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Chemical Imbalance May Explain Painkiller's Cardiac Danger

Date:
September 19, 2005
Source:
Cell Press
Summary:
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.
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The increased rate of cardiovascular complications in patients takingthe cox-2 inhibitor painkiller rofecoxib (Vioxx) may result from achemical imbalance, according to an animal study in the September CellMetabolism. The findings suggest that low-dose aspirin might preventthe cardiac damage of such drugs and might also lead to the developmentof new anti-inflammatory drugs without the adverse side effects, theresearchers said.

Earlier studies in humans have found that cox-2 inhibitors cause adecline in prostacyclin, a chemical that normally keeps blood vesselsopen and prevents blood clots. That drop occurs without a change inconcentration of thromboxane, a related agent that constricts vesselsand promotes clot formation.

The new study by researchers at Duke University and Durham VAMedical Centers found that, in mice prone to high blood pressure, aninability to respond to prostacyclin led to cardiac complications,including hypertension, enlarged hearts and severe scarring of theheart. Moreover, they showed, unrestrained action of thromboxane in theabsence of prostacyclin accentuated the intensity of cardiac damagecaused by the high blood pressure.

"The current results suggest that such a chemical imbalance inpatients taking selective cox-2 inhibitor painkillers may present acardiovascular hazard--particularly for people already predisposed tohigh blood pressure," said study author Thomas Coffman.

"Hypertension is the most common cardiovascular complicationassociated with cox-2 inhibition, yet not everybody who takes the drugsdevelops high blood pressure," he continued. "The mice appear to havecharacteristics similar to the subset of patients who are prone toexperience this side effect."

Cox-2 inhibitors and other nonsteroidal, anti-inflammatorydrugs (NSAIDs)--including aspirin and ibuprofen--all reduceinflammation and pain by blocking the function of cyclo-oxygenases,also known as cox enzymes. The cox enzymes, cox-1 and cox-2, normallyproduce prostanoids--a family of related chemicals, includingprostaglandins and thromboxanes, with many important functionsthroughout the body.

Prostaglandins produced by both enzymes promote inflammation,pain, and fever, while others made by cox-1 protect the stomach fromthe damaging effects of acid. The cox-1 and cox-2 enzymes,respectively, also produce thromboxane and prostacyclin.

Traditional NSAIDs relieve pain and inflammation bysimultaneously blocking the function of both cox enzymes, Coffmanexplained. In contrast, rofecoxib and other cox-2 inhibitorsselectively limit cox-2, thereby avoiding the gastrointestinalcomplications of over-the-counter NSAIDs.

A 2004 study, however, found an early rise in blood pressureand an increased rate of heart attack and stroke in patients treatedwith rofecoxib for more than 18 months. Last year, the manufacturerwithdrew the drug from the market.

The current findings may lead to new drugs that avoid thepitfalls of both traditional NSAIDs and existing cox-2 inhibitors, theresearchers said.

"Ultimately, through the dissection of these intricatepathways, it may be possible to identify drugs that provide all thetherapeutic effects of NSAIDs and cox-2-selective inhibitors but lacktheir adverse side effects," added Matthew Breyer of VanderbiltUniversity Medical School in an accompanying preview. "Until that time,one can only marvel at the combination of therapeutic andcardioprotective effects of nature's own compound, salicylate, and itschemically modified derivative, aspirin."

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The researchers include Helene Francois, Krairerk Athirakul, DavidHowell, Rajesh Dash, Lan Mao, Howard A. Rockman, and Thomas M. Coffmanof Duke University and Durham VA Medical Centers, Durham, NC; Garret A.FitzGerald of the University of Pennsylvania, Philadelphia, PA; andHyung-Suk Kim and Beverly H. Koller of the University of NorthCarolina, Chapel Hill, NC. This work was supported by funding from theMedical Research Service of the Veterans Administration and by NationalInstitutes of Health (B.H.K. and T.M.C.).

Francois et al.: "Prostacyclin Protects Against Elevated BloodPressure 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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Cell Press. "Chemical Imbalance May Explain Painkiller's Cardiac Danger." ScienceDaily. ScienceDaily, 19 September 2005. <www.sciencedaily.com/releases/2005/09/050918132504.htm>.
Cell Press. (2005, September 19). Chemical Imbalance May Explain Painkiller's Cardiac Danger. ScienceDaily. Retrieved July 1, 2015 from www.sciencedaily.com/releases/2005/09/050918132504.htm
Cell Press. "Chemical Imbalance May Explain Painkiller's Cardiac Danger." ScienceDaily. www.sciencedaily.com/releases/2005/09/050918132504.htm (accessed July 1, 2015).

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