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Study claims painkillers raise heart attack risk
April 16, 2006 - WASHINGTON: Painkillers called COX-2 inhibitors may increase the risk of heart attacks by raising blood pressure and making the blood more likely to clot, researchers said on Thursday.
They do so by the same mechanisms that they use to reduce pain and inflammation, said University of Pennsylvania School of Medicine researcher Dr Garret Fitzgerald, who led the study. But the finding shows that a new generation of anti-inflammatory drugs could avoid the problem, Fitzgerald reported in the Journal of Clinical Investigation.
The COX-2 inhibitors were originally designed to be a safer long-term treatment than aspirin and other analgesics for arthritis and similar pain. They fell under a cloud when it was found they could raise the risk of heart problems.
Merck and Co pulled its drug Vioxx from the market in September 2004 after a study showed that it doubled the risk of heart attacks and strokes in people who took Vioxx for at least 18 months. A jury on Tuesday awarded $9 million in punitive damages to a New Jersey man who had blamed Vioxx for his heart attack and more than 7,000 other people have sued.
Pfizer Inc suspended sales of its COX-2 inhibitor Bextra and now includes a strong “black box” warning for its COX-2 Celebrex, the only such drug now on the market.
Fitzgerald has for years had a theory that COX-2 drugs depress a protective fat called prostacyclin, while leaving unaltered a harmful one called thromboxane.
He and collaborator Colin Funk, now at Queen’s University, Ontario, genetically manipulated mice and tested them.
They found that disrupting the COX-2 gene, interfering with the enzyme through different genetic routes, and genetically disrupting prostacyclin’s effects all made the mice prone to blood clots and raised blood pressure.
“One does not need additional explanations to understand what we have seen in clinical trials,” Funk said in a statement.
“COX-2 inhibitors confer a small, but absolute cardiovascular risk using the same mechanism by which they relieve pain and inflammation,” he said. Aspirin, long known to reduce the risk of heart attacks and stroke, interfered with the process. It might be possible to take aspirin alongside a COX-2 but that would make no sense because the whole point of COX-2 inhibitors is to avoid the serious risk of stomach bleeding caused by aspirin, Fitzgerald said.
“I think aspirin would do exactly what you might expect - attenuate, but not abolish the risk,” Fitzgerald said in an e-mail. Fitzgerald and Funk tested another enzyme, called microsomal prostaglandin E synthase or mPGES-1.
COX, or cyclooxygenase, is an enzyme that comes in two forms - COX-1 and COX-2. Aspirin and other analgesics such as ibuprofen, known as non-steroidal anti-inflammatory drugs or NSAIDS, affect both COX-1 and COX-2 but have well-known side effects including sometimes fatal internal bleeding.
But some research has shown that interfering with mPGES-1 works as well as NSAIDS in reducing pain and inflammation and some big drug companies are working on developing drugs that do this.
Fitzgerald and his colleagues showed that deleting mPGES-1 did not cause clotting or raise blood pressure in the mice.
“Selective inhibitors of mPGES-1 may retain much of the benefit of drugs like Vioxx and Celebrex, while diminishing the risk of heart attack and stroke by having precisely the opposite effect on prostacyclin,” Fitzgerald said. reuters.
Scientists Suggest Alternative to Cox-2 Drugs
THURSDAY, April 13 (HealthDay News) -- 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."
Researchers resolve how COX inhibitors cause heart hazards, and offer alternative treatment strategy
13-Apr-2006 - Inhibitors of cyclooxygenase-2 (COX-2) were developed to relieve inflammatory pain as effectively as nonsteroidal anti-inflammatory drugs (NSAIDS), but without one of their major side effects, gastrointestinal bleeding. However, an unexpected adverse cardiovascular effect – a higher incidence of myocardial infarction – was subsequently detected, causing the highly publicized withdrawal of COX-2 inhibitors from the market in late 2004. A number of large, randomized, controlled trials designed to test the efficacy of different COX-2 inhibitors for a variety of indications have confirmed the cardiovascular toxicity, suggesting that this is an effect of all drugs in this class.
However, just how this class of drug causes this heart hazard has remained controversial. Now, in a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, Garret FitzGerald and colleagues from the University of Pennsylvania School of Medicine report how COX-2 inhibitors increase the incidence of myocardial infarction and stroke. In addition, they propose a new therapeutic approach that retains the beneficial anti-inflammatory effects of NSAIDS and COX-2 inhibitors, while avoiding their adverse cardiovascular consequences.
COX-2 inhibitors are believed to exert both their beneficial and their adverse effects by suppression of COX-2–derived prostacyclin (PGI2) and prostaglandin E2 (PGE2). These substances help prevent platelet clumping in blood vessels and vessel relaxation and/or constriction, respectively. Therefore, the challenge has been to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. FitzGerald and colleagues now show that selective inhibition, knockout, or mutation of COX-2, or deletion of the receptor for COX-2–derived PGI2, accelerates the formation of blood clots and elevates blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin.
PGE2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). In the effort to propose an alternative therapeutic option to COX-2 inhibitors, FitzGerald et al. showed that deletion of mPGES-1 suppressed PGE2 expression, augmented PGI2 expression, but most importantly, affected neither blood clotting nor blood pressure. These results suggest that inhibitors of mPGES-1 may offer anti-inflammatory efficacy by depressing PGE2, while avoiding the adverse cardiovascular consequences associated with COX-2–mediated PGI2 suppression.
Contact: Brooke Grindlinger
press_releases@the-jci.org
212-342-9006
Journal of Clinical Investigation
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TITLE: Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function
AUTHOR CONTACT:
Garret A. FitzGerald
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Phone: (215) 898-1184; Fax: (215) 573-9135; E-mail: garret@spirit.gcrc.upenn.edu
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