Klinik und Poliklinik für Innere Medizin II, Nephrologie, Klinikum der Universität, University of Regensburg, Germany Email: bernhard.kraemer{at}klinik.uni-regensburg.de
Sixty scientists discussed recent progress in cyclooxygenase-2 (COX-2) research at the Third International Meeting on Cyclooxygenase-2. K. Brune, Erlangen, showed that besides mediation of peripheral inflammation and pain (e.g. via nociceptors) PGE2 production is increased in the spinal cord during peripheral pain (i.e. rat paw oedema), due to increased COX-2 expression. PGE2 inhibits, via the EP2 receptor inhibitory neurons in the dorsal horn of the spinal cord. M. Turini, Lausanne, discussed the role of prostaglandins in tumourigenesis/malignancy. PGE2 is antiapoptotic, whereas COX-2 blockade is proapoptotic. COX-2 blockade may even be effective in cell lines that do not express COX-2 and blocks angiogenesis, for instance in intestinal polyps. M. Steinbauer, Regensburg, reviewed data on the use of aspirin/NSAIDs, decreasing the risk of colon cancer by a reduction of the number of polyps. In a colon carcinoma cell line, celecoxib conferred a survival benefit with a decreased growth of liver metastases. A. Reichle, Regensburg, reported a phase I/II trial with the PPAR agonist pioglitazone+rofecoxib combined with trofosfamide/capecitabine in advanced, progressive disease of solid tumours and haematologic neoplasias. Clinical responses were observed in 2635%. The median progression-free survival time was 4 months. T. McIntyre, University of Utah, showed that certain alkyl phospholipid oxidation products (hexadecyl azelaoyl posphatidylcholine; azPC) in oxidized LDL are specific, high affinity extracellular ligands and agonists for PPAR
that induce PPAR-responsive genes. AzPC and rosiglitazone induces COX-2 expression and PGE2 secretion in primary human monocytes. This interaction of PPAR
and COX-2 may be of importance for atherosclerosis. M. Fleck, Regensburg, mentioned that 70 million prescriptions of NSAIDs are made per year in the USA and 30 billion NSAIDs are sold over the counter for rheumatological disorders. Ten per cent stop NSAID use after 6 months due to dyspepsia, and severe gastrointestinal adverse events are observed in 13/1000 patients per year. This amounts to 103 000 hospitalizations/year in the USA, with a mortality rate of 510%. COX-2 inhibitors are as efficacious as NSAIDs in patients with osteoarthritis/rheumatoid arthritis, and are associated with decreased numbers of gastroduodenal ulcers/clinically relevant gastrointestinal events. S. Laufer, Tübingen, reviewed combined COX-2 and 5-lipoxygenase inhibition in rheumatology. Licofelone is such a combined inhibitor, which blocks the shunt to leukotrienes that is important for inflammation, for instance LTB4 for neutrophil activation and LTC4 for vasoconstriction. Licofelone blocks leucocyte adherence and is well tolerated, but the role in clinical medicine has yet to be defined. G. Rogler, Regensburg, discussed that patients with inflammatory bowel disease frequently have an involvement of joints (16% in ulcerative colitis, 33% in Crohn's disease), which responds well to NSAIDs/COX-2 inhibitors. However, NSAIDs and also COX-2 inhibitors may worsen the course of inflammatory bowel diseases and should at present not be used. S. Holmer, Regensburg, discussed the risk for heart failure after intake of a NSAID (relative risk 2.9/1.7 during treatment with a thiazide/loop diuretic). This has clinical implications as in the USA, NSAIDs were at the fifth rank of prescribed drugs. A dynamic balance between endothelium-(COX-2)-derived prostacyclin inhibiting thrombosis and platelet-(COX-1)-derived thromboxaneA2 promoting thrombosis might be disturbed by COX-2 inhibitors by blocking prostacyclin formation. In the VIGOR study rofecoxib was compared with naproxen; aspirin use was not permitted. Thrombotic/cardiovascular events were more frequent with rofecoxib than naproxen. In contrast, in the CLASS study with a rate of aspirin intake of
22%, no difference for vascular adverse events was found (celecoxib versus diclofenac/ibuprofen). Overall, the data regarding the cardiovascular risk of COX-2 inhibitors are inconclusive, as the available trials were not adequately powered. Caution should be exerted in prescribing COX-2 inhibitors in high cardiovascular risk patients and it may be prudent to add aspirin. T. Yang, NIH/NIDDK, Bethesda, reviewed the stimulation of renal COX-2 in macula densa due to low salt, loop diuretics, inhibition of the reninangiotensin system and in the inner medulla due to high salt, dehydration and LPS. Stimulation of medullary COX-2 by high salt is mediated by reactive oxygen species via Erk, and p38. Stimulation of first NOS I then COX-2, and renal renin is proposed with a negative feedback from PGE2 to NOS I. M. Breyer, Vanderbilt, showed that angiotensin-II induced hypertension was blunted by COX-1 inhibition and augmented by COX-2 inhibition. Furthermore in COX-2 knockout mice the angiotensin-II induced blood pressure response was augmented and in COX-1 knockouts blunted, suggesting that COX-1 derived prostanoids mediate the angiotensin-II induced increase in blood pressure, whereas COX-2 derived prostanoids act counterregulatory. C. Blume, Düsseldorf, discussed the potential of COX-2 inhibition in human renal disease. Experimental data are controversial, with beneficial effects in some experimental models (e.g. passive Heyman nephritis) and detrimental effects in others (e.g. anti-Thy1.1). The timing of COX-2 inhibition may also be of importance. M. Kömhoff, Marburg, reviewed COX-2 in Bartter's syndrome, focusing on the hyperprostaglandin E2 syndrome where COX-2 is prominently expressed in macula densa, and the disease activity can be controlled with COX-2 inhibitors as effectively as with indomethacin. Microsomal PGE2 synthase is co-localized with COX-2. M. Kammerl, Regensburg, showed that intact COX-2 is essential for renal development, for stimulation of the renin system during low-sodium diet/diuretic use, for normal renal perfusion, and for intact sodium/volume excretion during low sodium diet/loop diuretic use. Large clinical trials have reported similar rates of oedema formation and hypertension with COX-2 inhibitors when compared with NSAIDs. Acute renal failure may develop in susceptible patients with a single dose of a COX-2 inhibitor. M. Goppelt-Strübe, Erlangen, reported up-regulated COX-2 staining in proximal tubules of renal allografts with vascular rejection but also with acute renal failure. Interestingly, infiltrating cells in interstitial nephritis did not stain for COX-2. R. M. Nüsing, Marburg, presented results in prostanoid receptor knockout mice. EP1, EP3 and EP4 knockout mice were associated with diminished diuresis, natriuresis and PGE2 excretion, whereas IP knockout mice showed stimulated natriuresis and unchanged PGE2 excretion.