Introduction to "Nimesulide: Beyond COX-2" T.D. Warner Timothy D. Warner, PhD, Department of The sulfonanilide compound nimesu- d i rect bl o cking effects on calcium Cardiac, Vascular and Inflammation lide (Fig. 1) is a proven nonsteroid anti- channels (14). It must be stated, how- Research, The William Harvey Research i n fl a m m at o ry drug (NSAID) that is eve r, t h at pro b ably some of these Institute, St. Bartholomew's and the Royal anti-inflammatory, analgesic and anti- effects are seen only at concentrations London School of Medicine and Dentistry, pyretic, and with a rapid onset of ac- exceeding those achieved with thera- Charterhouse Square, London, EC1M tion. It has been appreciated since the peutic doses. On the other hand, a s 6BQ, U.K. E-mail: [email protected] e a rly 1970s that NSAIDs have the reported in these proceedings, there is common ability to block the formation very recent evidence that low concen- Clin Exp Rheumatol 2001; 19 (Suppl. 22): of prostanoids via inhibition of cyclo- t rations of nimesulide can bl o ck the S1-S2. oxygenase (COX) (1). More recently it formation of COX-2 (15) and inhibit © Copyright CLINICAL AND has become apparent that there are two chondrocyte death (16). Therefore, in EXPERIMENTAL RHEUMATOLOGY 2001. COX isoforms: constitutively express- addition to its ability to block COX-2 ed COX-1, associated with the physio- selectively, other non-COX-dependent logical production of prostanoids, and effects may underlie nimesulide's abili- inducible COX-2, associated with the ty to produce positive therapeutic out- production of prostanoids at inflamma- comes with relatively few side effects. tory sites (see 2). Studies in vitro (3, 4) This relative safety and tolerability oc- and ex vivo (5, 6) have demonstrated curs in patients of all ages, even though that nimesulide is about 5-20 fold more the elderly are often treated simultane- potent an inhibitor of human cycloox- ously with several medicines, and even genase-2 (COX-2) than of cyclooxyge- in patients with histories of advers e nase-1 (COX - 1 ) , p o s s i bly due to its reactions to aspirin or other NSAIDs ability to exploit the larger enzymatic (17). Various studies have found that channel in COX-2 allowing the forma- gastric mucosal damage by nimesulide tion of electro s t atic interactions (7). is either similar to placebo or better This COX-2 selectivity supports the than re fe rence compounds (18, 1 9 ) . notion that at therapeutic doses nime- Besides preferential COX-2 inhibition, sulide may spare the functional and a contri bution to this ga s t ro i n t e s t i n a l p ro t e c t ive pro s t aglandins fo rmed by tolerability may be nimesulide's very COX-1 in the gastric mucosa and kid- weak acidity (pKa 6.5), which presum- ney, while greatly inhibiting the forma- ably reduces substantial accumulation tion by COX-2 of prostanoids involved in the gastric mucosa, and its minimal in inflammation and pain (see 2). This e ffect on ox i d at ive phosphory l at i o n . may well provide at least some expla- nation for the finding that nimesulide causes relatively few adverse gastroin- testinal and renal effects (8). In addition to its effects on prostanoid fo rm at i o n , nimesulide may also pro- duce a range of other beneficial anti- i n fl a m m at o ry effects. These incl u d e inhibition of the neutrophil oxidative response, reduction in the synthesis of cartilage-degrading enzymes, reduction of histamine action and release, inhibi- tion of hyperalgesia caused by tumour necrosis factor- (see 9), reduction in the release of urokinase, interleukin-6 (10) and elastase (11), inhibition of the activity of collagenase (12) and depres- sion of tumour necrosis factor- release Fig. 1. Nimesulide. (13). In addition, nimesulide may have S-1 Nimesulide: Beyond COX-2 / T.D. Warner F u rt h e rm o re, ve ry recent wo rk has full in vitro analysis. Proc Natl Acad Sci USA 1998; 50: 1417-23. found that at the higher intraga s t ri c 1999; 96: 7563-8. 