UC DAVIS (US)—Scientists have discovered a novel mechanism that explains why long-term, high-dosage use of the well-known arthritis pain medication, Vioxx, has led to heart attacks and strokes.

The research in rodents may pave the way for a safer drug for millions of arthritis patients who suffer acute and chronic pain.

Using metabolomic profiling to analyze murine (rodent) plasma, the scientists discovered that Vioxx causes a dramatic increase in a regulatory lipid that could be a major contributor to heart attack and stroke associated with high levels of the drug and other selective COX-2 inhibitors, known as “coxibs.”

“This is a major breakthrough that can lead to a better medication for people suffering from acute pain,” says Bruce Hammock, distinguished professor of entomology at University of California at Davis.

The research is published in the Proceedings of the National Academy of Sciences.

“Our metabolomics study discovered that 20-hydroxyeicosatetrasanoic acid, also known as 20-HETE, contributes to the Vioxx-mediated cardiovascular events,” says Jun-Yan Liu, a bioanalytical chemist at UC Davis and senior author of the paper.

Millions of arthritis patients took Vioxx, a nonsteroidal anti-inflammatory drug (NSAID) and coxib, for acute and chronic pain before Merck & Co. voluntarily withdrew it in September 2004 due to concerns about the increased risk of heart attacks and strokes.

It was on the market for five years.

The chronic administration of high levels of selective COX-2 inhibitors, particularly ro
fecoxib, and valdecoxib, increases the risk for cardiovascular disease, Liu says.

“The recent discovery of  Hammock and co-workers at UC Davis that murine plasma concentrations of 20-HETE may be a significant biomarker which may predict the susceptibility of patients to having an unfavorable cardiovascular event while taking selective COX-2 inhibitors such as rofecoxib is an important and novel finding,” says Garrett J. Gross, professor of pharmacology and toxicology at the Medical College of Wisconsin, Milwaukee, who is not associated with the research.

“This discovery may help to unravel the unexpected occurrence and potential mechanism responsible for sudden cardiac death in a number of patients taking COX-2 inhibitors for inflammatory disorders such as arthritis.

“This a highly significant finding which may lead to a safer use of these drugs in selective patients with disabling inflammatory disorders and may lead to the development of more selective drugs for use in these types of patients.”

“Vioxx and other drugs in this class were looked on as extremely promising in moderation,” says Ralph devere White, professor of urology at UC Davis.

“The fact that the Hammock lab discovered why the drug could lead to heart attacks and strokes and is able to quantify the deleterious facts is extremely exciting. I hope that patients can safely use this drug in the future or block the deleterious effects so it will have all of the benefits and none of the adverse side effects.”

Nationally, some 46 million individuals suffer from arthritis. “And almost one million patients are admitted to hospitals every year because of their arthritis,” Hammock says. “They do need effective and safer drugs to relieve their pain.”

The UC Davis scientists predict their research will open up new strategies to develop safer coxibs. For example, inhibiting the regulation of the enzymes CYP4A and CYP4F could lower the circulation level of 20-HETE and that may reduce the cardiovascular events of coxibs.

Researchers from Peking University contributed to the study.

The work was supported in part by grants from the National Institute of Environmental Health Sciences (NIEHS) Superfund and the National Heart, Lung, and Blood Institute (NHLBI), as well as a Veterans Affairs merit review grant; a major National Basic Research grant from China, an American Heart Association Western Affiliates postdoctoral fellowship award and an Elizabeth Nash Memorial Fellowship from the Cystic Fibrosis Foundation.

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