GASTROINTESTINAL TOXICITY BY NSAID A. Soriano Izquierdo, X. Caserras Bessa, M. Sans cuffia and J.I. Frez Elizalde Department of Gastroenterology.

Institut Clinic of Digestive Malalties. Hospital . Barcelona. Introduction One hundred years have passed since Felix Hoffman, laboratories Bayer, synthesiz ed acetylsalicylic acid, the first non-steroidal anti-inflammatory drugs (NSAIDs ). Forty years later by endoscopic studies showed that aspirin could damage the gastric mucosa. The introduction of new more potent anti-inflammatory agents wit h more capacity and better understand possible harmful gastroduodenal lesions in duced by NSAIDs and made the pharmaceutical industry worked in the search for ne w molecules effective but much safer. Since the beginning of the 70 new NSAIDs h ave been developed that thought they had gastrointestinal toxicity, but few, if any, have proven to be completely safe. This group of drugs is one of the most w idely used, with more than 25 million prescriptions a year in Spain. (Aspirin is the best-selling drug in our country without a prescription). Although NSAIDs a re generally well tolerated in a small but significant proportion of patients wi th gastrointestinal adverse effects occur which result in a substantial morbidit y and mortality. Epidemiology of gastrointestinal complications Although the prevalence of adverse effects varies widely, at least 10% to 20% of patients have dyspepsia while taking AINE1. 15% to 25% of patients taking NSAID s develop gastroduodenal ulcer, which is bleeding in 2% to 4% of misMedicine 200 0, 8 (2): 77-83 We (only about one in ten of NSAID-induced ulcer bleeding). Thirteen of 1,000 rh eumatoid arthritis patients taking NSAIDs for a year have a gastrointestinal com plication grave2. The mortality among patients hospitalized for upper gastrointe stinal bleeding induced by NSAIDs is 5% to 10%. The mortality attributed to gast rointestinal toxic effects of NSAIDs is of 0.22% per year and, although it may s eem small, we must not forget that a large number of patients exposed to them, o ften for long perídos of time, so the risk throughout their lives is important. It is estimated that 16,500 deaths related to the use of NSAIDS occur each year in the U.S. among patients with rheumatoid arthritis and osteoarthritis. This nu mber is similar to the number of deaths from acquired immunodeficiency syndrome (AIDS) and considerably greater than the number of deaths from multiple myeloma, asthma, cancer of the cervix or Hodgkin3 disease. A breakdown of these data, we could say that deaths due to gastrointestinal toxic effects of NSAIDs are the 1 5th most common cause of death in the U.S.. This "silent epidemic" is still unkn own by many physicians and most patients. Also, keep in mind that all previous d ata are not collected statistics of deaths due to the use of nonprescription NSA IDs. so this kind of symptoms does not serve to discriminate against the population a t risk. Advanced age, however, is an important risk factor for suffering a compl ication gastrointestinal4 (those over 60 have a risk five times higher when comp ared with controls and the risk increases linearly with age). Although previous studies had suggested that the risk decreased with chronic use them, a recent st udy indicates that the risk of gastrointestinal bleeding associated with NSAIDs remains constant over an extended period of observación2. Also described an incr ease of injuries in the small intestine and colon as extending the treatment tim e. Other risk factors have been identified in multiple studies are the high dose s of NSAIDs (over twice the usual dose), the use of two or more NSAIDs, a histor y of peptic ulcer or gastrointestinal bleeding, concomitant use of corticosteroi ds , severe associated diseases and the simultaneous use of anticoagulants (Tabl e 1) 5-8. The discovery that infection with H. pylori plays a role in the develo pment of peptic ulcer disease has raised the issue of a possible synergistic act

