Best Practice & Research Clinical Gastroenterology Vol. 15, No. 5, pp.

691703, 2001

doi:10.1053/bega.2001.0229, available online at http://www.idealibrary.com on

1 Pathogenesis of NSAID-induced gastroduodenal mucosal injury

John L. Wallace*
PhD

Professor Mucosal Inammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

The use of non-steroidal anti-inammatory drugs (NSAIDs), even in the era of selective COX-2 inhibitors, remains limited by the ability of these agents to cause gastroduodenal ulceration and bleeding. This damage is caused mainly through the ability of these agents to inhibit prostaglandin synthesis, which has a negative impact on several components of mucosal defence. Many NSAIDs also have topical irritant eects on the epithelium which may be particularly important in the production of small intestinal injury. While the presence of acid in the lumen of the stomach may not be a primary factor in the pathogenesis of NSAIDinduced gastroenteropathy it can make an important contribution to the chronicity of these lesions and to bleeding by impairing the restitution process, interfering with haemostasis and inactivating several growth factors that are important in mucosal defence and repair. Through better understanding of the pathogenesis of ulcers induced by NSAIDs, some new approaches to the development of more eective and safer anti-inammatory drugs have been taken in recent years. Key words: ulcer; non-steroidal anti-inammatory drug; nitric oxide; acid; neutrophils; cyclooxygenase.

The ability of non-steroidal anti-inammatory drugs (NSAIDs) to cause ulceration and bleeding in the upper gastrointestinal tract has been recognized for over 60 years1, and has more recently been referred to as an `epidemic'.2,3 Approximately 20% of regular users of NSAIDs will develop an ulcer of the stomach or duodenum. NSAIDs are very widely used, particularly for relieving the symptoms of osteoarthritis and rheumatoid arthritis. The ulcerogenic eects of NSAIDs have become more evident to the public in recent years as a result of the aggressive marketing of selective inhibitors of cyclooxygenase (COX)-2. These agents have been proposed to exhibit the benecial eects of conventional NSAIDs without causing gastrointestinal damage. In this chapter, the mechanisms through which NSAIDs induce ulcers, cause bleeding and impair ulcer healing are reviewed. The contributions of acid and Helicobacter pylori to NSAIDassociated ulceration are also reviewed.
*Correspondence to: Department of Pharmacology & Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada. 15216918/01/050691 13 $35.00/00 c 2001 Harcourt Publishers Ltd. *

692 J. L. Wallace

INHIBITION OF GASTRIC PROSTAGLANDIN SYNTHESIS The discovery that NSAIDs exert their anti-inammatory eects via inhibition of prostaglandin synthesis led directly to the proposal that prostaglandins play an important role in gastric mucosal defence.4 This was followed by the demonstration that microgram quantities of exogenous prostaglandins could protect the gastrointestinal tract from injury induced by noxious agents and NSAIDs.5 The importance of prostaglandins in mucosal defence is underscored by the evidence that the ability of an NSAID to induce gastric damage correlates well with its ability to suppress gastric prostaglandin synthesis.69 Agents that are weak inhibitors of gastric prostaglandin synthesis, including selective COX-2 inhibitors, are less ulcerogenic.810 There is also a good correlation between the time- and dose-dependency of suppression of gastric prostaglandin synthesis by NSAIDs and their ability to cause gastric ulcers.68 While the importance of prostaglandins in mucosal defence has been well recognized for nearly 30 years, a question that remained largely unanswered is why suppression of gastric prostaglandin synthesis resulted in mucosal injury. The simple answer is that virtually every component of mucosal defence is to some extent prostaglandin-dependent, so inhibition of prostaglandin synthesis by NSAIDs leads to an increased susceptibility of the stomach and duodenum to injury induced by luminal irritants. Moreover, suppression of prostaglandin synthesis leads to marked alterations in the microcirculation of the stomach and intestine that appear to be critical and to early events in the pathogenesis of ulceration (discussed in more detail below). Suppression of prostaglandin synthesis can also have a negative impact upon the secretion of mucus and bicarbonate by the gastric and duodenal epithelium, the proliferation of epithelial cells, the function of immunocytes (e.g. mast cells) within the lamina propria and upon repair processes (discussed below).11,12 It is important to bear in mind that inhibition of prostaglandin synthesis does not always result in mucosal injury. Other endogenous mediators, such as nitric oxide, also play an important role in mediating mucosal defence. Indeed, nitric oxide carries out many of the same actions as prostaglandins, and there appears to be co-operative modulation of prostaglandin and nitric oxide synthesis.13,14 Specically, in situations of prolonged suppression of prostaglandin synthesis, the production of and/or reactivity to nitric oxide has been shown to be increased.15 COX-1 versus COX-2: which is more important in mucosal defence? In 1991, several groups demonstrated that the primary enzyme responsible for prostaglandin synthesis, cyclo-oxygenase, existed in at least two forms. COX-1 is the predominant form expressed in the normal gastrointestinal tract1618 but COX-2 can be detected and has been shown to be rapidly up-regulated in response to a number of stimuli. For example, in the rat's stomach, COX-2 was found to be induced within an hour of administration of aspirin or indomethacin16, or following a period of ischaemia and re-perfusion.19 There is mounting evidence that even a very small contribution of COX-2 to total gastric prostaglandin synthesis can be very important. Gretzer et al20 demonstrated that the increased resistance of the rat stomach to injury following exposure to a mild irritant was prevented by pre-treatment with highly selective COX-2 inhibitors. Similarly, ischaemiare-perfusion injury in the rat's stomach was signicantly exacerbated by pre-treatment with highly selective COX-2 inhibitors.19 The most likely explanation for these ndings is that COX-2 is up-regulated in response to tissue hypoxia in an eort to restore blood ow through the production

Pathogenesis of NSAID-ulcer 693

of vasodilatory prostaglandins. COX-2 has been shown to play a very important role in ulcer healing21,22 such that its inhibition leads to a signicant impairment of healing processes and, more specically, of angiogenesis. Moreover, in situations of gastrointestinal inammation, COX-2-derived prostaglandins serve an important function of promoting healing and down-regulating the inammatory response. Thus, inhibition of COX-2 in experimental colitis resulted in a marked exacerbation of the colonic injury, leading to perforation and death.23 There is also mounting evidence to suggest that the gastric damage induced by conventional NSAIDs does not occur because of the ability of these agents to inhibit COX-1; rather, dual suppression of COX-1 and COX-2 is necessary for damage to be produced.10 We found that selective inhibition of COX-1, while greatly reducing gastric prostaglandin synthesis, did not produce gastric damage.10 Selective inhibition of COX-2 did not cause any detectable suppression of gastric prostaglandin synthesis and did not cause gastric damage. However, when selective inhibitors of COX-1 and COX-2 were administered, gastric damage was consistently produced. These ndings were substantiated by the demonstration that a conventional NSAID with greater potency for inhibition of COX-1 than COX-224, ketorolac, did not produce gastric damage in the rat when given in a dose that markedly suppressed COX-1 activity but had no eect on COX-2.10 However, when doses were used that produced inhibition of both COX-1 and COX-2, gastric damage was consistently observed. These observations are consistent with studies of mice in which the gene for COX-1 had been disrupted. These mice exhibit negligible gastric prostaglandin synthesis, but no `spontaneous' gastric damage.25 Administration of a conventional NSAID (indomethacin), however, consistently resulted in the production of gastric damage. Taken together, these studies clearly show that both COX-1 and COX-2 signicantly contribute to gastrointestinal mucosal defence. Clinically, there is also evidence that suppression of both COX-1 and COX-2 is necessary for production of gastroduodenal ulcers. In a recent outcomes study, the use of low-dose aspirin by patients taking a selective COX-2 inhibitor (celecoxib), increased the incidence of ulcer complications such that there was no longer any benet, in terms of safety, as compared to the use of conventional NSAIDs plus lowdose aspirin.26 EFFECTS ON THE MICROCIRCULATION The component of mucosal defence that appears to be most profoundly altered by NSAIDs is the gastric microcirculatory response to injury. Normally, exposure of the mucosa to an irritant results in a rapid increase in mucosal blood ow. This is mediated via sensory aerent neurons and is probably aimed at removing any toxins or bacterial products that enter the lamina propria, neutralizing back-diusing acid and contributing to the formation of a microenvironment over sites of supercial mucosal injury that is conducive to repair.27 Impairment of this hyperaemic response has been shown to greatly increase the susceptibility of the mucosa to injury28 and to impair rapid repair of epithelial damage (restitution).27 NSAIDs have a very well characterized ability to reduce gastric mucosal blood ow.2931 Prostaglandins of the E and I series are potent vasodilators that are continuously produced by the vascular endothelium. Inhibition of their synthesis by an NSAID leads to an increase in vascular tone. In addition to these eects, NSAIDs also produce damage to the vascular endothelium.32,33 Indeed, this is a very early event

694 J. L. Wallace

following administration of NSAIDs to experimental animals32,33, and one that is also seen in ischaemiare-perfusion-associated damage in the gastrointestinal tract.34 In the latter, neutrophils have been implicated as playing a crucial role in the induction of endothelial injury.35 We therefore examined the role of the neutrophil in the pathogenesis of experimental NSAID-gastropathy. NSAID administration to rats resulted in a rapid and signicant increase in the number of neutrophils adhering to the vascular endothelium in both gastric and mesenteric venules.9,3638 This occurred within 1560 minutes of administration of the NSAID, consistent with the period of time required for suppression of prostaglandin synthesis by these drugs.27 The adherence of neutrophils to the endothelium was dependent on the expression of the b2 integrins (CD11/CD18) on the neutrophil and intercellular adhesion molecule-1 (ICAM1) on the vascular endothelium.38 Up-regulation of ICAM-1 on the vascular endothelium in the gastric microcirculation was shown to occur within 1530 minutes of administration of an NSAID to rats, and this could be prevented by administration of exogenous prostaglandins.39 Of course, the fact that NSAIDs caused neutrophils to adhere to the vascular endothelium does not necessarily mean that these cells contributed to the ensuing mucosal injury. To test this hypothesis, we examined the eects of NSAIDs in rats in which circulating neutrophils had been depleted, either with an anti-neutrophil serum or with methotrexate. These neutropenic rats developed little if any gastric damage or endothelial injury following administration of an NSAID.40 We next demonstrated that treating rabbits or rats with monoclonal antibodies that blocked NSAID-induced neutrophil adherence to the vascular endothelium also markedly reduced the extent of NSAID-induced gastric damage.33,38 A role for neutrophils in the pathogenesis of NSAID-gastropathy was further supported by the observation that administration of prostaglandins at doses previously shown to prevent gastric injury also prevented NSAID-induced leukocyte adherence.36,37 There are a number of ways in which adherence of neutrophils to the vascular endothelium contributes to the formation of gastroduodenal ulcers. Neutrophil adherence to the vascular endothelium is accompanied by the release of proteases (e.g. elastase, collagenase) and oxygen-derived free radicals (e.g. superoxide anion) from these cells. These substances may mediate much of the endothelial and epithelial injury caused by NSAIDs. Indeed, NSAID-induced mucosal injury can be markedly reduced by scavengers of oxygen-derived free radicals41,42 and by inhibitors of neutrophilderived proteases.43,44 Neutrophil adherence to the endothelium could also contribute to NSAID-induced mucosal injury by obstructing normal ow through capillaries, thereby reducing gastric mucosal blood ow. In this respect, it is noteworthy that the well-characterized ability of NSAIDs to reduce gastric blood ow2931 has been shown to occur subsequent to the appearance of `white thrombi' in the gastric microcirculation.30 Role of tumour necrosis factor-a Taken together, the studies described above suggest that, in response to suppression of prostaglandin synthesis by NSAIDs, there is a rapid up-regulation of expression of ICAM-1 on the vascular endothelium and an up-regulation of b2 integrin expression on circulating neutrophils, resulting in increased adherence of neutrophils to the endothelium. However, it remained to be determined whether the increase in expression of adhesion molecules occurred as a consequence of the reduction of prostaglandin synthesis, or was triggered by another chemical signal produced in response to NSAID administration. Santucci, Fiorucci and co-workers suggested that tumour necrosis

Pathogenesis of NSAID-ulcer 695

factor-a (TNFa) might be such a signal for NSAID-induced neutrophil adherence within the gastric microcirculation.45 Prostaglandins have well characterized inhibitory eects on the release of TNFa from macrophages and mast cells46,47, and TNFa is a wellcharacterized stimulus for the expression of adhesion molecules.48 The levels of TNFa in the plasma of rats have been shown to increase signicantly following administration of indomethacin, in parallel with the accumulation of neutrophils in the gastric microcirculation and with the development of gastric injury.45 Moreover, pre-treatment with pentoxifylline, an inhibitor of TNFa synthesis, dose-dependently reduced neutrophil accumulation in the gastric microcirculation and gastric damage.45 Further evidence supporting a role for TNFa in the pathogenesis of NSAID-gastropathy comes from the studies of Appleyard et al49 who demonstrated protective eects against NSAID-induced gastric damage in the rat of a number of structurally unrelated inhibitors of TNFa synthesis and of an anti-TNFa antibody.49

Role of leukotrienes Leukotrienes are another group of mediators that might contribute to the increase in neutrophil adherence and the mucosal injury that occurs after NSAID administration. Leukotrienes, like prostaglandins, are derived from arachidonic acid. They have been shown to increase the susceptibility of the gastric mucosa to injury36,5052, at least in part through stimulatory eects on neutrophil adherence to the vascular endothelium.36 Inhibitors of leukotriene synthesis and leukotriene receptor antagonists have been shown to exert protective eects in experimental NSAID-gastropathy.5052 There is also evidence of elevated leukotriene B4 production following NSAID administration to laboratory animals36 and humans.53 Inhibitors of leukotriene synthesis and an LTB4 receptor antagonist have been shown to prevent NSAIDinduced neutrophil adherence to the vascular endothelium in vivo36 and in vitro.54

Microcirculatory eects of inhibition of COX-1 versus COX-2 As mentioned above, suppression of prostaglandin synthesis in the gastrointestinal tract results in an impairment of mucosal defence. An important question in the light of the contribution of both COX-1 and COX-2 to mucosal defence, therefore, is: what is the mechanistic basis for the impairment of mucosal defence by suppression of COX-1 versus suppression of COX-2? Given recent evidence that prostacyclin synthesis in humans occurs primarily via COX-2, we postulated that suppression of COX-2 by NSAIDs may underlie at least some of the disturbances in the gastrointestinal microcirculation that occur after administration of these drugs.10 To do this, we employed selective inhibitors of COX-1 and COX-2. The reduction of gastric blood ow following NSAID administration appears to be due primarily to the inhibition of COX-1 as it could be mimicked by administration of a selective COX-1 inhibitor but not by a selective COX-2 inhibitor (Figure 1). On the other hand, the neutrophil adherence that is observed following NSAID administration appears to be due to suppression of COX-2. Administration of a selective COX-2 inhibitor (celecoxib) caused signicant adherence of neutrophils to the vascular endothelium of post-capillary mesenteric venules in rats, similar in magnitude to what was observed following administration of a conventional NSAID. In contrast, a selective COX-1 inhibitor had no eect on neutrophil adherence within mesenteric venules.10

696 J. L. Wallace
NSAID

COX-1 inhibition

Topical irritation

COX-2 inhibition

Decreased blood Flow

Epithelial damage

Neutrophil adherence

Mucosal injury

Figure 1. Schematic diagram illustrating three of the main components of the pathogenesis of NSAIDinduced gastrointestinal mucosal injury. Suppression of COX-1 causes a profound reduction of mucosal prostaglandin synthesis which probably impairs many components of mucosal defence. Among these, the reduction of mucosal blood ow may be most important. Suppression of COX-2 leads to an increase in the number of neutrophils adhering to the vascular endothelium in the gastrointestinal microcirculation, which has been shown to be an important factor in ulcer development. Many NSAIDs, particularly acidic ones, also exert topical irritant eects on the mucosa, leading to epithelial injury.

TOPICAL IRRITANT EFFECTS OF NSAIDS While NSAIDs are capable of causing gastroduodenal ulcers when administered parenterally5557, it is likely that the topical irritant properties of these drugs still make an important contribution to their overall ulcerogenic properties (Figure 1). The ability of aspirin directly to damage the epithelial lining of the stomach was rst suggested by Davenport in the 1960s.58 What he referred to as `breaking of the barrier' resulted in back-diusion of acid into the mucosa, leading to the rupture of mucosal blood vessels. These topical irritant properties are predominantly associated with acidic NSAIDs. The unionized forms of these drugs can enter epithelial cells in the stomach and duodenum where, within the neutral intracellular environment, they are converted to an ionized state. This has been referred to as `ion trapping'.59 As the drug accumulates within the epithelial cell, osmotic movement of water results in cellular swelling, eventually to the point of lysis.59,60 NSAIDs may also damage the gastroduodenal epithelium via uncoupling of mitochondrial respiration in epithelial cells.60,61 Various NSAIDs have been shown to uncouple oxidative phosphorylation60,61, leading to a depletion of ATP and therefore a reduced ability to regulate normal cellular functions, such as maintenance of intracellular pH. The ability of NSAIDs to uncouple oxidative phosphorylation may also be related to some extent to acidic moieties (such as carboxylic acid residues) because substitutions at these sites interfere with the ability of the compounds to act as uncouplers.61 A third mechanism through which NSAIDs may exert topical irritant eects on the mucosa is through their ability to decrease the hydrophobicity of the mucus gel layer in the stomach. Lichtenberger and co-workers have proposed that this layer is a

Pathogenesis of NSAID-ulcer 697

primary barrier to acid-induced damage in the stomach.62,63 They have demonstrated that gastric mucosal surface is hydrophobic. Moreover, this hydrophobicity can be reduced by various pharmacological agents, including NSAIDs6365, and this eect persisted for long periods of time after stopping treatment with NSAIDs.62,64 Many attempts have been made to modify NSAIDs such that their topical irritant eects are reduced. These include formulation of the drugs in slow-release or enteric coated tablets, and preparation of the drug as a pro-drug that requires hepatic metabolism in order to be active (e.g. sulindac). However, the incidence of gastroduodenal ulceration with pro-drugs is comparable to what is seen with standard NSAIDs6668, an observation which has been used to support the view that topical irritant properties of NSAIDs are not paramount in terms of their ability to induce frank ulceration in the stomach. However, this possibility cannot be completely excluded because most NSAIDs are excreted in bile. Thus, even with parenteral administration of the NSAID, reux of duodenal contents into the stomach would result in topical exposure of the gastric mucosa to these drugs. IMPAIRMENT OF REPAIR PROCESSES In addition to being able to induce ulcers in the stomach and duodenum, NSAIDs can interfere with the healing of pre-existing ulcers. Indeed, NSAIDs are able to interfere with the rapid repair processes that come into play when the surface epithelium is damaged (i.e. restitution), as well as interfering with the more prolonged process of healing when a penetrating ulcer forms in the stomach or duodenum. Restitution Damage to the gastric epithelium is not an usual event, but progression of this type of damage to an ulcer is rare. One of the reasons for this is that the stomach and duodenum are able to repair epithelial injury very rapidly (i.e. within minutes) via the process of restitution. Restitution involves the rapid migration of healthy cells from the gastric pits over areas which have been denuded; thus, an intact epithelial barrier is rapidly reestablished.69 The cells move along the basement membrane, which has been shown to be crucial to the restitution process.6972 The basement membrane can be damaged by acid, which results in impairment of restitution and progressive erosion of deeper layers of the mucosa.27,73,74 Damage to the basement membrane is prevented, in most situations, by the formation over sites of injury of a microenvironment in which the pH is maintained at near neutral.27,73 A `mucoid cap' consisting of mucus, cellular debris and plasma proteins forms within seconds of gastric epithelial injury. This layer traps the plasma that leaks from the underlying microcirculation.73 It is the plasma that accounts for the near-neutral pH within the protective mucoid cap because even a very brief interruption of mucosal blood ow results in a rapid decrease in the pH within the mucoid cap and this, in turn, results in the formation of haemorrhagic erosions.33 As reviewed above, NSAIDs decrease mucosal blood ow. In doing so, NSAIDs can interfere with the appropriate functioning of the mucoid cap and therefore with the process of restitution. Indeed, we observed that following systemic administration of an NSAID to a rat in which supercial epithelial damage had been induced, the pH within the mucoid cap began to decline in parallel (temporally) with the inhibition of prostaglandin synthesis .33 Within minutes, the formation of haemorrhagic erosions was clearly evident. These eects could be prevented by administration of prostaglandins.33

698 J. L. Wallace

Ulcer healing The ability of NSAIDs to delay the healing of ulcers and promote their bleeding is well characterized.75,76 The eects on ulcer healing are probably related to the ability of NSAIDs to suppress prostaglandin synthesis. At a site of ulceration, and particularly around the ulcer margin, cyclo-oxygenase-2 is the primary contributor to prostaglandin synthesis. Studies in mice and rats initially demonstrated the marked up-regulation of cyclo-oxygenase-2 in ulcerated gastric tissue21,22, and this has been conrmed in humans.77 Treatment of laboratory animals with selective inhibitors of cyclo-oxygenase2 resulted in signicant delaying of ulcer healing.21,22 These observations, and reports of selective cyclo-oxygenase-2 inhibitors exacerbating intestinal inammation and ulceration23, suggest that caution should be exercised in regarding the new cyclooxygenase-2 inhibitors as `GI-safe'.78,79 Ulcer bleeding is generally believed to be due to suppression of platelet aggregation by NSAIDs. Such an eect is due to inhibition of COX-1 within the platelet. However, recent data suggest that ulcer bleeding may be due to other factors. While the use of COX-2 inhibitors is associated with less ulcer formation than that which occurs with conventional NSAIDs, the proportion of those ulcers that bleed is the same.80

ROLE OF ACID NSAID-induced ulcers have been observed in patients who are achlorhydric81,82, suggesting that gastric acid secretion does not play a role in the pathogenesis of NSAIDinduced gastroduodenal ulcers. Early studies of histamine H2 receptor antagonists for prevention of NSAID-induced ulcers yielded unpromising results, further suggesting that acid was not an important contributor to these ulcers.8385 More recently, however, studies employing higher doses of H2 antagonists or using proton pump inhibitors have clearly demonstrated signicant benecial eects in terms of preventing NSAID-induced ulcers.86,87 The results of these studies suggest that profound suppression of acid secretion is necessary in order to have a signicant impact on the incidence of NSAID-induced ulcers. There are a number of ways in which acid could contribute to NSAID-induced ulcer formation. Acid can certainly exacerbate damage to the gastric mucosa induced by other agents.69 Acid can also interfere with haemostasis by limiting the ability of platelets to aggregate.88 As outlined above, acid can interfere with the process of restitution, resulting in the conversion of supercial injury to deeper mucosal necrosis. Finally, as several growth factors (e.g. broblast growth factor) that are important for maintenance of mucosal integrity and for repair of supercial injury are acid-labile, the presence of acid in the lumen can limit the contributions of these factors to mucosal defence and repair.89 It is important to note that NSAIDs can increase gastric acid secretion, although it is not clear whether such eects have any impact on ulcer formation or healing. Prostaglandins exert inhibitory eects on parietal cells90, so the inhibition of their synthesis by NSAIDs can result in an increase in gastric acid secretion.91 It was recently reported that this eect of NSAIDs is attributable to inhibition of COX-1 rather than COX-2.92 Indeed, even in the inamed stomach, COX-2-derived prostaglandins do not appear to exert any signicant eect on gastric acid secretion.92

Pathogenesis of NSAID-ulcer 699

Role of Helicobacter pylori The two greatest risk factors for peptic ulcer disease are use of NSAIDs and colonization of the upper gastrointestinal tract by Helicobacter pylori. Because these two factors produce gastroduodenal injury through dierent mechanisms, they may have additive eects in terms of producing ulcers. This is quite a controversial issue, with conicting results having been reported as to the presence or absence of such an interaction. H. pylori has been shown to enhance gastric mucosal prostaglandin synthesis, while NSAIDs suppress it.93 Thus, it has been suggested that infection with H. pylori could actually be protective against NSAID-induced ulceration. Hawkey has suggested that `as a broad generalisation, in therapeutic studies of NSAID users, those who have no ulcer at trial entry are more prone to ulcer development if they are H. pylori-positive'.93 However, in patients who have ulcers at baseline, H. pylori-positive individuals are less likely to develop ulcers, particularly if taking acid-suppressive therapy. In a study of patients who were starting NSAIDs for the rst time, with no history of a previous ulcer and no ulcer at the start of the study, the use of bismuth-based eradication therapy was associated with a much lower incidence of gastric ulcer after 2 months.94 On the other hand, eradication of H. pylori has been associated, paradoxically, with a slower healing of gastric ulcers when compared to patients who did not undergo eradication therapy. In the case of duodenal ulcers, there appears to be more clear evidence that eradication of H. pylori is benecial (whether or not the patient continues to take NSAIDs).93

SUMMARY Substantial progress has been made over the past three decades towards better understanding of the pathogenesis of gastroduodenal ulcers induced by NSAIDs. This had led to the development of several new types of NSAID that have greatly reduced gastrointestinal toxicity relative to conventional NSAIDs. For example, selective inhibitors of cyclo-oxygenase-2, which spare the major form of cyclo-oxygenase in the gastrointestinal tract, produce fewer gastric and duodenal ulcers than do the conventional NSAIDs that inhibit both cyclo-oxygenase-1 and -2. Some questions remain about the eectiveness of selective COX-2 inhibitors versus conventional NSAIDs, particularly with respect to producing analgesia, and with respect to toxicity in other organs (e.g. cardiovascular system). Nitric oxide-releasing NSAIDs represent another approach to reducing the adverse eects of this class of drugs.95,96 There is also considerable evidence that concomitant use of proton-pump inhibitors can greatly reduce the gastrointestinal toxicity of conventional NSAIDs. When cost issues are taken into consideration, this approach may have advantages over the use of some of the newer NSAIDs, such as selective COX-2 inhibitors.

Practice points . where an NSAID is needed, choose the NSAID with the lowest toxicity prole . in high-risk patients, co-prescribe a proton-pump inhibitor with a conventional NSAID or with a COX-2 inhibitor . caution should be exercised in use of COX-2 inhibitors in patients taking lowdose aspirin

700 J. L. Wallace

Research agenda . further dene the critical events which lead to gastroduodenal injury following NSAID administration (at a molecular level) . better understand the contribution of prostaglandins derived from COX-2 in mucosal defence and repair . design better anti-inammatory drugs that lack GI toxicity but have an ecacy similar to, or better than, conventional NSAIDs

Acknowledgements
Dr Wallace is a Medical Research Council of Canada Senior Scientist and an Alberta Heritage Foundation for Medical Research Scientist. He holds the Crohn's and Colitis Foundation of Canada Chair in Intestinal Disease Research.

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Pathogenesis of NSAID-ulcer 701 18. Ferraz JGP, Sharkey KA, Reuter BK et al. Induction of cyclooxygenase-1 and -2 in the rat stomach during endotoxemia: role in resistance to damage. Gastroenterology 1997; 113: 195204. 19. Maricic N, Ehrlich K, Gretzer B et al. Selective cyclo-oxygenase-2 inhibitors aggravate ischaemiareperfusion injury in the rat stomach. British Journal of Pharmacology 1999; 128: 16591666. *20. Gretzer B, Ehrlich K, Maricic N et al. Selective cyclo-oxygenase-2 inhibitors and their inuence on the protective eect of a mild irritant in the rat stomach. British Journal of Pharmacology 1998; 123: 927935. 21. Mizuno H, Sakamoto C & Matsuda K. Induction of cyclooxygenase-2 in gastric mucosal lesions and its inhibition by the specic antagonist delays healing in mice. Gastroenterology 1997; 112: 387397. 22. Schmassmann A, Peskar BM, Stettler C et al. Eects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. 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