Peking University, Sept. 24, 2010: A joint project by researchers from University of California, Davis (UCD) and Peking University (PKU) has discovered the mechanism of how the long-term and high-dose use of the arthritis painkiller "Vioxx" causes heart attacks and strokes. The research is expected to free the thousands of people suffering from arthritis in acute or chronic pain from the potential danger of that medicine.
Through the metabolic analysis of murine plasma, scientists found that Vioxx would cause a noticeable increase of regulatory lipids, which are related to heart attacks, resulting in Celebrex-related strokes.
"This discovery is going to be advantageous to patients with acute pain in the safe use of the medicine,” said one of the leading researchers of the project, Bruce Hammock, entomologist, chemist, and professor of entomology from UCD. The other members are researchers from the laboratories of Nipavan Chiamvimonvat, cell biologist of cardiology from UCD, and of Zhu Yi, physiologist from PKU. The research paper, "Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events," was published in the Sept. 13 issue of the Proceedings of the National Academy of Sciences (PNAS) of the Unitied States.
"Our metabolic study found that 20-HETE is related to cardiovascular events mediated by Vioxx,” said Liu Junyan, senior author of the paper and bio-analytical chemist from UCD.
In 2004, the Merck & Co., Inc. decided to call back the anti-arthritis medicine Vioxx throughout the world, because it could increase the risk of heart diseases and strokes.
"Taking in high dose selective COX-2 inhibitors, especially Rofecoxib and Valdecoxib for a long period, will increase the risk of heart diseases,” said Liu.
Garrett J. Gross, cardiologist and professor of Department of Pharmacology and Toxicology, Medical College of Wisconsin, considers the discovery very significant.
"The study found that the 20-HETE concentration in plasma could act as a significant biomarker which could predict the sensitivity of patients of cardiovascular disease to selective COX-2 inhibitors such as Rofecoxib,” said Gross. “This is an important discovery, for it reveals the potential mechanism which causes the sudden cardiac death of patients of inflammatory disease such as arthritis, who take selective COX-2 inhibitors. It will also help patients of inflammatory disease to take drugs more safely, and help develop new alternative medicine.
Ralph deVere White, professor of Urology from UCD School of Medicine and Medical Science, also finds this discovery extremely exciting.
When asked about his evaluation of the discovery, Richard Roman, professor and chairman of Department of Pharmacology and Toxicology, University of Mississippi Medical Center, said that “the painkiller Vioxx was recalled because its users were more susceptible to heart attacks and strokes. The mechanism of its side effects was unclear in the past, and the research by Hammock and his fellow team is an important breakthrough because it proves Rofecoxib’s capability of increasing the concentration of 20-HETE. 20-HETE is a factor of the cerebral vascular shrinkage, and it can lead to the platelet aggregation and blood clots as well.”
Roman went on that their team “further proved that the compounds can inhibit the COX2 enzyme which has an significant role in the metabolism and inactivation of 20-HETE. This means that other medicine of similar kinds may have equivalent risk of causing cardiovascular disease as Vioxx. Besides, the risk of having cardiovascular disease may be predictable from measuring the 20-HETE concentration in plasma.”
"More examinations and studies in patients taking COX2 inhibitors are needed to be conducted. Currently we are only carrying out researches in rats, and the effects of the COX2 enzyme on the metabolism of 20-HETE may be different in human bodies and in rats,” commented Roman.
According to Hammock, there are about 4.6 million arthritis patients in the US, and a million of them are receiving treatment in hospital. They need more effective and safer medicine to ease their pains.
Scientists from UCD expected their research to accelerate the development of safer drugs of the kind of Celebrex. For example, inhibiting the CYP4A and CYP4F enzyme can lower the circulating level of 20-HETE, so that the risk of heart attacks caused by such drugs can be reduced.
Translated by: PAN Huanming
Edited by: Jacques
Source: PKU News (Chinese)
