The increased rate of cardiovascular complications in patients taking the cox-2 inhibitor painkiller rofecoxib (Vioxx) may result from a chemical imbalance, according to an animal study in the September Cell Metabolism. The findings suggest that low-dose aspirin might prevent the cardiac damage of such drugs and might also lead to the development of new anti-inflammatory drugs without the adverse side effects, the researchers said.
Earlier studies in humans have found that cox-2 inhibitors cause a decline in prostacyclin, a chemical that normally keeps blood vessels open and prevents blood clots. That drop occurs without a change in concentration of thromboxane, a related agent that constricts vessels and promotes clot formation.
The new study by researchers at Duke University and Durham VA Medical Centers found that, in 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 absence of prostacyclin accentuated the intensity of cardiac damage caused by the high blood pressure.
"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 study author Thomas Coffman.
"Hypertension is the most common cardiovascular complication associated with cox-2 inhibition, yet not everybody who takes the drugs develops high blood pressure," he continued. "The mice appear to have characteristics similar to the subset of patients who are prone to experience this side effect."
Cox-2 inhibitors and other nonsteroidal, anti-inflammatory drugs (NSAIDs)--including aspirin and ibuprofen--all reduce inflammation and pain by blocking the function of cyclo-oxygenases, also known as cox enzymes. The cox enzymes, cox-1 and cox-2, normally produce prostanoids--a family of related chemicals, including prostaglandins and thromboxanes, with many important functions throughout the body.
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. The cox-1 and cox-2 enzymes, respectively, also produce thromboxane and prostacyclin.
Traditional NSAIDs relieve pain and inflammation by simultaneously blocking the function of both cox enzymes, Coffman explained. In contrast, rofecoxib and other cox-2 inhibitors selectively limit cox-2, thereby avoiding the gastrointestinal complications of over-the-counter NSAIDs.
A 2004 study, however, found an early rise in blood pressure and an increased rate of heart attack and stroke in patients treated with rofecoxib for more than 18 months. Last year, the manufacturer withdrew the drug from the market.
The current findings may lead to new drugs that avoid the pitfalls of both traditional NSAIDs and existing cox-2 inhibitors, the researchers said.
"Ultimately, through the dissection of these intricate pathways, it may be possible to identify drugs that provide all the therapeutic effects of NSAIDs and cox-2-selective inhibitors but lack their adverse side effects," added Matthew Breyer of Vanderbilt University Medical School in an accompanying preview. "Until that time, one can only marvel at the combination of therapeutic and cardioprotective effects of nature's own compound, salicylate, and its chemically modified derivative, aspirin."
The researchers include Helene Francois, Krairerk Athirakul, David Howell, Rajesh Dash, Lan Mao, Howard A. Rockman, and Thomas M. Coffman of Duke University and Durham VA Medical Centers, Durham, NC; Garret A. FitzGerald of the University of Pennsylvania, Philadelphia, PA; and Hyung-Suk Kim and Beverly H. Koller of the University of North Carolina, Chapel Hill, NC. This work was supported by funding from the Medical Research Service of the Veterans Administration and by National Institutes of Health (B.H.K. and T.M.C.).
Francois et al.: "Prostacyclin Protects Against Elevated Blood Pressure And Cardiac Fibrosis" Publishing in Cell Metabolism, Vol. 2, September 2005, pages 201-207. DOI 10.1016/j.cmet.2005.08.005 www.cellmetabolism.org.
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