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Investigating Vioxx Toxicity
Air oxidation of arthritis drug's anion forms a potentially toxic product

A. MAUREEN ROUHI

Oxidation to a maleic anhydride derivative may be a factor in the long-term toxicity of rofecoxib (Vioxx), a new report suggests. This previously unknown reactivity is not shared by other cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex), valdecoxib (Bextra), and lumiracoxib (Prexige). The hypothesis, if proven true, runs counter to the assumption that other COX-2 inhibitors pose the same risk to humans as Vioxx.

Vioxx was withdrawn from the market last September by its manufacturer, Merck, after a clinical trial indicated that it poses an increased risk of cardiovascular events.

Vioxx is a weak acid, and the anion formed when it releases its acidic proton is highly reactive toward atmospheric oxygen, according to laboratory studies by Harvard University chemists Leleti Rajender Reddy and E. J. Corey. The products are principally a maleic anhydride and lesser amounts of a -hydroxybutenolide [Tetrahedron Lett., published online Dec. 25, 2004, http://dx.doi.org/10.1016/j.tetlet.2004.12.055].

According to the authors, the maleic anhydride has not been reported as a Vioxx metabolite. They suggest that some of it may survive long enough in vivo to react with the nucleophilic groups of biomolecules and tissues. “The consequences of this may be a low-level chronic toxicity that is cumulative and possibly dangerous over periods of many months. It is perhaps not irrelevant that the cardiotoxicity of Vioxx was not apparent from short-term (one year or less) studies,” they write.

Merck’s withdrawal of Vioxx has cast doubts on other COX-2 inhibitors in the market or in development. However, as the authors point out, the formation of an oxygen-reactive anion is unique to Vioxx. The difference in the structures of Vioxx and other COX-2 inhibitors has been “overlooked in the medical and general literature,” they write.

In a footnote, the authors say that they have disclosed their findings to the Food & Drug Administration. Corey is a scientific adviser to Pfizer, the maker of Celebrex and Bextra.

Doctor Testifies Against Vioxx in Federal Trial

November 30, 2005 - HOUSTON — Merck & Co.'s (MRK) former blockbuster drug Vioxx helped cause a blood clot that triggered the fatal heart attack of a Florida man, a pathologist testified on Wednesday at the first federal trial concerning the pain killer's safety.

"It is my opinion that it contributed to his death," Dr. Colin M. Bloor told jurors in the second day of the trial that centers on whether Vioxx caused Richard "Dicky" Irvin's fatal heart attack in May 2001. The 53-year old manager of a seafood distributor had been taking Vioxx for about a month to alleviate back pain when his colleagues found him dead at his desk.

A lawyer for Merck said Bloor, professor emeritus for pathology at the University of California, San Diego, was not an expert on Vioxx, however, and hadn't bothered to read Food and Drug Administration reports on the painkiller or what Merck's experts have written about the drug.

The case pits Irvin's widow, Evelyn Irvin Plunkett, against Merck, which has scored a loss in Texas and a win in its home turf of New Jersey in the first two state-level Vioxx cases. Merck faces about 7,000 state and federal lawsuits and analysts have estimated its liability could reach $50 billion.

Bloor testified that a blood clot, unattached to artery walls, caused Irvin's heart attack. Blood clots are clumps in vessels or the heart that form from the coagulation of blood.

Irvin's autopsy showed moderate to severe clogged arteries, and a blood clot in a major coronary artery caused an irregular heartbeat and death.

Merck has claimed the clot formed when plaque, or a fatty deposit in the wall of an artery, ruptured with no help from Vioxx. Plunkett alleges that Vioxx — which inhibits an enzyme that promotes inflammation and thins the blood — led to the clot formation.

Whitehouse Station, N.J.-based Merck withdrew Vioxx from the market in September 2004 after a long-term study showed the drug doubled risk of heart attack or stroke if taken for 18 months or longer. By then, more than 20 million Americans had used Vioxx.

Bloor said records he had seen of Irvin's health didn't suggest he was at high risk for the type of clot that led to his heart attack, so he sought other explanations for the cause. He said that because clinical tests have shown that Vioxx may cause blood clots to form, it was a factor in the heart attack.

But under cross examination, Merck attorney Phil Beck pointed out inconsistencies between what Bloor said on the stand and a report that he wrote in 2005 for the plaintiff when he was retained as an expert witness. In that report, Bloor failed to mention Vioxx as a cause of the heart attack. Beck also noted that only two paragraphs of the 18-page report address specifics of Irvin's case.

Bloor told Beck that when he wrote the report he had only seen one set of the slides of Irvin's arteries. He said he has since seen three other sets which led him to conclude Vioxx was a factor in the heart attack.

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•Merck Posts Higher Profit, Lower Sales
•Vioxx Judge Nixes Key Merck Witness Testimony
•Heart Doc: Vioxx Likely Caused Heart Attack

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