When the Food and Drug Administration of the United States approved the anti-inflammatory drugs Celebrex and Vioxx earlier this year, it marked the beginning a new era of custom Engineered analgesics that target a specific enzyme. But the results in rats, described in Nature Medicine this month , suggest the authors of the study that new drugs can delay the healing of chronic tissue damage in people. A scientist with Searle, which makes Celebrex, disagree, arguing that the enzyme inhibitors are a safe and effective treatment for chronic inflammatory conditions such as rheumatoid arthritis.
reddish and painful swelling around burns, infected wounds, and chronic irritation are signs that the immune system is trying to limit the damage and stimulate healing. Aspirin and related drugs exert their soothing effects by blocking cyclooxygenase-1 (COX-1) and COX-2, a pair of related enzymes which catalyze the production of inflammatory prostaglandins molecules. COX-1 is thought to help supply prostaglandins that maintain the lining of the stomach and salt balance in the kidney; COX-2 is activated only during injury and infection. To avoid side effects of aspirin, such as irritation and ulcers of the stomach, drug developers in recent years, designed compounds which block the COX-2 alone. But sporadic studies, mostly in animals have suggested that this tactic may delay the healing of ulcers.
Paul Colville-Nash, a researcher of inflammation in St. Bartholomew's Hospital in London, and his colleagues wanted to know whether the COX -2 levels decrease as the inflammation decreases. The team induced inflammation in the lining of the lungs of rats, then gave the animals is two COX-2 inhibitors - NS-398, a compound that only inhibits COX-2, or indomethacin, which blocks both cyclooxygenase - or an injection of saline. Researchers measured the severity of inflammation and the levels of COX-2 and prostaglandins that inflammation subsided.
After a start, well known COX-2 boost, the team found a second peak, even more important as COX-2 levels decreased inflammation. In addition, the team noticed a simultaneous increase in a different set of prostaglandins, called PGD 2 and PGJ 2 , which appear to play a role in suppressing inflammation. When they blocked the activity of COX-2 2 days after the rat lung irritant, inflammation persists; then, inflammation had cleared in control animals. "This suggests that COX-2 also contributes to the determination inflammation of the body," says Colville-Nash.
Experts differ on what the results might mean for the use of COX-2 to treat people. in rheumatoid arthritis, for example, episodes of acute inflammation are broken by periods of remission, during which COX-2 inhibitors could do more harm than good, says Colville-Nash. James Lefkowith, immunologist at Searle in Skokie, Illinois, disagrees. "There is no evidence in humans that COX-2 inhibition has a detrimental role in rheumatoid arthritis," he said. But the study is "clearly interesting," said Lefkowith because it alludes to a possible role in the inflammation of the enigmatic PGD 2 and PGJ 2 .
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