Evaluation of the effects of COX-2 inhibitors on the healing of skin wounds

摘要

Cyclooxygenase enzymes are the first in a cascade of enzymes that convert arachidonic acid into prostaglandins (PG) and thromboxane (Tx), which are involved in inflammation, cancer and embryonic development. COX isoforms comprise both constitutive (COX-1) and inducible (COX-2) enzymes. While PG and Tx derived from COX-1 play many physiologic roles, those synthesized by COX-2 are associated with sustained inflammatory conditions. In addition, COX-2 is expressed at high levels in many tumor types andhas been shown to have pro-angiogenic properties. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, indomethacin, naproxen and diclofenac, inhibit both COX-1 and COX-2 non-selectively and are widely used for the treatment of various inflammatory and non-inflammatory conditions, such as arthritis, pain, and cardiovascular diseases. However, NSAIDs can cause serious side effects, mostly due to the inhibition of COX-1. These side effects include gastroduodenal ulceration in about 25 percentof users, which can often be associated with bleeding and perforation, inhibition of platelet aggregation leading to adverse bleeding events, and in some patients, a decrease in renal blood flow and glomerular filtration rate. The hypothesis that these side effects result from the inhibition of COX-1 prompted the development of compounds having a lower IC50 for COX-2 than for COX-1 in an in vitro enzyme assay in an attempt to minimize these side effects. COX-2 inhibitors are prescribed for the treatmentof inflammation and pain associated with rheumatoid arthritis and osteoarthritis, as well as for painful conditions, such as dysmenorrhea. COX-2 inhibitors offer safety advantages, as evidenced by significant reductions in gastrointestinal toxicity andinhibition of platelet function (i.e., bleeding), thereby validating the COX hypotheses that many side effects of NSAIDs widely used in pain were mediated by PGs produced by COX-1. Consequently, COX-2 inhibitors also have potential advantages as therapyfor the management of post-surgical pain.