Painkillers suspected of causing fatal heart disease may act by starting the process of hardening the arteries, researchers proposed.

The drugs, known as COX-2 inhibitors, include Merck and Co.'s Vioxx, which earned the company $2.55 billion a year but was pulled off the market on Sept. 30 after a study showed it doubled the risk of heart attack and stroke.

Tests on mice suggest COX-2 inhibitors might be especially dangerous to younger women, who are normally protected by biology from heart disease.

The research, published in Friday's issue of the journal Science, also supports the theory that there could be a "class effect," meaning that all brands of COX-2 inhibitors could raise the risk of heart disease.

"I believe the evidence is very strong that we have a class effect to deal with here," said Dr. Garret FitzGerald, a cardiologist and pharmacologist at the University of Pennsylvania who led the study.

His team found that a fatty acid made by the cyclooxygenase-2, or COX-2, enzyme protects female mice from hardening of the arteries. Shutting down COX-2 long term may actually kick-start the process, known as atherosclerosis, FitzGerald said in a telephone interview.

"This raises the specter that if we treat long enough, you are going to have some problems with these people," he said.

COX-2 inhibitors were invented as a safer alternative to aspirin and other non-steroidal anti-inflammatory drugs, or NSAIDS, such as ibuprofen, which can cause stomach bleeding.

Some NSAIDS, notably aspirin, also make blood less likely to clot, and can help protect against heart disease.

They work by interfering with two enzymes in the body called COX-1 and COX-2. The COX-2 inhibitors selectively affect the enzyme associated with pain and inflammation while leaving alone COX-1, which is thought to protect the stomach.

AS EFFECTIVE AS ASPIRIN

The COX-2s, which also include Pfizer's Celebrex, are as effective as aspirin at easing pain and long-term may be safer on the stomach.

Other makers of COX-2s are hoping to prove their drugs are different enough from Vioxx to escape the heart disease risk.

FitzGerald, who has done much research on the drugs, said last week that another COX-2 inhibitor, Pfizer's Bextra, more than doubled the number of heart attacks or strokes among patients already at high risk of heart disease.

Now FitzGerald says the risks posed by COX-2s may be greatest among young women. "How do we retain the usefulness of these drugs, which work and which are particularly valuable to people who suffer gastrointestinal effects with NSAIDS?" he asked.

FitzGerald's study also sheds light on why younger women have less heart disease than those past menopause. Estrogen triggers COX-2 activity, which leads to protection from atherosclerosis.

In mice, estrogen generates a fatty acid from COX-2 called PGI2, which limits activation of blood platelets that can cause clots and may damage artery walls. PGI2 also reduces oxidative stress that damages the insides of arteries, he found.

Reference Source 89
November 19, 2004

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