Mouse study may explain Vioxx side-effects

Cell biologists in the US may have discovered why the anti-inflammatory drug Vioxx and other Cox-2 inhibitors can cause life-threatening heart problems in some patients. The answer, they say based on studies in mice, lies in how these drugs change levels of tissue factor (TF), a protein that initiates blood clotting. 

Over 80 million patients suffering from arthritis and other painful conditions were prescribed Vioxx, the trade name for the drug rofecoxib, following approval by the US Food and Drug Administration in 1999. But Merck dramatically withdrew the drug in 2004 after studies showed it increased the risk of heart attacks or strokes in some people. 

"Although COX-2 inhibitors have a bad reputation, they are certainly a useful set of medications. I think that in the future we will see them return, although perhaps in a different or improved form."

Sudhansu Dey

Since then, several theories to explain the cardiovascular side-effects have been put forward, but none have been firmly proven. Now, Timothy Hla and colleagues at the University of Connecticut have identified a biological mechanism in mice that they believe is behind the dangerous side-effects observed in humans.

 ’Put simply, the Cox-2 inhibitors suppress the activity of a receptor called PPAR δ, which in turn causes increased TF levels,’ Sudhansu Dey, who worked on the project, told Chemistry World. ’Since TF is the primary initiator of blood clotting, this can certainly promote cardiovascular problems.’ 

The team believe that, in theory, drugs that stimulate PPAR δ could be used alongside Cox-2 inhibitors to prevent the cardiovascular side-effects. If this were to prove effective, then we may see Cox-2 medications return to pharmacists’ shelves in the future. 

’We are gearing up to do some human studies now,’ said Dey. ’Although Cox-2 inhibitors have a bad reputation, they are certainly a useful set of medications. I think that in the future we will see them return, although perhaps in a different or improved form.’ 

Recent studies have also shown that dangerous side-effects only occur in a small proportion of patients - mainly those with a history of cardiovascular disease. The work may help to identify those at risk in the future, Dey added. 

Lewis Brindley