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In experiments with mice, the researchers have found that when cox-2 inhibitors like Vioxx block the cox-2 enzyme, it does reduce pain. But it also increases the production of a protein called tissue factor (TF), which can in help initiate unwanted clotting.
Since heart attacks and strokes are triggered by blood clots, it is possible that the overproduction of TF is, in part, responsible for cox-2 inhibitors' dangerous side effects, the University of Connecticut-led team reported in the Aug. 27 online edition of The Journal of Experimental Medicine.
"We provide a mechanism to understand the side effects caused by cox-2 inhibitors," said lead researcher Mallika Ghosh, a post doctorate fellow at the university's Center for Vascular Biology in the department of cell biology at the University of Connecticut Health Center.
Previously, the increased cardiovascular risk associated with cox-2 inhibitors was linked to prostacyclin, another protein important for preventing clotting. It's been shown that cox-2 inhibitors do lower prostacyclin levels.
However, Ghosh's team now proposes an alternate explanation for the added risk.
"We found increased levels of TF in the blood, heart and lungs in mice treated with a cox-2 inhibitor," Ghosh said. "With this mechanism, we can understand why cox-2 inhibitors contribute to the development of cardiovascular events," she said.
The researchers found they could reduce the high levels of TF in cox-2-treated mice by using TF-reducing agents. It may be possible to make cox-2 inhibitors safer by giving TF-blocking drugs along with these pain killers, the researchers proposed.
"If we can extend our work in humans and reduce TF levels, then we can reduce the risk of these side effects," Ghosh said. "In addition, measuring levels of TF could help identify people at high risk for cardiovascular side effects from cox-2 inhibitors," she said.
Ghosh believes the TF-linked risk applies to all cox-2 inhibitors, not just Vioxx or Bextra, which was also taken off the market in 2005. A third cox-2, Celebrex, remains on pharmacy shelves.
"Patients need to be careful when they take these medications, especially if they have a history of cardiac problems," she said.
This same risk may also apply to traditional pain medications called non-steroidal anti-inflammatory drugs (NSAIDs), such as Aleve and ibuprofen (brand named Advil, Motrin), Ghosh said. "No one has looked at what happens if you take high doses of NSAIDs," she said.
One expert believes that more study is needed, however, even when it comes to the cox-2s.
"We have always assumed that the problem with cox-2 inhibitors was linked to prostacyclin," said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic and a noted expert on the drugs. "These [data] are suggesting that there may be more to the cardiovascular risk of cox-2 inhibitors, and it may relate to TF," he said.
However, blocking TF to mediate that risk is still speculative, Nissen said. "The problem is that there are no approved TF-blockers, so it's not even feasible to consider this," he said.
In addition, it still isn't definite that TF is an important mechanism in humans linking cox-2 inhibitors with cardiovascular risk, Nissen said.
"This study is very speculative, very preliminary," he said. "The finding needs to be confirmed in clinical trials."
SOURCES: Mallika Ghosh, Ph.D., post doctorate fellow, Center for Vascular Biology, department of cell biology, University of Connecticut Health Center, Farmington; Steven E. Nissen, M.D., chairman, department of cardiovascular medicine, Cleveland Clinic, Ohio; Aug. 27, 2007, The Journal of Experimental Medicine online
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