ion between H. pylori and NSAID use, as discussed in the previous chapter devote d to infection by H. pylori. The ability to produce side effects varies with the NSAID, having described a higher toxicity ketorolac and piroxicam and intermedi ate naproxen, indomethacin,€ketoprofen and diclofenac. Ibuprofen was the least t oxic 9,10. There have been no controlled prospective studies on the toxicity of newer NSAIDs such as nabumetone, etodolac and the oxaproxin, although they seem to have a lower risk of bleeding (0.5%). Risk factors for developing gastrointestinal complications Only a minority of patients who suffer a serious gastrointestinal complication d ispéptico1 relate any history, Pathogenesis of gastroduodenal mucosal injury induced by NSAIDs Gastroduodenal mucosal injury occurs when the harmful effects of gastric acid ex ceeding the capacity defen77 © DOYMA 2001 Digestive Disorders (II) TABLE 1 Risk factors for development of gastrointestinal complications induced b y NSAIDs Odds ratio (95%) established risk factors age (risk increases linearly) 60-79 ye ars> 79 years ulcer Background Concomitant use of corticosteroids High doses of NSAIDs, including the use of various NSAIDs concomitant administration of antico agulants Diseases serious potential risk factors associated with infection conco mitant H. " pylori? Smoking Drinking alcohol NSAIDs: NSAIDs. may occur as a result of indirect mechanisms, such as biliary excretion and subs equent duodenogastric reflux of active metabolites of NSAIDs. 3 (2,2-4) 4.2 (2,3-7,6) 13.5 (10,3-17,7) 10.6 (3,2-35,1) 8.6 (5, 8-12,6) 6.4 (2, 8-14,6) The role of protaglandinas Despite the importance of local damage that can lead to NSAIDs, the dominant rol e in their ability to exercise it adversely affecting their systemic effects, de creasing protaglandinas synthesis in the mucosa. The use of preparations of ente ric-coated aspirin and NSAIDs or rectal injection has failed to prevent the deve lopment of ulcers. Aspirin doses as low as 30 mg are sufficient to decrease the synthesis of protaglandinas in the gastric mucosa (Fig. 2). The protaglandinas d erived from arachidonic acid, which in turn comes from the action of phospholipa se A2 on cell membrane phospholipids (Fig. 3). The metabolism of arachidonic aci d to leukotriene protaglandinas and is catalyzed by the cyclooxygenase pathway a nd the pathway of 5-lipoxygenase, respectively. Two cyclooxygenase isoforms have been identified in mammalian cells, cyclooxygenase-1 (COX-1) and cyclooxygenase -2 (COX-2) 11. Despite having a similar structure, are encoded by different gene s and differ in their distribution and expression in tissues. The gene for COX-1 is expressed constitutively in tissues, whereas COX-2 is thought to be an induc ible gene, being almost undetectable in most (but not all) of the tissues in con ditions physiological. It therefore appears that while TABLE 2 Basic mechanisms of gastroduodenal mucosal injury by NSAIDs Direct action on the gastrointestinal mucosa Increased permeability oversimplification of the mucosa (Fig. 1). The gastroduodenal mucosal damage ind uced by NSAIDs may occur as a result of local action and systemic action (Table 2). Systemic effects are largely due to the inhibition of endogenous prostagland in synthesis, leading to a decrease in epithelial mucus, bicarbonate secretion, blood flow of the mucosa, epithelial proliferation and resistance mucosal damage . The worsening of the mucosal resistance allows endogenous factors such as acid

, pepsin, and bile salts, as well as exogenous factors such as NSAIDs and ethano l or other possibly harmful agents can damage the. Local damage The local mucosal damage is initiated by the acidic properties of aspirin and ma ny other NSAIDs. Because of its low dissociation constant, weak acids remain in their nonionized lipophilic form in the acidic gastric lumen, which promotes the ir migration through the mucus layer and the plasma membrane into the epithelial cell, NSAIDs pass where the ionized form that can capture hydrogen ions. NSAIDs can also cause local mucosal damage by decreasing the hydrophobicity of gastric mucus, allowing gastric acid and pepsin damage the epithelial surface. In addit ion, the local lesion PH 6.0 1.5 transmucosal potential blood flow Moco HCO3 HCO3 Bicarbonate HCO3 Restitution Alteration of ion exchange reduction Minor nutrient microcirculation tissue isch emia Prostaglandins Nitric Oxide Growth Factors Inhibition of mucus production and reduced bicarbonate secretion decreased abili ty antisecretory Fig 1. Factors involved in gastroprotection. Reduction cytoprotection 78 © DOYMA 2001 GASTROINTESTINAL TOXICITY BY NSAID mice with the gene for COX-1 not spontaneously develop úlceras13 altered, and Wa llace et al13 have reported that the damage of NSAIDs is associated with an incr eased adhesion of neutrophils to the endothelium stomach as a result of increase d expression of intercellular adhesion molecule 1 (ICAM-1). Fig 2. Images of scanning electron microscopy of the gastric mucosa. Left, norma l mucosa. On the right, gastric mucosa after administration of acidified aspirin . Note the structural changes of the