pump blood to
the body's tissues.

Mice lacking both the prostacyclin and the thromboxane
receptors continue to suffer from high blood pressure, but do
not develop the other cardiac complications, they found. The
results reveal the adverse cardiovascular consequences of
thromboxane when left unconstrained by prostacyclin, the team
reported. Furthermore, the findings point to the imbalance of
blood vessel agents as the culprit behind the most serious
cardiac complications in the animals.

The mice represent an extreme example of what might happen
in patients taking cox-2 inhibitors, Coffman said. While
prostacyclin activity can be substantially reduced in patients
taking the painkillers, the animals lacked this important blood
component altogether, he explained.

"Our data suggests that therapies that block unrestrained
thromboxane actions – for example, low doses of aspirin --
might protect against end-organ damage without affecting blood
pressure in patients taking cox-2 inhibitors," Coffman said.
"However, the practical utility of such an approach would
depend on whether such a therapy would retain the
gastrointestinal protection afforded by cox-2 inhibitors

The researchers will next explore the effects of cox-2
inhibitors themselves in the salt-sensitive mice. Further study
of the animals might also reveal the genetic factors that
underlie the predisposition of particular individuals to
develop high blood pressure and cardiac complications during
therapy with cox-2 inhibitors.

Collaborators on the study include Helene Francois, Krairerk
Athirakul, David Howell, Rajesh Dash, Lan Mao and Howard
Rockman, of Duke; Hyung-Suk Kim and Beverly Koller of
University of North Carolina, Chapel Hill; and Garret
Fitzgerald of University of Pennsylvania.

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