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Research in mice suggests that a newer class of painkilling drugs called
COX-2 inhibitors could trigger a chain of events potentially harmful
to the cardiovascular system.
Researchers speculate, though, that their findings might explain
the outcome of a recent major trial in which patients taking a COX-2
inhibitor -- the arthritis drug Vioxx -- had higher rates of heart
attack and other cardiovascular complications compared with patients
on naproxen.
Naproxen, used in painkillers such as Aleve, belongs to a group
of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs),
which includes many familiar painkillers such as aspirin and ibuprofen.
Aspirin is also well known for its heart-healthy blood-thinning
effects.
COX-2 inhibitors -- which besides Vioxx include the arthritis drugs
Celebrex, among others -- are a newer type of NSAID shown to be
easier on the stomach. Unlike older forms such as aspirin, they
work by selectively blocking the COX-2 enzyme. Traditional NSAIDs
inhibit both the COX-2 and COX-1 enzymes, and this is believed to
underlie the gastrointestinal side effects that can come with the
drugs.
But the new mouse research suggests that the selectivity of COX-2
inhibitors could create an imbalance that
promotes blood clotting and blood vessel constriction.
COX-1 makes thromboxane A2, which promotes blood vessel constriction
and "stickiness" in blood cells called platelets. COX-2
is the major source of prostacyclin, which helps prevent platelets
from clumping and promotes blood vessel dilation.
The researchers hypothesized that the heart-healthy ways of prostacyclin
might counter the ill cardiovascular effects of thromboxane A2 in
the body -- meaning that blocking only COX-2, and therefore prostacyclin,
could allow thromboxane A2 to go about its business unchecked.
The researchers found that mice without a PGI2 receptor -- which
mimics the clinical effect of taking COX-2 inhibitors -- had an
enhanced vascular response to injury and showed increased thromboxane
A2 formation and platelet activation. This exaggerated response
was canceled out in mice lacking both thromboxane A2 and PGI2 receptors
Recently Merck & Co. Inc., the maker of Vioxx, announced that
the arthritis drug's labeling would be changed
to state that it carries higher cardiovascular risks than naproxen
-- a move required by the US Food and Drug Administration following
the Vioxx-naproxen trial.
However, that labeling also highlights data from two other studies
showing that Vioxx users had a lower rate of cardiovascular problems
compared with study participants taking an inactive placebo, although
the difference was not statistically significant.
Science
April 19, 2002;296:539-541
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