mucus layer and epithelial surface. COX-1 is an enzyme that functions normally in most tissues including the gastric mucosa, kidney, and platelets, COX-2 can be induced by inflammatory stimuli and mitogens in different tissue types, including macrophages and synovial cells. I t has been suggested that anti-inflammatory properties of NSAIDs are mediated th rough the inhibition of COX-2, whereas adverse effects such as gastroduodenal ul ceration, occur as a result of its action by inhibiting the COX-111, 12. It based in current str ategies for developing new NSAIDs much safer, trying to selectively inhibit COX2 and do not act on the COX-1 (Table 3). Although it appears that the suppressio n of gastric prostaglandins is the fundamental mechanism responsible for the gas trointestinal toxicity of NSAIDs, some studies suggest that other mechanisms may

be involved. For example, Spectrum of injury produced by NSAIDs In most patients, the gastroduodenal mucosal damage induced by NSAIDs is superfi cial and heals itself. Less than 1% of patients in treatment for six months deve loped gastrointestinal bleeding, perforation or stenosis, peptic ulcer, which ca n occur without previous symptoms in more than 80% of casos14. Although rare, th ese complications can lead to death. Other serious complications of NSAIDs are l ess common pill esophagitis, ulcers, perforations and strictures in the small in testine (strictures shaped diaphragm are very characteristic of NSAID), NSAID en teropathy (malabsorption, protein loss, microhaemorrhages, etc.) stenosis in the colon, acute colitis (mainly due to mefenamic acid and meclofenamate) Normal gastrointestinal tract Foci of inflammation Membrane phospholipids Phospholipase A2 Arachidonic acid Endotoxin Cytokines Growth Factors (+) (-) Constitutive Cyclooxygenase-1 NSAIDs physiological functions (-) (-) Inducible Cyclooxygenase-2 Functions inflammatory TABLE 3 Classification of NSAIDs according to their potency to inhibit cyclooxyg enase-2 Nimesulide COX-2/COX-1 Index 0.1 0.6 0.7 0.8 1.3 2.8 15 60 100 166 175 250 Corticosteroids Prostanoids physiological integrity of the gastrointestinal muco sa Prostanoids Atherosclerosis pathological renal function mitogenesis and growt h regulation of female reproduction bone formation renal function Any other feat ures? Meloxicam Naproxen Diclofenac sodium salicylate Flurbiprofen Ibuprofen Indometac in Fig 3. Biosynthesis of prostaglandins by the cyclooxygenase pathway. NSAIDs: NSA IDs. The immediate precursor of protaglandinas, arachidonic acid, derived from m embrane phospholipids is catalyzed by two isoenzymes cyclooxygenase (also known as prostaglandin H synthase), cyclooxygenase-1 and cyclooxygenase-2. The gene fo r COX-1, the enzyme that maintains homeostasis, is expressed constitutively and maintains the homeostasis of organs, including the integrity of the gastric muco sa. By contrast, the gene for COX-2 inflammatory enzyme, is inducible. Although both pathways can be inhibited variably by different NSAIDs, only the gene for C OX-2 has a repressor element of the response to corticosteroids in the promoter region. Dotted arrows show the inhibitory effect (-) of pharmacological agents o r stimulatory (+) of various proinflammatory agents. Aspirin Piroxicam Sulindac Tolmetin COX-2: cyclooxygenase-2, COX-1: COX-1. 79 © DOYMA 2001

Digestive Disorders (II) solitary colonic ulcers, diverticulosis complications of pre-existing and exacer bations of inflammatory bowel disease.€It has been shown to increase intestinal permeability in patients treated with NSAIDs. No data currently on the use of pr eventive drugs NSAID-induced damage in the small intestine or the colon. The spe ctrum at the gastric level includes a combination of subepithelial hemorrhage, e rosions (superficial) and ulcerations (deeper lesions and large) that are often called NSAID gastropathy (Figs. 4 and 5). After taking the NSAIDs, appear within minutes ultrastructural lesions in the gastric surface epithelium and within a few hours and are visible by endoscopy hemorrhages and erosions in the gastroint estinal epithelium. However, it seems that the mucosa of the people who take asp irin long can adapt to this attack repeatedly. No area of the stomach is resista nt to NSAIDs, the antrum is the area most frequently and severely affected. The duodenal mucosa injury is less common than gastric damage, but the complications of NSAID-associated ulcers occur with almost equal frequency in both locations. Prospective endoscopic studies have shown that 10% to 25% of patients with chro nic arthritis treated