13. AZAB A, FRAIFELD V, KAPLANSKI J: Nime- 5. SHAH A A , M U R R AY FE, FITZGERALD D J: sulide prevents lipopoly s a c ch a ri d e - i n d u c e d concentrations that might be obtained The in vivo assessment of nimesulide cyclo- elevation in plasma tumor necrosis factor- with oral doses, nimesulide inhibited oxygenase-2 selectivity. Rheumatology 1999; in rats. Life Sci 1998; 63: PL323-7. murine gastric acid secretion induced 38 (Suppl. 1): 19-23. 14. KNOCK GA,AARONSON PI : Calcium channel by histamine or a stable acetylcholine 6. PANARA MR, PADOVANO R, SCIULLI MG et antagonistic properties of the cyclo-oxyge- al.: Effects of nimesulide on constitutive and nase-2 inhibitor nimesulide in human myo- analogue (20). Finally, the pharmaco- inducible prostanoid biosynthesis in human m e t rial myo cytes. Br J Pharmacol 1 9 9 9 ; kinetics of nimesulide are similar in beings. Clin Pharmacol Ther 1998; 63: 672- 127: 1470-8. patients of all ages, and clinical prob- 81. 15. DI BATTISTA JA, FAHMI H, HE Y, ZHANG M, lems relating to this aspect are few and 7. GARCIA-NIETO R, PEREZ C, GAGO F:Auto- MARTEL-PELLETIER J, PELLETIER J-P: Dif- mated docking and molecular dynamics sim- fe rential reg u l ation of interl e u k i n - 1 - of minor consequence (21). ulations of nimesulide in the cyclo-oxyge- induced cy cl o ox y genase-2 gene ex p re s s i o n In concl u s i o n , nimesulide exhibits a nase active site of human prostaglandin-en- by nimesulide in human synovial fibroblasts. range of actions that may underlie its doperoxide synthase-2 (COX-2). J Comput - Clin Exp Rheumatol 2001: 19 (Suppl. 22): er-Aided Mol Design 2000; 14: 147-60. S3-S5. efficacy in the treatment of pain, in- 8. RAINSFORD KD: Relationship of nimesulide 16. MUKHERJEE P, RACHITA C,AISEN PS,PASI- fl a m m ation and feve r, coupled with safety to its pharmacokinetics:assessment of NETTI GM: Non-steroidal anti-inflammatory good gastrointestinal and renal safety a dve rse reactions. R h e u m at o l ogy 1999; 38 drugs protect against chondrocyte apoptotic and tolerability compared to other (Suppl. 1): 4-10. death. Clin Exp Rheumatol 2001: 19 (Suppl. 9. BENNETT A , VILLA G: N i m e s u l i d e : A n 22): S7-S11. NSAIDs. This pro file is re flected in NSAID that preferentially inhibits COX-2, 17. BAVBEK S, CELIK G, EDIGER D, MUNGAN D, nimesulide's exceptional market rank- and has various unique pharmacological acti- DEMIREL Y S, M I S I R L I G I L Z: The use of ing at or near the top of the NSAID list vities. Exp Opinion Pharmacother 2000; 1: nimesulide in patients with acetylsalicy l i c in many countries. 277-86. acid and nonsteroidal anti-inflammatory drug 10. PELLETIER JP, M I N E AU F, F E R NANDES J, intolerance. J Asthma 1999; 36: 657-63. KIANSA K, RANGER P, MARTEL-PELLETIER 18. MARINI U, SPOTTI D, MAGNI E, MONTI T: References J: Two NSAIDs, nimesulide and naproxen, D o u bl e - blind endoscopic study compari n g 1. 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TAVARES IA, BISHAI PM, BENNETT A: Ac- charide (LPS)-primed neutrophils; inhibitory gy 1999; 38 (Suppl. 1): 33-8. tivity of nimesulide on constitutive and in- effect of the anti-inflammatory drug nime- 20. TAVARES IA,BORRELLI F, WELSHNJ: Inhibi- ducible cyclo-oxygenases. Arzneim.-Forsch/ sulide. Clin Exp Immunol 1997; 110: 139- tion of gastric acid secretion by nimesulide: Drug Res 1995; 45: 1093-6. 143. A possible factor in its gastric tolerability. 4. WARNER T D, GIULIANO F, VO J N OVIC I, 12. BA R R ACCHINI A , FRANCESCHINI N, A M I- Clin Exp Rheumatol 2001: 19 (Suppl. 22): BUKASA A, MITCHELL JA, VANE JR: Non- COSANTE G et al.: Can non-steroidal anti- S13-S15. steroid drug selectivities for cyclooxygenase- inflammatory drugs act as metalloproteinase 21. BERNAREGGI A: Clinical pharmacokinetics 1 rather than cyclooxygenase-2 are associat- modulators? An in vitro study of inhibition of of nimesulide. 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