Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic.
The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels. We now better understand the roles of COX-1 and COX-2 in functions as disparate as the perception of pain and the progression of cancers. Clinical use of COX-2-selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure. This review will discuss how the latest studies help us understand the roles of COX-1 and COX-2 and what clinically proven benefits the newer generation of COX-2-selective inhibitors offer
Warner
Timothy D
TD
The William Harvey Research Institute, Barts & the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. t.d.warner@qmul.ac.uk
Mitchell
Jane A
JA
D000544:Alzheimer Disease / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control; D003110:Colonic Neoplasms / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D003875:Drug Eruptions / Q000201:enzymology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D017288:Pain Threshold / Q000187:drug effects; D010437:Peptic Ulcer / Q000139:chemically induced / Q000517:prevention & control; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000145:classification / Q000235:genetics / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases