Their findings offer the prospect of a new generation of anti-inflammatory drugs that will bypass this issue, says co-author Colin Funk, a professor of Biochemistry and Physiology at Queen's, and Canada Research Chair in Molecular, Cellular and Physiological Medicine. Although these results are in mice, not people, they raise an exciting possibility which can be tested in humans, he adds.
The study is published in the on-line edition of the Journal of Clinical Investigation.
Since the association of selective inhibitors of COX-2 such as 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, the researchers say.
Co-author with Dr. Funk on the study is Dr. Garret FitzGerald, director of Penn's Institute for Translational Medicine and Therapeutics. Funding comes from the U.S. National Institutes of Health and a grant from Merck.
The investigators first compared genetically manipulated mice that mimic the impact of either COX-2 inhibitors or low-dose aspirin with healthy mice treated with or without COX-2 inhibitors, such as Celebrex. "The trials showed that COX-2 inhibitors confer a small, but absolute cardiovascular risk using the same mechanism by which they relieve pain and inflammation," Dr. Funk reports.
With these mice they were able to show that the likely outcome of aspirin is to diminish the hazardous effects of the COX-2 inhibitors. The investigators were surprised to find that not only the clotting response, but also the rise in blood pressure caused by drugs like Celebrex, was reduced. Although these studies indicate that aspirin would limit the cardiovascular risk, however, it would also be expected to add to the risk of stomach problems.
A more promising finding came from a drug target that might substitute for COX-2: an enzyme called microsomal prostaglandin E synthase (mPGES)-1. The researchers showed that blocking this enzyme in mice did not predispose the animals to thrombosis or elevate blood pressure.
"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 [a protective fat that Vioxx and Celebrex depresses]," says Dr. FitzGerald.
PLEASE NOTE: PDF copies of the study are available upon request.
Nancy Dorrance, Queen's News & Media Services, 613.533.2869
Therese Greenwood, Queen's News & Media Services, 613.533.6907
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