with NSAIDs have both gastric and duodenal ulcers, which i s five to fifteen times more than expected in a healthy population of the same a ge. known but may be due to masking of dyspeptic symptoms associated with mucosal da mage. Therefore, although the H2 receptor antagonists are effective in reducing dyspeptic symptoms, its routine use in asymptomatic patients taking NSAIDs can n ot be recommended. Patients receiving H2 receptor antagonists for the treatment of dyspepsia should be carefully monitored by the risk of suffering serious comp lications. The initial dose should be low (eg 400 mg of cimetidine, 150 mg of ra nitidine or nizatidine, or famotidine 20 mg administered twice daily in each cas e), and would be adjusted to the needs of each patient (Table 4 .) Fig 5. Histological image of a gastric erosion. There was an abundant inflammato ry component. Inhibitors of proton pump In two recent studies inhibitor omeprazole proton pump was compared with the mis oprostol16 ranitidina15 or a synthetic analogue of prostaglandin E 1 for treatme nt and prevention of NSAID-induced ulcer. In both studies, omeprazole achieved g reater symptomatic relief. Since inhibitors proton pump might prevent the develo pment of gastroduodenal ulcers associated with the use of AINE17, can be a safe and effective form of therapy for dyspepsia associated with these anti-inflammat ory. The daily doses to be used would be 20 mg of omeprazole, 30 mg of lansopraz ole or pantoprazole 40 mg before breakfast (Table 4). Treatment of dyspepsia associated with NSAIDs 10% to 20% of patients taking NSAIDs have dispépticos1 symptoms. However, these symptoms correlate very little with the endoscopic appearance and severity of mu cosal damage, with more than 40% of people who have been verified by endoscopy, the presence of erosive gastritis are asymptomatic, and conversely, 50% of patie nts with dyspepsia have normal-appearing mucosa. H2 receptor antagonists of histamine Several studies have shown a clear improvement of dyspeptic symptoms in patients taking NSAIDs with concomitant use of H2 receptor antagonists of histamine. In a recent study by Singh et al1, however, showed that asymptomatic patients with rheumatoid arthritis who were taking these histamine antagonists had a significa ntly increased risk of gastrointestinal complications than nonusers. The explana tion for this finding was not Management of gastroduodenal ulcers associated with nonsteroidal anti-inflammato ry drugs The use of NSAIDs delay ulcer healing and is currently the most important factor

involved in the ulcer refractory to medical therapy or surgical 18. The optimal treatment of patients with NSAID-induced ulcer should include the elimination o f any potentially aggravating factor. The most obvious place Fig 4. Endoscopic image of antral erosion after the ingestion of NSAIDs. 80 © DOYMA 2001 GASTROINTESTINAL TOXICITY BY NSAID TABLE 4 Current recommendations for the treatment of dyspepsia and gastrointesti nal mucosal damage induced by NSAIDs Dyspepsia Empiric treatment with H2 receptor antagonists (eg€400 mg of cimetidin e, 150 mg of ranitidine or nizatidine, or famotidine 20 mg twice daily) or inhib itors proton pump (eg, omeprazole 20 mg, 30 mg of lansoprazole or pantoprazole 4 0 mg daily before breakfast) Infection with H. individualized therapy pylori inf ection eradication therapy only in patients with peptic ulcer history, active ga stroduodenal ulcer if NSAIDs are stopped treatment with H2 receptor antagonists (eg, 800 mg of cimetidine, 150 mg of ranitidine or nizatidine, or famotidine 40 mg daily bedtime) or inhibitors proton pump (see above) If you continue to take NSAIDs inhibitors proton pump (see above) prophylactic therapy Concomitant treat ment with misoprostol (≥ 200 mg three times daily) or inhibitor proton pump (see above) or an NSAID act preferentially or selectively on COX-2 NSAIDs: NSAIDs. hacienda great efforts in the field of prevention. The first thing we have to av oid is its use and replaced, if possible, less toxic agents for the gastroduoden al mucosa, such as acetaminophen or magnesium salicylate. If use is unavoidable, there are two options: administer medication at the same time to protect the mu cosa or use less gastroerosive anti-inflammatory agents. Concomitant Therapy Sucralfate Although preliminary studies suggested that sucralfate could reduce t he mucosal damage induced by NSAIDs, Agrawal et al19 in a randomized study with a large number of patients, observed no benefit with this drug in the prevention of gastric ulcers in patients with osteoarthritis