As reported by the Boston Globe, March 25, 2005.

A Balanced Look at COX-2 Drugs

By Timothy Hla

The recent voluntary withdrawal of the anti-inflammatory drug Vioxx by Merck, the halting of clinical trials in which Celebrex was being tested for colon cancer and Alzheimer's disease treatments, and the news that Bextra usage is associated with higher risk of cardiovascular complications have caused significant concern over the entire class of ''COX-2 inhibitors," a widely popular and profitable class of new anti-inflammatory drugs.

The outcome of this crisis has significant implications not only for millions of patients, physicians, the insurance industry, and drug companies but also for public trust of the regulatory agencies, the biomedical research enterprise, and the healthcare system. Because COX-2 inhibitors have tremendous potential for the prevention and/or treatment of cancer and Alzheimer's disease, it is extremely important that thoughtful consideration of risks vs. benefits be given to current as well as proposed future uses of these drugs.

As one of the scientists involved in the discovery of the human COX-2 gene, I believe that the potential role of COX-2 is significant enough that we must not to let the commotion over adverse effects force us to ignore an entire class of drugs with tremendous potential for controlling human disease.

COX-2 was discovered in the early 1990s as a gene expressed in inflamed tissues when cells were activated and proliferating. This was different from the COX-1 gene, which is present in all cells. Both genes are needed for the secretion of hormone-like substances called prostaglandins that mediate inflammation, pain, fever, and cell proliferation. Because COX-1 prevents stomach ulcers, drug companies rushed to develop COX-2 inhibitors and succeeded in the late 1990s when Celebrex and Vioxx were approved. The promise was that COX-2 inhibitors would be better than the older anti-inflammatory drugs (aspirin, Ibuprofen, Naproxen) because they would be safer for the stomach. They were certainly more expensive than their older cousins.

Here is where theory diverged from scientific facts. COX-2 inhibitors did not turn out to be as free of side effects as originally thought. Separate studies showed that normal, un-inflamed blood vessels made COX-2, suggesting that taking COX-2 inhibitor drugs might lead to abnormal blood vessel function. These findings fueled an intense debate in the research community but had little effect on the marketing of the COX-2 inhibitors. Indeed, the drugs were promoted aggressively by direct consumer advertising. Physicians were also persuaded about the presumed benefits of COX-2 inhibitors. Successful marketing efforts made COX-2 inhibitors the darlings of Wall Street as sales climbed into billions of dollars in the United States alone. Very few skeptics were questioning about side effects or whether the cost of these new drugs to the healthcare system was justified by their purported benefit.

Ultimately, in 2004, findings from multiple studies that use of COX-2 inhibitors poses a small but significant risk of heart attacks and strokes led to the withdrawal of Vioxx, a barrage of media coverage, and federal and congressional hearings. Wall Street responded promptly as well; the stock value of Vioxx's manufacturer, Merck, plunged on the company's announcement of withdrawal of the drug.

It is important to point out that we do not really know why use of COX-2 inhibitors is associated with elevated risk of heart attacks and strokes in some patients. Particular genetic traits may make some individuals more susceptible to side effects of COX-2 inhibitors. These factors must be defined through future research.

COX-2 inhibitors appear extremely promising to prevent and/or treat cancer and Alzheimer's disease. They control inflammation in the brain and inhibit new blood vessel growth (angiogenesis) in cancers. Therefore, COX-2 inhibitors may provide a new weapon in the control of those diseases. It is incumbent on biomedical researchers to seek these answers.

Clearly, this case illustrates that when commercial decisions get ahead of science and evidence-based medicine, undesirable outcomes can occur. But to ignore the entire class of drugs because of the ''COX-2 hoopla" would not be wise. New knowledge on how COX-2 contributes to disease as well as normal blood vessel function is urgently needed. Scientific and medical answers must be sought aggressively, and that information should be the basis for future regulatory and marketing decisions much more so than the present. Pharmaceutical companies must join forces with the academic research and medical communities to honestly and critically look at all the benefits and side effects in the effort to develop better ways of controlling disease. The public deserves better.

Timothy Hla is a professor of cell biology and director of the Center for Vascular Biology at the University of Connecticut Health Center.