The International Symposium on Prostaglandins and Related Compounds, first held in Vienna 1972, revisited the city after 24 years for the 10TH Symposium. For the many re searchers working in this multi-disciplinary field it was an opportunity to exchange their ex periences and share new data with colleagues from all around the world. This scientific exchange was largely encouraged by the unseasonably cold and rainy weather. For the first time, there was quite a large attendance from the former Communist countries. Eugene Garfield prepared a key note address delivered during the meeting (The Sci entist 1996, 12) reviewing the contribution of the Nobel Laureates U.S. von Euler, l.R. Vane, S.K. Bergstrom, and B.I. Samuelsson, discussing the relevance of the more than 40,000 pa pers in this area published since 1991. Overall, there is still a rapidly growing interest, and in particular a great variety of clinical applications of this family of compounds which were dis cussed in detail during the meeting. Beside the lectures there were 19 workshops covering nearly all the topics of key in terest. All the speakers were invited to prepare a manuscript which has resulted in the volume now in your hands. Special thanks to Dr. Patrick Wong and the new publisher of this series who helped to publish the proceedings in the usual quality and reasonable period of time. Looking forward to seeing all of you again in Florence in 1999, hopefully with much more sun."

The mainstay of therapy for rheumatoid disease is the non-steroid antiinflammatory drugs (NSAIDs), despite their inherent gastrointestinal toxicity and ability to cause renal damage in susceptible patients. The theory that the beneficial and toxic effects of NSAIDs stem from a reduction in prostanoid production through inhibition of cyclooxygenase implied that particular toxicities were inevitable with NSAIDs and would always be correlated with efficacy. However, over the years, it became apparent that at therapeutic doses, some NSAIDs had greater toxic side-effects than others, a fact not explained by the general theory. A significant clarification arose from the discovery that there are two distinct isoforms of COX, a constitutive enzyme (COX-I) responsible for the production of prostanoids necessary for platelet aggregation and protection of the gastric mucosa and kidney; and an inducible enzyme (COX-2) that is newly synthesized at sites of tissue damage and produces prostaglandins that manifest pathological effects. It became clear that different NSAIDs had greater or lesser effects on COX-I when used in therapeutic doses, explaining the variation in side-effects. ' The elucidation of the crystal structure of these different enzymes and the skills of medicinal chemists have led to the synthesis of new chemicals with a selectivity for the inducible enzyme, and thus with therapeutic efficacy without those toxic effects result ing from inhibition of the constitutive enzyme.

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.

In 1971, Vane proposed that the mechanism of action of the aspirin-like drugs was through their inhibition of prostaglandin biosynthesis. Since then, there has been intense interest in the interaction between this diverse group of inhibitors and the enzyme known as cyclooxygenase (COX). It exists in two isoforms, COX-l and COX-2 (discovered some 5 years ago). Over the last two decades several new drugs have reached the market based on COX-l enzyme screens. Elucidation of the three-dimensional structure of COX-l has provided a new understanding for the actions of COX inhibitors. The constitutive isoform of COX, COX-l has clear physiological functions. Its activation leads, for instance, to the production of prostacyclin which when released by the endothelium is anti-thrombogenic and anti-atherosclerotic, and in the gastric mucosa is cyto protective. COX-l also generates prostaglandins in the kidney, where they help to maintain blood flow and promote natriuresis. The inducible isoform, COX-2, was discovered through its activity being increased in a number of cells by pro inflammatory stimuli. A year or so later, COX-2 was identified as a distinct isoform encoded by a different gene from COX-I. COX-2 is induced by inflammatory stimuli and by cytokines in migratory and other cells. Thus the anti-inflammatory actions of non-steroid anti-inflammatory drugs (NSAIDs) may be due to the inhibition of COX-2, whereas the unwanted side-effects such as irritation of the stomach lining and toxic effects on the kidney are due to inhibition of the constitutive enzyme, COX-I.

The International Symposium on Prostaglandins and Related Compounds, first held in Vienna 1972, revisited the city after 24 years for the 10TH Symposium. For the many re searchers working in this multi-disciplinary field it was an opportunity to exchange their ex periences and share new data with colleagues from all around the world. This scientific exchange was largely encouraged by the unseasonably cold and rainy weather. For the first time, there was quite a large attendance from the former Communist countries. Eugene Garfield prepared a key note address delivered during the meeting (The Sci entist 1996, 12) reviewing the contribution of the Nobel Laureates U.S. von Euler, l.R. Vane, S.K. Bergstrom, and B.I. Samuelsson, discussing the relevance of the more than 40,000 pa pers in this area published since 1991. Overall, there is still a rapidly growing interest, and in particular a great variety of clinical applications of this family of compounds which were dis cussed in detail during the meeting. Beside the lectures there were 19 workshops covering nearly all the topics of key in terest. All the speakers were invited to prepare a manuscript which has resulted in the volume now in your hands. Special thanks to Dr. Patrick Wong and the new publisher of this series who helped to publish the proceedings in the usual quality and reasonable period of time. Looking forward to seeing all of you again in Florence in 1999, hopefully with much more sun."