October 15, 2004

Vioxx flap causing some pain to researchers

Featured Image

Dean John Chapman acknowledged the standing ovation he received upon his introduction at graduation in May, 2000. That year’s VUSM class was the last to receive its degrees from Chapman.
photo by Dana Johnson

Vioxx flap causing some pain to researchers

Arthritis patients aren't the only ones concerned about the withdrawal of Vioxx from pharmacy shelves: Cancer scientists worry the decision may hinder research aimed at preventing colorectal cancer.

Merck & Co. pulled its blockbuster anti-inflammatory medication from the market on Sept. 30 because patients in a long-term study who took the drug had an increased risk of heart attack and stroke. The study, conducted in patients at risk of developing recurrent and pre-cancerous colon polyps, was also stopped.

“The Vioxx trial would have provided important mechanistic information on polyp prevention,” says Larry Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology. “There was no choice but to stop it, but potentially valuable information may have been lost.”

A related medication, Celebrex, also is being tested in patients at risk for colorectal cancer. Last week in an on-line editorial in the New England Journal of Medicine, former Vanderbilt faculty member Garret A. FitzGerald, M.D., now chair of Pharmacology at the University of Pennsylvania, cited studies suggesting that all COX-2 inhibitors may increase “cardiovascular risk.”

“Everybody is scrambling to find out,” responds Raymond N. DuBois, M.D., Ph.D., Hortense B. Ingram Professor of Molecular Oncology at Vanderbilt, who is involved in the Celebrex trial. “So far nothing's really reared its head.”

Scientists at the National Cancer Institute have reviewed the data on several thousand patients in the Celebrex study, “and they still do not see any cardiovascular problems with (it),” DuBois says.

Both Vioxx and Celebrex block the pro-inflammatory cyclooxygenase-2 (COX-2) enzyme. But their chemical structures are not identical, and they are metabolized — or broken down by the body — in different ways.

That could explain the difference in side effects, says DuBois, who is internationally known for his research linking COX-2 to colon cancer. Vioxx is a more specific inhibitor of the COX-2 enzyme, and more potent than Celebrex in relieving the pain and inflammation of arthritis.

Vioxx also has been associated with fluid retention and increased blood pressure, presumably by acting on the kidneys, and that in turn could raise the risk for serious heart problems.

Research by Marie R. Griffin, M.D., Wayne A. Ray, Ph.D., and their colleagues at Vanderbilt has contributed to mounting evidence that long-term use of Vioxx in high doses significantly increases the risk of heart attack and heart-related death.

The Vioxx experience also is leading to calls for lengthier testing of new drugs to detect long-term side effects. In the now-halted polyp prevention study, for example, increased rates of heart attacks and strokes were observed only among patients who had been taking Vioxx for at least 18 months.

“Something needs to be done to make sure this doesn't happen again,” DuBois says. “Careful post-marketing studies are extremely important.” q

, and may give us the information we need.”

In the future, it may be possible to screen patients — based on their genetic makeup — for their risk of developing serious drug side effects. “The technology is really moving forward,” DuBois says, “but we don't know all of the key predictive factors right now.”