taking NSAIDs. H2 receptor an tagonists prospectivos20 In two large studies, 21 were observed at doses of rani tidine 150 mg twice a day, was effective in preventing the development of duoden al ulcers in NSAID takers, but the same dose of ranitidine was ineffective to pr event gastric ulcers (most frequent injuries caused by NSAIDs duodenal ulcers). Therefore, the use of H2 receptor antagonists can not be recommended for the pre vention of ulcers associated with NSAIDs, by not preventing the development of g astric ulcers. Inhibitors of proton pump inhibitors Although proton pump have pr eviously demonstrated their effectiveness in healing of gastroduodenal ulcers in NSAID takers, only two recent estudios22, 23 has been systematically evaluated their effectiveness in preventing mucosal damage . These studies suggest that, l ike misoprostol, inhibitors of proton pump are superior to H2 receptor antagonis ts. Although a prospective analysis of clinical outcomes has not been done, thes e agents appear to be effective in preventing 81 practice is to try to replace the non-toxic NSAID analgesic such as acetaminophe n or anti-rheumatic drugs less harmful. If the NSAID can be suspended, several a ntisecretory agents or sucralfate may be used as an effective treatment of the u lcer. If NSAIDs can not be removed, the healing of the ulcer will depend entirel y on the drug chosen to treat it. Mucosal protective agents Sucralfate appears to be as effective as H2 receptor antagonists in healing gast ric ulcers unrelated to the taking of NSAIDs. However, it has proved beneficial in the prevention or treatment of gastric ulcers caused by NSAIDs. Prostaglandin

s exert their therapeutic effect by enhancing the mucosal defensive properties a nd inhibiting gastric acid secretion. Although effective in the prevention of ga stroduodenal mucosal damage induced by NSAIDs, their role in the treatment of ul cers associated with NSAIDs is unclear. NSAID-ras has not been evaluated in depth. When continuing with anti-inflammator y therapy, healing is delayed, depending primarily on the initial size of the ul cer. Different studies show the superiority of inhibitors of proton pump on H2 r eceptor antagonists in the treatment of gastroduodenal ulcers induced by NSAIDs, is suspended or not making antiinflamatorios15 (Table 4). When will eradicate Helicobacter pylori? Since it is not clear the possible synergistic relationship between H. pylori an d NSAIDs to cause gastrointestinal lesions, currently only recommended screening and eradication therapy of infection in patients with peptic ulcer history (Tab le 4). Prevention of gastroduodenal ulcers associated with NSAIDs Because of the prevalence and severity of gastroduodenal complications associate d with NSAID use are haAntisecretory drugs The efficacy of H2 receptor antagonists in the treatment of ulcerative© DOYMA 2001 Digestive Disorders (II) recurrence of ulcers during continued NSAID use (Table 4). Prostaglandins Despit e the proven effectiveness of misoprostol in preventing gastroduodenal ulcers in different jobs, there seems to reduce dyspeptic symptoms. One study found that while low doses (200 mcg per day) of misoprostol was associated with fewer side effects, this drug needs to take at least three times a day to be effective in t he prevention of gastric ulcers caused by AINE24. Although misoprostol can be ve ry effective, frequent side effects (occurring in more than 20% of patients), am ong which are diarrhea, abdominal pain and increased uterine contractility which could trigger a spontaneous abortion, limit their use (Table 4). Other agents a cexamate The Sulglicotide and zinc, although they look promising as prophylactic agents, require confirmatory studies before we can recommend in the prevention of gastroduodenal ulcers from NSAIDs. Prophylaxis with prostaglandins or inhibit ors of proton pump in all patients taking NSAIDs would be unnecessary and cost p rohibitive, so that only patients with risk factors for developing NSAID gastrod udenales injuries should be treated. Inhibitors highly selective cyclooxygenase-2 Two new agents, celecoxib and rofec oxib appear to maintain their selectivity of action on the COX-2 at much higher doses than necessary to act as anti-inflammatories. These agents are 100 times m ore selective in their ability to inhibit COX-2 NSAIDs currently available and n o differences in the production of ulcers when compared with placebo. Celecoxib began shipping in February this year in the U.S. and marketing in Spain, like ro fecoxib appears imminent. Despite