New test could bring COX-2 inhibitors back into arthritis arena
A class of drug for treating arthritis that has been largely shelved because of fears about side effects may be given a new lease of life, after the discovery of a way to identify who should avoid using it.
COX-2 inhibitors – a type of non-steroidal anti-inflammatory drug (NSAID) – can increase the risk of heart attack in some people.
“Although the majority of arthritis sufferers could safely use COX-2 inhibitors, the fear of heart attacks has left some patients confused and worried about their medication and GPs nervous about prescribing them,” explains Prof Jane Mitchell, one of the study leaders. “This problem is made worse because we now know that most NSAIDs, not just COX-2 selective drugs, carry a similar risk of heart attacks in some patients.
“If we could identify which people have an increased risk, these patients could be offered more appropriate treatments, and we can start to look at ways of reducing or averting the risk entirely.”
NSAIDs prevent the production of prostaglandins, chemical messengers in tissues and joints that trigger pain and inflammation. Prostaglandins are produced by two enzymes (COX-1 and COX-2) that are found at sites of inflammation as well as in other sites around the body.
The research team looked at if removing COX-2 causes changes in gene activity in mice. Taking out COX-2 did bring changes in three genes in the kidney that predicted a rise in levels of a molecule linked to cardiovascular disease, called ADMA. The team then found that taking NSAIDs led to a rise in ADMA levels in mice and in 16 human volunteers.
”ADMA is an independent risk factor for cardiovascular disease,” explains Dr James Leiper, also involved in the study. “In people increases of ADMA similar to those we found are linked with significant increases in cardiovascular disease and death. Our discovery that COX-2 inhibitors raise ADMA levels provides a plausible mechanism for the increased cardiovascular risk associated with these drugs and provides insights into how this risk might be mitigated’.
So higher ADMA levels might work as an indicator of who is at greater risk of heart attack.
“If we are right, ADMA could be used as a biomarker in a simple blood test to identify who may be at risk, and regular screening would allow GPs to monitor patients’ ADMA levels to ensure these remain within safe limits whilst taking the drug,” says Prof Mitchell. “In some settings, giving more L-arginine can offset the damaging effects of ADMA, so it’s possible that supplements containing L-arginine could provide an antidote to the heart attack risk of NSAIDs. This would be simple to test as L-arginine is already widely available in health food shops as a sports and cardiovascular health supplement. More work is needed for which we would need major funding, but I believe it’s worth looking at whether these types of supplements could protect those at risk.”
Image credit: Markus Unger
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