Scientists Suggest Alternative to Cox-2 Drugs

[GUNNER]

More than a year after two cox-2 painkillers, Vioxx and Bextra, were pulled from store shelves, U.S. scientists say they've figured out how these drugs triggered heart problems in some users.

According to the researchers, the findings also point the way toward a new class of drugs that might offer the benefits of cox-2s, without the dangers.

"The development of a drug that can provide us with the proven gastrointestinal risk reduction of a cox-2 inhibitor, and avoid the adverse cardiovascular consequences that we've seen in existing cox-2 drugs, would be a very important contribution to our armamentarium," said Dr. Mark Fendrick, an expert on cox-2 analgesics and a professor of internal medicine at the University of Michigan.

He was not involved in the study, which was led by Dr. Garret FitzGerald, a professor of cardiovascular medicine and pharmacology and chairman of the department of pharmacology at the University of Pennsylvania School of Medicine. His team published its findings in the April 13 online edition of the Journal of Clinical Investigation.

Cox-2 inhibitors such as Vioxx, Bextra and Celebrex (which remains available to U.S. consumers) sold in the billions, mainly because their long-term use for ailments such as arthritis does not boost risks for stomach ulcers, unlike other pain relievers.

The drugs fall into the general class of pain relievers known as non-steroidal anti-inflammatory drugs (NSAIDs), which also include medications such as aspirin, ibuprofen and naproxen (Aleve). Cox-2s work by suppressing a key enzyme called cyclooxegenase-2 (cox-2), which in turn dampens the production of two cox-2-derived compounds, prostacyclin (PGI2) and prostaglandin 2 (PGE2).

Trouble is, both PGI2 and PGE2 are thought to help maintain cardiovascular health by preventing platelets in blood vessels from clumping together. So, researchers speculated that cox-2 suppression might keep PGI2 and/or PGE2 from doing their job, boosting risks for stroke or heart attack.

Earlier this year, FitzGerald's team discovered that a patient's cardiovascular reaction to cox-2 inhibitors may rely, in part, on his or her genetics. In a study published in the January issue of Gastroenterology, the team found "substantial variability" in how well Vioxx or Celebrex inhibited the cox-2 enzyme, suggesting that certain patients might be at higher risk than others.

In the new JCI study, the researchers tried to discern which of the two cox-2-derived compounds, PGI2 or PGE2, was most important when it came to heart risks associated with cox-2 suppression.

To do so, they tracked the cardiovascular health of mice genetically engineered to either lack cox-2 expression, or cell receptors responsive to PGI2 or PGE2.

According to FitzGerald, his team has pinpointed "depression of cox-2-dependent PGI2" as the biochemical culprit boosting heart risks. Mice with suppressed PGI2 activity showed evidence of increased blood pressure and clotting risk similar to that seen in a minority of human cox-2 users, he said.

The team also suppressed the other compound, PGE2, by inhibiting an enzyme called microsomal PGE synthase-1 (mPGES-1). This enzyme works as a partner with cox-2 in the biosynthesis of PGE2.

The team found that inhibiting mPGES-1 suppressed PGE2 (just as cox-2 medications do) while increasing PGI2 to heart-healthy levels. The result? No measurable effect on either blood pressure or clotting in the treated mice.

According to FitzGerald, this is "the first evidence that mPGES-1 inhibitors might minimize the risk of these cardiovascular problems, by affecting the PGI2 'story' in precisely the opposite way."

In fact, he said, "drugs targeting these enzymes are under accelerated development. Basically, they increase PGI2 in mice and do not appear to predispose them to hypertension and clotting the way that drugs that inhibit cox-2 manage to do."

Fendrick agreed that the new approach appears promising. "Basically, we want PGE2 to be depressed in the anti-inflammatory [pain] cascade, but at the same time, in the cardiovascular system we don't want to suppress cox-2," he said.

But he also noted that research into the safety and efficacy of "mPGES-1 inhibitor" drugs is in its infancy, and it will be many years before consumers see these medications available in pharmacies -- if ever.

In the meantime, he said, combination therapies exist that can provide individuals with stomach- and heart-safe pain relief.

"For pain, what I tend to recommend is an older, traditional NSAID -- the FDA advisory panel would recommend naproxen [Aleve]," he said. And to help reduce gastrointestinal risk, Fendrick prescribes a proton pump inhibitor drug such as Nexium or Prilosec. According to the Michigan expert, this combination "will give similar amounts of pain relief with an anti-inflammatory effect, a roughly similar GI risk profile to the cox-2s, and a lessened concern of cardiovascular adverse events."