the enthusiasm for these selective inhibitors of COX-2, its use poses some problems. For example, COX-2 might generate endogen ous biologically important prostanoids. The mice that have been removed the gene for COX-2 have impaired renal function and the regulation of bone resorption, a nd in female mice worsens their reproductive capacity. Mizuno et al 25 have sugg ested that the expression of COX-2 at the gastric level may be necessary for nor mal healing of gastroduodenal ulcers. As positive effects of the use of such age nts is their likely ability to reduce the risk of colorectal adenomas and adenoc arcinomas in humans to inhibit COX-2 mRNA which has been increasing in these sit uaciones26. Although they look very promising agents, close monitoring will be i

mportant to define its benefit and safety course in the future. dundancia in preserving normal physiological function is not unique and is the r ationale for the development of new formulations in which nitric oxide to compen sate for the removal of the mucosal prostaglandins by NSAIDs. Prophylactic use o f aspirin with nitric oxide donor group is being investigated also in ischemic h eart disease and cerebrovascular ischemia. Other possibilities are currently bei ng developed NSAIDs associated with phospholipids "zwitterionic" basic fibroblas t growth factors and peptides trefoil29. Its clinical usefulness should be demon strated in future studies. REFERENCES 1. Singh G, Ramey DR, Morfelden D, Shi H, Hatoum HT, Fries JF. Gastro intestinal tract Complications of nonsteroidal anti-inflammatory Drug Treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern M ed 1996, 156 (14): 1530-1536. 2. Singh G, Triadafilopoulos G. Epidemiology of NS AID induced gastrointestinal complications. J Rheumatol 1999, 26 (Suppl 56): 1824. 3. G. Singh Recent considerations in nonsteroidal anti-inflammatory drug gas tropathy. Am J Med 1998; 105 (1B): 31S-38S. 4. Bjorkman DJ. Nonsteroidal anti-in flammatory drug-induced gastrointestinal injury. Am J Med 1996, 101 (1A): 25S-32 S. 5. Hallas J, Lauritsen J, Villadsen HD, Gram LF. Nonsteroidal anti-inflammato ry drugs and upper gastrointestinal bleeding, Identifying High-Risk Groups by Ex cess Risk estimates. Scand J Gastroenterol 1995; 30 (5): 438-444. 6. Hochain P, Berkelmans I, Czernichow P Duhamel C, Tranvouez JL, Lerebours E, et al. Which Pa tients taking non-aspirin non-steroidal anti-inflammatory drugs bleed? A case-co ntrol study. Eur.J Gastroenterol Hepatol. 1995, 7 (5): 419-426. 7. Shorr RI, Ray WA, Daugherty JR,€Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at High Risk for hemorrhagi c peptic ulcer disease. Arch Intern Med 1993, 153 (14): 1665-1670. 8. Langman MJ , Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RF, et al. Risks of bleedin g peptic ulcer Associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994, 343 (8905): 1075-1078. 9. Garcia RL, Jick H. Risk of upper gastroi ntestinal bleeding and perforation Associated with individual non-steroidal anti -inflammatory drugs. Lancet 1994, 343 (8900): 769-772. 10. Garcia RL, Cattaruzzi C, Troncon MG, L. Agostinis Risk of hospitalization for upper gastrointestinal tract bleeding Associated with ketorolac, Other nonsteroidal anti-inflammatory d rugs, calcium antagonists, and Other antihypertensive drugs. Arch Intern Med 199 8; 158 (1): 33-39. 11. Crofford LJ. COX-1 and COX-2 tissue expression: Implicati ons and predictions. J Rheumatol 1997, 24 (Suppl 49): 15-19. Development of new safer NSAIDs Recent studies and endoscopic surveillance has confirmed that the incidence of g astroduodenal mucosal lesions is reduced with the use of nabumetone, etodolac, m eloxicam, nimesulide and flosulide. The safety of meloxicam seems to be due to i ts preferential action on COX-2, with less effect on COX-1. Nabumetone and etodo lac inhibit COX-2 preferentially at low doses, but at higher doses lose this spe cificity. 82 NSAIDs with nitric oxide donor groups Nitric oxide plays a key role in maintaini ng gastroduodenal mucosal integrity, exercising many of the effects that endogen ous prostaglandins 27 as the modulation of mucosal blood flow, promote secretion of mucus and bicarbonate, and stimulate epithelial restitution. It has been sug gested that nitric oxide and prostaglandins may act synergistically in protectin g the mucosa. Salvemini et al 28 have shown that nitric oxide stimulates cycloox ygenase enzymes. This re© DOYMA 2001 GASTROINTESTINAL TOXICITY BY NSAID 12. Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol 19

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