New Targets in Inflammation : Inhibitors of COX-2 or Adhesion Molecules Proceedings of a Conference Held on April 15–16, 1996, in New Orleans, USA, Supported by an Educational Grant From Boehringer Ingelheim

For the past 100 years the mainstay of therapy for rheumatoid arthritis (RA) has been aspirin or other drugs of the non-steroid anti-inflammatory group. In 1971 Vane pro­ posed that both the beneficial and toxic actions of these drugs was through inhibition of prostaglandin synthesis. The recent discovery that prostaglandins responsible for pain and other symptoms at inflammatory foci are synthesized by an inducible cyclooxygenase (COX-2) that is encoded by a gene distinct from that of the consti­ tutive enzyme (COX-I) provided a new target for therapy of RA. A drug that would selectively inhibit COX-2 would hopefully produce the symptomatic benefit provided by existing NSAIDs without the gastrointestinal and renal toxicity due to the inhibition of COX-I. Drugs selective for COX-2 are now available. Experimental studies have shown them to be effective with minimal toxicity, and in clinical trials gastric and renal toxicities are less. Highly selective COX-2 inhibitors, perhaps designed with knowledge of the crystal structures of COX-I and COX-2, are also available. Other experimental studies, including those in animals lacking effective genes for COX-lor COX-2 and in experimental carcinomas, suggest there is still much to be learned of the pathophysiological functions of these enzymes. The inflammatory response is a complex reaction involving many mediators that derive from white blood cells, endothelial cells and other tissues. Preliminary data have revealed that inhibitors of the cytokines and adhesion molecules that play a crucial role in the migration of white cells to inflammatory sites may be useful in RA. Front Matter....Pages i-ix The history of anti-inflammatory drugs and their mechanism of action....Pages 1-12 Structure of prostaglandin H 2 synthase-1 (COX-1) and its NSAID binding sites....Pages 13-21 Differential inhibition of cyclooxygenases 1 and 2 by NSAIDs....Pages 23-38 Blockade of inflammatory hyperalgesia and cyclooxygenase-2....Pages 39-45 Brain COX-2 in experimental models of epilepsy and stroke: signalling pathways leading to enhanced expression....Pages 47-53 New highly selective cyclooxygenase-2 inhibitors....Pages 55-62 Characteristics of cyclooxygenase-1 and cyclooxygenase-2-deficient mice....Pages 63-70 X-ray crystal structure of human cyclooxygenase-2....Pages 71-74 Risk of gastrointestinal side effects caused by non-steroid anti-inflammatory drugs(NSAIDs)....Pages 75-81 Expression and regulation of cyclooxygenase-2 in synovial tissues of arthritic patients....Pages 83-91 Differential target tissue presentation and COX-2/COX-1 inhibition by non-steroid anti-inflammatory drugs: a rationale for a new classification....Pages 93-104 Clinical experience with meloxicam, a selective COX-2 inhibitor....Pages 105-116 Enzymatic regulation of the prostaglandin response in a human model of inflammation....Pages 117-123 Cyclooxygenase-2 and intestinal cancer....Pages 125-130 Cytokines and adhesion molecules in the lung inflammatory response....Pages 131-138 Adhesion molecules as targets for therapy in rheumatoid arthritis....Pages 139-144 Back Matter....Pages 145-147 This volume contains the proceedings of the William Harvey Research Conference held in New Orleans on the 15th and 16th of April 1996. It reviews the general pathophysiological significance of the isoforms of cyclooxygenase and the likely value of selective COX-2 inhibitors in the treatment of rheumatoid conditions. The volume also covers the possible use of antibodies against cytokines and cell adhesion receptors in the treatment of inflammatory conditions