Jan. 18, 1999 A much-anticipated series of new drugs just coming to market promises to ease the pain of arthritis, menstrual cramps, headaches, and other afflictions equally as well as aspirin, ibuprofen, and related over-the-counter medications but without the sometimes serious side effects of those drugs. Stomach ulcers are among the worst of these side effects, leading to tens of thousands of hospitalizations and thousands of deaths annually.
A new study from the University of Pennsylvania Medical Center, however, raises the possibility of a downside to these so-called "super aspirins," or COX-2 inhibitors, one that could not have been detected in the clinical trials performed to date. The researchers looked closely at the pharmacology of the COX-2 inhibitors and discovered aspects of their action in the body that may elevate the risk of heart attacks, strokes, and other adverse cardiovascular events. A report on the study appears in the current issue of the Proceedings of the National Academy of Science, published January 5.
"The clinical trials designed to show that the COX-2 inhibitors work in treating arthritis have not shown evidence of a cardiovascular risk," says Garret A. FitzGerald, MD, chairman of the department of pharmacology and senior author on the study. "However, they would have been roughly an order of magnitude too small in their sample sizes to detect what we see as a possible problem associated with the use of these drugs. So, the question hangs out there for future experience: Will a cardiovascular risk emerge over time as the COX-2 inhibitors reach more and more patients?"
Aspirin and ibuprofen are members of a class of pain relievers known as nonsteroidal anti-inflammatory drugs, or NSAIDs. These drugs work by inhibiting an enzyme called cyclooxygenase, or COX. Scientists discovered early this decade that there are two forms of the enzyme, COX-1 and COX-2, and that the first, COX-1, protects the lining of the stomach, while the second, COX-2, is responsible for triggering pain and inflammation. Current NSAIDs block both forms of the enzyme, and programs to develop drugs that distinguish between the two began shortly after this information became known. The selective COX-2 inhibitors are the eagerly awaited result of these efforts.
In their somewhat surprising observation, FitzGerald and his colleagues found that the COX-2 inhibitors suppress prostacyclin, a hormone-like substance produced in the walls of blood vessels that acts to dilate the vessels and inhibit platelet aggregation, or clotting. The finding was unexpected because it was not thought at the time that COX-2 is expressed normally by vessel-wall cells nor, therefore, that it plays a role in the production of prostacyclin in healthy individuals. Subsequent in vitro research in other laboratories, however, indicates that blood flow stimulates the expression of COX-2 by blood vessels. The Penn results suggest that the same is true in vivo.
Excessive aggregation of platelets can lead to thrombosis, dangerous clotting that can result in heart attacks and strokes. So, the fact that COX-2 inhibitors interfere with the production of prostacyclin, a naturally occurring agent protective against thrombosis, may mean that the new drugs will increase the likelihood of adverse cardiovascular events in at-risk populations. Indeed, mice genetically engineered to be unable to use prostacyclin properly have been shown to be prone to thrombotic events. Many older people, including some of those who may want to take COX-2 inhibitors for their arthritis, for example, could be among those at risk for such events.
While it is true that current NSAIDs also suppress prostacyclin, these drugs have the further action of paralyzing platelets, thus limiting their ability to aggregate. This is the reason that low-dose aspirin regimens are often prescribed by doctors for their cardiovascular disease patients to reduce the odds of thrombotic events. The COX-2 inhibitors do not offer this additional protective action while they do remove the body's inherent ability to control platelet aggregation through prostacyclin production.
"One option may be for patients who are at particular risk for adverse cardiovascular events to combine COX-2 therapies with low-dose aspirin," FitzGerald suggests. "But this is a strategy that would need to be tested in clinical trials."
The current study was performed with Celebrex, the COX-2 compound from G. D. Searle and Co. that was approved for sale on December 31, 1998, by the Food and Drug Administration. FitzGerald notes, however, that the potential risk factor identified in the experiments done in his laboratory is not a property solely of Celebrex. Results of a study involving Vioxx, a COX-2 inhibitor from Merck & Co., have shown similar results, he says.
The lead author on the study is B. F. McAdam, MD. In addition to senior author FitzGerald, the remaining authors are F. Catella-Lawson, MD; I. A. Mardini, MD; S. Kapoor, PhD; and J. A. Lawson, BS. Funding for the study was provided by G. D. Searle and Co.
The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page http://www.med.upenn.edu to EurekAlert! http://www.eurekalert.org, an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news services Newswise http://www.newswise.com.
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