[Non-steroidal anti-inflammatory agents with selective inhibitory activity on cyclooxygenase-2. Interest and future prospects].
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels.


BACKGROUND
The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis.


CONCLUSIONS
Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations.
Blain
H
H
Service de médecine interne C et gérontologie clinique, centre Antonin-Balmes, CHU, Montpellier, France.
Jouzeau
J Y
JY
Netter
P
P
Jeandel
C
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000145:classification* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000145:classification* / Q000627:therapeutic use; D004381:Duodenal Ulcer / Q000139:chemically induced; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases